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Liu CP, Jiang AY, Chen F, Wu J, Wang SY, Cao L, Liao T, Zheng YQ. Predictive Value of Laryngeal Mucosa Pepsin in Therapeutic Response of Laryngopharyngeal Reflux. J Voice 2024; 38:1412-1418. [PMID: 35760633 DOI: 10.1016/j.jvoice.2022.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 11/24/2022]
Abstract
OBJECTIVES/HYPOTHESIS To investigate the predictive capability of pepsin level in the laryngeal mucosa to the therapeutic effect of proton-pump inhibitors in patients with suspected laryngopharyngeal reflux (LPR), so as to verify whether it can be referred to as a biomarker of LPR. STUDY DESIGN Prospective case study. METHODS Sixty patients with clinical empiric LPR were enrolled, with an reflux symptom index (RSI) ≥ 13 and an reflux finding score (RFS) > 7 as screening criteria. Biopsy specimens from the interarytenoid mucosa were obtained under topical anesthesia for pepsin immunohistochemical staining. Two parameters were observed in these patients with different pepsin levels after the administration of esomeprazole for 12 weeks: the RSI and the RFS. RESULTS Among the 60 cases, 35 cases were negative or weakly positive for pepsin (Pepsin(-) group), and 25 cases were moderately positive or strongly positive for pepsin (Pepsin(+) group). After therapy, the RSI significantly decreased from 17.00 (15.00, 19.00) to 6.00 (5.00, 11.00) in the Pepsin(+) group (Z = -4.38, P < 0.01), but no difference was found in the RFS (T = 1.48, P > 0.05). No significant difference was observed in the RSI (T = 2.01, P > 0.05) or the RFS (T = 2.01, P > 0.05) in the Pepsin(-) group either before or after therapy. An improvement in the RSI ≥ 50% was taken as the standard of effective therapy. The effective rate in the Pepsin(+) group was 72.0% (18/25), while it was 14.3% (5/35) in the Pepsin(-) group. There was a significant difference in the effective rate between the two groups (χ2 = 20.55, P < 0.01). CONCLUSIONS Proton-pump inhibitors exhibited better effects in patients with higher pepsin levels in the laryngeal mucosa. Laryngeal mucosa pepsin may serve as an ideal indicator to screen patients suitable for proton-pump inhibitor therapy and a reliable biomarker to identify patients with LPR.
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Affiliation(s)
- Cai-Peng Liu
- Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Ai-Yun Jiang
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fang Chen
- Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Jian Wu
- Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Shu-Yue Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Lei Cao
- Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Tao Liao
- Department of Otorhinolaryngology Head and Neck Surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Yi-Qing Zheng
- Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China; Department of Otorhinolaryngology Head and Neck Surgery, Sun Yat-sen Memorial Hospital of Sun Yatsen University, Guangzhou, China.
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Yang M, Cao J, Liu T, Li B, Wang J, Pan S, Guo D, Tao Z, Hu X. Chaperonin-containing TCP1 subunit 6A inhibition via TRIM21-mediated K48-linked ubiquitination suppresses triple-negative breast cancer progression through the AKT signalling pathway. Clin Transl Med 2024; 14:e70097. [PMID: 39556022 PMCID: PMC11571564 DOI: 10.1002/ctm2.70097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/26/2024] [Accepted: 11/03/2024] [Indexed: 11/19/2024] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is distinguished by a significant likelihood of distant recurrence and an unfavourable prognosis. However, the underlying molecules and mechanisms have not been fully elucidated. METHODS We investigated the expression profile and clinical relevance of chaperonin-containing TCP1 subunit 6A (CCT6A) in TNBC. We performed cell function assays on TNBC cells with CCT6A knockdown or overexpression. To further explore the mechanism of action of CCT6A, RNA sequencing and co-immunoprecipitation-mass spectrometry analyses were utilized. Rescue and ubiquitination assays evaluated the impact of TRIM21-mediated CCT6A ubiquitination and degradation on TNBC progression in vitro and in vivo. Finally, we studied the potential of Ipatasertib, a pharmacological AKT inhibitor, and/or anti-PD1 therapy in inhibiting TNBC progression. RESULTS Elevated CCT6A expression in TNBC patients was associated with an adverse prognosis and lymph node metastasis. Mechanistically, CCT6A facilitated cell migration, invasion, epithelial-mesenchymal transition and proliferation by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The TRIM21 RING domain is an E3 ligase, facilitating the K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Moreover, in the tumour tissues of the CCT6A-overexpressing mice, the quantity of CD8+ T cells and the concentration of secreted interferon-gamma were decreased, whereas in the group double-overexpression of CCT6A and TRIM21, they were elevated; the opposite was observed in the knockdown and double-knockdown groups. Ipatasertib demonstrated enhanced efficacy in inhibiting cell proliferation, invasion and migration in TNBC cells ectopically expressing CCT6A. When Ipatasertib and anti-PD1 therapies were combined, both the tumour volume and mass exhibited a notable reduction, while the expression of CD45+CD8+ T cells increased, and that of CD45+CD4+CTLA4+ and CD45+CD4+PD1+ T cells decreased. CONCLUSIONS Our findings indicate that TRIM21 inhibits TNBC progression by facilitating the K48-linked ubiquitination-mediated degradation of CCT6A via the PI3K/AKT signalling pathway. This highlights the potential of Ipatasertib and/or anti-PD1 as therapeutic strategies, particularly for TNBC patients overexpressing CCT6A. KEY POINTS Chaperonin TCP1 subunit 6A (CCT6A) plays an oncogenic role in triple-negative breast cancer (TNBC) through the AKT signaling pathway. TRIM21 facilitated K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Our study collectively underscores the potential of Ipatasertib in conjunction with anti-PD1 therapy as a promising strategy to counteract CCT6A/AKT hyperactivity-driven TNBC progression.
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Affiliation(s)
- Mengdi Yang
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Jianing Cao
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Tiantian Liu
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Bin Li
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Jinyan Wang
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Shuangyue Pan
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Duancheng Guo
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Zhonghua Tao
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
| | - Xichun Hu
- Department of Breast and Urologic Medical OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghaiP. R. China
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Xing H, Gu X, Liu Y, Xu L, He Y, Xue C. NSUN2 regulates Wnt signaling pathway depending on the m5C RNA modification to promote the progression of hepatocellular carcinoma. Oncogene 2024; 43:3469-3482. [PMID: 39375506 DOI: 10.1038/s41388-024-03184-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/26/2024] [Accepted: 09/30/2024] [Indexed: 10/09/2024]
Abstract
5-Methylcytosine (m5C) RNA modification is a highly abundant and important epigenetic modification in mammals. As an important RNA m5C methyltransferase, NOP2/Sun-domain family member 2 (NSUN2)-mediated m5C RNA modification plays an important role in the regulation of the biological functions in many cancers. However, little is known about the biological role of NSUN2 in hepatocellular carcinoma (HCC). In this study, we found that the expression of NSUN2 was significantly upregulated in HCC, and the HCC patients with higher expression of NSUN2 had a poorer prognosis than those with lower expression of NSUN2. NSUN2 could affect the tumor immune regulation of HCC in several ways. In vitro and in vivo experiments confirmed that NSUN2 knockdown significantly decreased the abilities of proliferation, colony formation, migration and invasion of HCC cells. The methylated RNA immunoprecipitation-sequencing (MeRIP-seq) showed NSUN2 knockdown significantly affected the abundance, distribution, and composition of m5C RNA modification in HCC cells. Functional enrichment analyses and in vitro experiments suggested that NSUN2 could promote the HCC cells to proliferate, migrate and invade by regulating Wnt signaling pathway. SARS2 were identified via the RNA immunoprecipitation-sequencing (RIP-Seq) and MeRIP-seq as downstream target of NSUN2, which may play an important role in tumor-promoting effect of NSUN2-mediated m5C RNA modification in HCC. In conclusion, NSUN2 promotes HCC progression by regulating Wnt signaling pathway and SARS2 in an m5C-dependent manner.
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Affiliation(s)
- Huiwu Xing
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, China
| | - Yingru Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lixia Xu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Chen Xue
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Shen Y, Li T, Sun C, Cheng X, Chen Z, Wang G, Yang X. Atg7 autophagy-independent role on governing neural stem cell fate could be potentially applied for regenerative medicine. Cell Death Differ 2024; 31:1375-1388. [PMID: 38898232 PMCID: PMC11445561 DOI: 10.1038/s41418-024-01330-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024] Open
Abstract
A literature review showed that Atg7 biological role was associated with the development and pathogenesis of nervous system, but very few reports focused on Atg7 role on neurogenesis at the region of spinal cord, so that we are committed to explore the subject. Atg7 expression in neural tube is incrementally increased during neurogenesis. Atg7 neural-specific knockout mice demonstrated the impaired motor function and imbalance of neuronal and glial cell differentiation during neurogenesis, which was similarly confirmed in primary neurosphere culture and reversely verified by Atg7 overexpression in unilateral neural tubes of gastrula chicken embryos. Furthermore, activating autophagy in neural stem cells (NSCs) of neurospheres did not rescue Atg7 deficiency-suppressed neuronal differentiation, but Atg7 overexpression on the basis of autophagy inhibition could reverse Atg7 deficiency-suppressed neuronal differentiation, which provides evidence for the existence of Atg7 role of autophagy-independent function. The underlying mechanism is that Atg7 deficiency directly caused the alteration of cell cycle length of NSCs, which is controlled by Atg7 through specifically binding Mdm2, thereby affecting neuronal differentiation during neurogenesis. Eventually, the effect of overexpressing Atg7-promoting neuronal differentiation was proved in spinal cord injury model as well. Taken together, this study revealed that Atg7 was involved in regulating neurogenesis by a non-autophagic signaling process, and this finding also shed light on the potential application in regenerative medicine.
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Affiliation(s)
- Yao Shen
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Tingting Li
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Chengyang Sun
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xin Cheng
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhi Chen
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Guang Wang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, 510632, China.
- Guangdong-Hong Kong Metabolism & Reproduction Joint Laboratory, Guangdong Second Provincial General Hospital, School of Medicine, Jinan University, Guangzhou, 510220, China.
| | - Xuesong Yang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, 510632, China.
- Clinical Research Center, Clifford Hospital, Guangzhou, 511496, China.
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Özden Akkaya Ö, Yağci A, Zik B, Kibria ASMG, Güler S, Çelik S, Altunbaş K. The effect of bisphenol A on the Notch (Notch2 and Jagged2) signaling pathway in the follicular development of the neonatal rat ovary. Biotech Histochem 2024; 99:238-259. [PMID: 39382141 DOI: 10.1080/10520295.2024.2361313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024] Open
Abstract
The formation of primordial follicles determines the pool size of follicles in the ovary, and is crucial for female reproductivity. Oocyte nest breakdown, and the formation of primordial follicles, largely depend upon the communication between oocytes and the surrounding pregranulosa cells. The neurogenic locus notch homolog protein (Notch) signaling pathway is the key player for this cell-to-cell communication, and is responsible for primordial folliculogenesis. However, different endocrine disruptors, including bisphenol A (BPA; a plasticizer and a constituent of reusable plastic containers) may affect the Notch signaling pathway, and might induce ovary dysfunction via Notch signaling. Consequently, we investigated the possible influence of BPA treatment on the proportional distribution of the follicular stages, follicle numbers, levels of apoptosis, and on Notch2 and Jagged2 expressions in the ovary. BPA was administered at doses of either 50 µg/kg/day or 50 mg/kg/day, at different time intervals, during neonatal and fetal periods in vivo. After collecting the ovaries from the various experimental groups, follicles were counted, and frequency of apoptosis was determined by TUNEL assay. In addition, Notch2 and Jagged2 expressions were assessed by immunohistochemical staining and qPCR. In summary, BPA treatment affected the follicle numbers and apoptosis level, and Notch2 and Jagged2 expressions varied with follicular stage. It was also observed that these parameters were dose and time dependent with respect to BPA exposure.
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Affiliation(s)
- Özlem Özden Akkaya
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Türkiye
| | - Artay Yağci
- Department of Histology and Embryology, Milas Veterinary Faculty, Muğla Sıtkı Koçman University, Muğla, Türkiye
| | - Berrin Zik
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Bursa Uludağ University, Bursa, Türkiye
| | - A S M Golam Kibria
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Türkiye
- Department of Anatomy and Histology, Faculty of Veterinary Medicine, Chattogram, Veterinary and Animal Sciences University, Chattogram, Bangladesh
| | - Sabire Güler
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Bursa Uludağ University, Bursa, Türkiye
| | - Sefa Çelik
- Department of Biochemistry, Faculty of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar, Türkiye
| | - Korhan Altunbaş
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Afyon Kocatepe University, Afyonkarahisar, Türkiye
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Lin T, Zhang S, Tang Y, Xiao M, Li M, Gong H, Xie H, Wang Y. ART1 knockdown decreases the IL-6-induced proliferation of colorectal cancer cells. BMC Cancer 2024; 24:354. [PMID: 38504172 PMCID: PMC10953198 DOI: 10.1186/s12885-024-12120-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/13/2024] [Indexed: 03/21/2024] Open
Abstract
Colorectal cancer (CRC) is a worldwide health concern. Chronic inflammation is a risk factor for CRC, and interleukin-6 (IL-6) plays a pivotal role in this process. Arginine-specific mono-ADP-ribosyltransferase-1 (ART1) positively regulates inflammatory cytokines. ART1 knockdown reduces the level of glycoprotein 130 (gp130), a key transducer in the IL-6 signalling pathway. However, the relationship between ART1 and IL-6 and the resulting effects on IL-6-induced proliferation in CRC cells remain unclear. The aims of this study were to investigate the effects of ART1 knockdown on IL-6-induced cell proliferation in vitro and use an in vivo murine model to observe the growth of transplanted tumours. The results showed that compared with the control, ART1-sh cancer cells induced by IL-6 exhibited reduced viability, a lower rate of colony formation, less DNA synthesis, decreased protein levels of gp130, c-Myc, cyclin D1, Bcl-xL, and a reduced p-STAT3/STAT3 ratio (P < 0.05). Moreover, mice transplanted with ART1-sh CT26 cells that had high levels of IL-6 displayed tumours with smaller volumes (P < 0.05). ART1 and gp130 were colocalized in CT26, LoVo and HCT116 cells, and their expression was positively correlated in human CRC tissues. Overall, ART1 may serve as a promising regulatory factor for IL-6 signalling and a potential therapeutic target for human CRC.
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Affiliation(s)
- Ting Lin
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Shuxian Zhang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yi Tang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ming Xiao
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ming Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Hanjuan Gong
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Hailun Xie
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yalan Wang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China.
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China.
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Zhang L, Su K, Liu Q, Li B, Wang Y, Cheng C, Li Y, Xu C, Chen J, Wu H, Zhu M, Mai X, Cao Y, Peng J, Yue Y, Ding Y, Yu D. Kidney-type glutaminase is a biomarker for the diagnosis and prognosis of hepatocellular carcinoma: a prospective study. BMC Cancer 2023; 23:1081. [PMID: 37946141 PMCID: PMC10633901 DOI: 10.1186/s12885-023-11601-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
PURPOSE The pathological diagnosis and prognosis prediction of hepatocellular carcinoma (HCC) is challenging due to the lack of specific biomarkers. This study aimed to validate the diagnostic and prognostic efficiency of Kidney-type glutaminase (GLS1) for HCC in prospective cohorts with a large sample size. METHODS A total of 1140 HCC patients were enrolled in our prospective clinical trials. Control cases included 114 nontumour tissues. The registered clinical trial (ChiCTR-DDT-14,005,102, chictr.org.cn) was referred to for the exact protocol. GLS1 immunohistochemistry was performed on the whole tumour section. The diagnostic and prognostic performances of GLS1 was evaluated by the receiver operating characteristic curve and Cox regression model. RESULTS The sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and area under the curve of GLS1 for the diagnosis of HCC were 0.746, 0.842, 0.979, 0.249, 0.588, and 0.814, respectively, which could be increased to 0.846, 0.886, 0.987,0.366, 0.732, and 0.921 when combined with glypican 3 (GPC3) and alpha-fetoprotein (AFP), indicating better diagnostic performance. Further, we developed a nomogram with GPC3 and GLS1 for identifying HCC which showed good discrimination and calibration. GLS1 expression was also related with age, T stage, TNM stage, Edmondson-Steiner grade, microvascular invasion, Ki67, VEGFR2, GPC3, and AFP expression in HCC. GLS1 expression was negatively correlated with disease-free survival (P < 0.001) probability of patients with HCC. CONCLUSIONS It was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application.
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Affiliation(s)
- Laizhu Zhang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ke Su
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qi Liu
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Binghua Li
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ye Wang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Chunxiao Cheng
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yunzheng Li
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Chun Xu
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jun Chen
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hongyan Wu
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Mengxia Zhu
- Department of Radiology, Nanjing Drum Tower Clinical Medical School, the Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoli Mai
- Department of Radiology, Nanjing Drum Tower Clinical Medical School, the Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yajuan Cao
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jin Peng
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yang Yue
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yitao Ding
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Decai Yu
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Zheng J, Zhang W, Zhang J. Establishment of a new prognostic risk model of GNG7 pathway-related molecules in clear cell renal cell carcinoma based on immunomodulators. BMC Cancer 2023; 23:864. [PMID: 37704946 PMCID: PMC10500784 DOI: 10.1186/s12885-023-11265-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 08/06/2023] [Indexed: 09/15/2023] Open
Abstract
Clear cell renal cell carcinoma (CCRCC) is a common tumor of the urological system for which surgery is the preferred treatment, but there is a lack of therapeutic options after surgery. This study aims to explore the biological role of GNG7 on CCRCC from a genetic perspective. Differences in mRNA expression and patient survival of GNG7 in patients with CCRCC and healthy patients were analyzed using the TCGA database. It was observed that GNG7 gene expression was downregulated in CCRCC tissue compared with healthy tissue, and high GNG7 predicted better prognosis for patients, and GNG7 also showed strong variability in clinical and TMN staging. The immune relevance of GNG7 and related genes was explored using renal cancer data from CCLE and TISIDB database. It was verified that the risk score constructed by 7 GNG7-related regulators might be used as an independent prognostic risk factor for CCRCC. A CCRCC prognostic model that involved 7 immune genes was further established to predict the survival probabilities of patients. At last, the GEO database and immunochemical tissue staining were used to validate GNG7 expression in CCRCC. Our study proposed a novel panel of genes to predict CCRCC OS based on GNG7-related immune genes, which may help to accurately predict the prognosis of CCRCC patients and make better clinical decisions for individual treatment.
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Affiliation(s)
- Jun Zheng
- Department of Urology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Weili Zhang
- Department of Urology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China
| | - Junyong Zhang
- Department of Urology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
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9
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Lu R, Tang P, Zhang D, Lin S, Li H, Feng X, Sun M, Zhang H. SOX9/NFIA promotes human ovarian cancer metastasis through the Wnt/β-catenin signaling pathway. Pathol Res Pract 2023; 248:154602. [PMID: 37315400 DOI: 10.1016/j.prp.2023.154602] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 05/03/2023] [Accepted: 06/06/2023] [Indexed: 06/16/2023]
Abstract
To our knowledge, Sex-determining Region Y box 9 (SOX9) has been in connection with a wide range of human cancers. Nevertheless, there remains uncertainty regarding SOX9's role in metastasizing ovarian cancer. In our study, SOX9 was investigated in relation to tumor metastasis in ovarian cancer as well as its potential molecular mechanisms. First, we exhibited an apparent higher expression of SOX9 in ovarian cancer tissues and cells than in normative ones, and the prognosis of patients whose SOX9 levels were high was markedly lower than that of patients whose SOX9 levels were low. Besides, highly expressed SOX9 was correlated with high grade serous carcinoma, poor tumor differentiation, high serum CA125 and lymph node metastasis. Second, SOX9 knockdown exhibited striking inhibition of the migration and invasive ability of ovarian cancer cells, whereas SOX9 overexpression had an inverse role. At the same time, SOX9 could promote ovarian cancer intraperitoneal metastasis in a nude mice in the vivo. In a similar way, SOX9 knockdown dramatically decreased the expression of nuclear factor I-A (NFIA), β-catenin as well as N-cadherin but had an increased in E-cadherin expression, as opposed to the results when SOX9 was overexpressed. Furthermore, NFIA silencing inhibited the expression of NFIA, β-catenin and N-cadherin, in the same way that E-cadherin expression was promoted. In conclusion, this study shows that SOX9 has a promotional effect on human ovarian cancer and that SOX9 promotes the metastasis of tumors by upregulating NFIA and activating on a Wnt/β-catenin signal pathway. SOX9 could be a novel focus for earlier diagnosis, therapy and prospective evaluation in ovarian cancer.
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Affiliation(s)
- Rong Lu
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004 Jiangsu Province, China; Department of Gynecology and Obstetrics, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, No.60, Huaihai Road (S.), Huai'an 223002 Jiangsu Province, China
| | - Peipei Tang
- Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an 223003 Jiangsu Province, China
| | - Di Zhang
- Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an 223003 Jiangsu Province, China
| | - Sen Lin
- Department of Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, No.60, Huaihai Road (S.), Huai'an 223002 Jiangsu Province, China
| | - Hong Li
- Department of Pathology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, No.60, Huaihai Road (S.), Huai'an 223002 Jiangsu Province, China
| | - Xian Feng
- Department of Pathology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, No.60, Huaihai Road (S.), Huai'an 223002 Jiangsu Province, China
| | - Meiling Sun
- Department of Gynecology and Obstetrics, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, No.60, Huaihai Road (S.), Huai'an 223002 Jiangsu Province, China
| | - Hong Zhang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004 Jiangsu Province, China.
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10
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Xing H, Jiang X, Yang C, Tan B, Hu J, Zhang M. High expression of RPL27A predicts poor prognosis in patients with hepatocellular carcinoma. World J Surg Oncol 2023; 21:209. [PMID: 37474947 PMCID: PMC10360225 DOI: 10.1186/s12957-023-03102-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/12/2023] [Indexed: 07/22/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers in the digestive system with rapid progression and poor prognosis. Recent studies have shown that RPL27A could be used as a biomarker for a variety of cancers, but its role in HCC is not clear. METHOD We analyzed the expression of RPL27A in the pan-cancer analysis and analyzed the relationship between the expression of RPL27A and the clinical features and prognosis of patients with HCC. We evaluated the expression difference of RPL27A in HCC tissues and paired normal adjacent tissues using immunohistochemistry. Furthermore, we analyzed the co-expression genes of RPL27A and used them to explore the possible mechanism of RPL27A and screen hub genes effecting HCC. In addition, we studied the role of RPL27A in immune infiltration and mutation. RESULTS We found that the expression level of RPL27A increased in a variety of cancers, including HCC. In HCC patients, the high expression of RPL27A was related to progression and poor prognosis as an independent predictor. We also constructed a protein interaction network through co-expression gene analysis of RPL27A and screened 9 hub genes. Enrichment analysis showed that co-expression genes were associated with ribosome pathway, viral replication, nuclear-transcribed mRNA catabolic process, and nonsense-mediated decay. We found that the expression level of RPL27A was closely related to TP53 mutation and immune infiltration in HCC. CONCLUSION RPL27A might become a biomarker in the diagnosis, treatment, and follow-up of patients with HCC.
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Affiliation(s)
- Huiwu Xing
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400010, China
| | - Xiangqi Jiang
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400010, China
| | - Chenyu Yang
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400010, China
| | - Bingqian Tan
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400010, China
| | - Jiqiang Hu
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400010, China
| | - Mingman Zhang
- Department of Hepatobiliary Surgery, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Pediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400010, China.
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11
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Wang J, Zhang P, Liu M, Huang Z, Yang X, Ding Y, Liu J, Cheng X, Xu S, He M, Zhang F, Wang G, Li R, Yang X. Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis. BMC Med 2023; 21:90. [PMID: 36894970 PMCID: PMC9999529 DOI: 10.1186/s12916-023-02807-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 02/22/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Pre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood. METHODS Human placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague-Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors. RESULTS In this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFβ1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats. CONCLUSIONS Our data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.
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Affiliation(s)
- Jingyun Wang
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology/Pneumology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ping Zhang
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
| | - Mengyuan Liu
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
| | - Zhengrui Huang
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
| | - Xiaofeng Yang
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
| | - Yuzhen Ding
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
| | - Jia Liu
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
| | - Xin Cheng
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
- Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, No.601 Huangpu Road West, Guangzhou, 510632, China
| | - Shujie Xu
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
- Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, No.601 Huangpu Road West, Guangzhou, 510632, China
| | - Meiyao He
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China
| | - Fengxiang Zhang
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China
| | - Guang Wang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China.
- Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, No.601 Huangpu Road West, Guangzhou, 510632, China.
| | - Ruiman Li
- Department of Gynaecology and Obstetrics, The First Affiliate Hospital of Jinan University, Jinan University, No.613 Huangpu Road West, Guangzhou, 510632, China.
| | - Xuesong Yang
- International Joint Laboratory for Embryonic Development & Prenatal Medicine, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, 510632, China.
- Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, No.601 Huangpu Road West, Guangzhou, 510632, China.
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12
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Ding X, Cui X, Shi J, Cheng X, Yao D, Gao Y, Zhang Y. Construction of a model of endometritis in domestic rabbits using equine-derived pathogens and evaluation of therapeutic effect of sensitive drugs. Front Vet Sci 2023; 10:1064522. [PMID: 36846263 PMCID: PMC9948609 DOI: 10.3389/fvets.2023.1064522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Pathogenic bacteria were isolated from the uterine lavage fluid of a mare with endometritis. After identification and purification, the pathogenic bacteria were injected into the uterus of rabbits to induce endometritis. Then, anatomical, blood routine, chemical examination, and histopathological examinations were performed on the rabbits. Rabbit uterus was collected, and quantitative polymerase chain reaction (qPCR) was used to detect the mRNA expression of inflammatory factors including IL-1β, IL-6, and TNF-α in the rabbit uterus. In addition, enzyme-linked immunosorbent assay (ELISA) was used to detect the uterine concentrations of the inflammatory factors IL-1β, IL-6, and TNF-α. Western Blot was used to detect the protein expressions of NF-kB, IkBα, and TNF-α in the NF-kB pathway. An antibiotic treatment group was also set up to verify the accuracy of the results. The clinical examination results showed that there was a significant increase of leukocytes in the blood of the rabbits in the model group (P < 0.01). The uterus was congested, enlarged, and purulent. The integrity of the uterine lining was destroyed, and there was a significant increase of lymphocytes in the uterus (P < 0.01). The qPCR and ELISA results showed that the expressions of the inflammatory factors IL-1β, IL-6, and TNF-α in the uterus of rabbits were significantly increased (P < 0.01). Western blot results showed that the inflammatory factors IL-1β, IL-6, and TNF-α play a role in promoting inflammation through the NF-kB pathway. The results of the test provide a simple, economical, and reliable means of studying the occurrence, development, prevention, and treatment of equine endometritis.
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Affiliation(s)
- Xuanpan Ding
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China,Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China
| | - Xiao Cui
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China
| | - Jinlian Shi
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China
| | - Xiaoli Cheng
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China
| | - Dan Yao
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China
| | - Yujin Gao
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China
| | - Yong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, China,Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou, China,*Correspondence: Yong Zhang ✉
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13
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Ferritin light chain deficiency-induced ferroptosis is involved in preeclampsia pathophysiology by disturbing uterine spiral artery remodelling. Redox Biol 2022; 58:102555. [PMID: 36446230 PMCID: PMC9706170 DOI: 10.1016/j.redox.2022.102555] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/09/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022] Open
Abstract
The proteomic analysis from samples of patients with preeclampsia (PE) displayed a low level of ferritin light chains (FTL), but we do not know what the significance of reduced FTL in PE pathophysiology is. To address this question, we first demonstrated that FTL was expressed in first- and third-trimester cytotrophoblasts, including extravillous trophoblasts (EVTs), of the human placenta. Furthermore, a pregnant rat model of FTL knockdown was successfully established by intravenously injecting adenoviruses expressing shRNA targeting FTL. In pregnant rats with downregulated FTL, we observed PE-like phenotypes and impaired spiral arterial remodelling, implying a causal relationship between FTL downregulation and PE. Blocking ferroptosis with ferrostatin-1 (Fer-1) significantly rescued the above PE-like phenotypes in pregnant rats with FTL knockdown. Furthermore, using trophoblast cell line and chorionic villous explant culture assays, we showed that FTL downregulation induced cell death, especially ferroptosis, resulting in defective uterine spiral artery remodelling. Eventually, this conclusion from the animal model was verified in PE patients' placental tissues. Taken together, this study revealed for the first time that FTL reduction during pregnancy triggered ferroptosis and then caused defective uterine spiral artery remodelling, thereby leading to PE.
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14
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Niu F, Duan Y, Man Y, Liu W, Dai T, Zhang H, Li C, Wei D. Mitochondrial protein LETM1 and its-mediated CTMP are potential therapeutic targets for endometrial cancer. Anticancer Drugs 2022; 33:632-641. [PMID: 35324530 DOI: 10.1097/cad.0000000000001301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an important mitochondrial protein, while its function in endometrial cancer remains unknown. This study aimed to explore the function of LETM1 in endometrial cancer and reveal the underlying mechanisms involving carboxy-terminal modulator protein (CTMP). Immunohistochemistry was performed to detect the expression of LETM1 and CTMP in normal, atypical hyperplastic and endometrial cancer endometrial tissues. LETM1 and CTMP were silenced in two endometrial cancer cell lines (ISK and KLE), which were verified by western blot. Cell viability, colony number, migration and invasion were detected by cell counting kit-8, colony formation, wound healing and trans-well assays, respectively. A xenograft mouse model was established to determine the antitumor potential of LETM1/CTMP silencing in vivo . In addition, CTMP was overexpressed to evaluate its regulatory relationship with LETM1 in endometrial cancer cells. The expression of LETM1 and CTMP proteins were higher in endometrial cancer tissues than atypical hyperplastic tissues and were higher in atypical hyperplastic tissues than normal tissues. LETM1 and CTMP were also upregulated in ISK and KLE cells. Silencing of LETM1 or CTMP could decrease the viability, colony number, migration and invasion of endometrial cancer cells and the weight and volume of tumor xenografts. In addition, CTMP was downregulated by LETM1 silencing in KLE cells, and its overexpression enhanced the malignant characteristics of si-LETM1-transfected KLE cells. Silencing of LETM1 inhibits the malignant progression of endometrial cancer through downregulating CTMP.
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Affiliation(s)
- Feifei Niu
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan
- Department of Obstetrics and Gynecology, Shengli Oilfield Central Hospital, Dongying
| | - Yan Duan
- Department of Obstetrics and Gynecology, Shengli Oilfield Central Hospital, Dongying
| | - Ying Man
- Department of Stomatology, Shengli Oilfield Central Hospital, Dongying, Shandong, China
| | - Wei Liu
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan
| | - Tianyu Dai
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Hui Zhang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Changzhong Li
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Deying Wei
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
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15
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Yang M, Li D, Jiang Z, Li C, Ji S, Sun J, Chang Y, Ruan S, Wang Z, Liang R, Dai X, Li B, Zhao H. TGF-β-induced FLRT3 attenuation is essential for cancer-associated fibroblast-mediated epithelial-mesenchymal transition in colorectal cancer. Mol Cancer Res 2022; 20:1247-1259. [PMID: 35560224 DOI: 10.1158/1541-7786.mcr-21-0924] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 04/04/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment. The effects of CAFs on the progression of colorectal cancer (CRC) remain controversial. In this study, we found the ectopic overexpression of Fibronectin leucine-rich transmembrane protein 3 (FLRT3) inhibited the process of Epithelial-mesenchymal transition (EMT), as well as the proliferation, migration, invasion, and promote apoptosis of CRC cells, whereas silencing FLRT3 expression resulted in the opposite phenomenon. FLRT3 downregulation was associated with a poor prognosis in CRC. Also, FLRT3 expression was significantly related to some clinicopathological factors, including T stage (p=0.037), N stage (p=0.042), and E-cadherin (p=0.002) level. Via univariate and multivariate analyses, M stage (p<0.0001), FLRT3 (p=0.044), and E-cadherin (p=0.003) were associated with overall survival and were independent prognostic factors for it. Mechanistically, CAFs secreted TGF-β, which downregulated FLRT3 expression by activating SMAD4 to promote aggressive phenotypes in CRC cells. Moreover, FLRT3 repressed tumorigenesis and lung metastasis, which could be reversed by LY2109761, a dual inhibitor of TGF-β receptor type I and II. Treatment with LY2109761 increased IFN-γ expression in CD8+ T cells and reduced the number of regulatory T cells in the tumor microenvironment. Taken together, we revealed the metastasis-suppressive function of FLRT3, which was attenuated during the CAFs-mediated activation of the TGF-β/SMAD4 signaling pathway to promote EMT in CRC. LY2109761 that significantly inhibited metastasis could be a new treatment option for advanced CRC. Implications: CAFs enhance CRC aggressiveness by reducing FLRT3 expression through activating TGF-β/SMAD4 signaling pathway. CAFs-targeted therapy and/or LY2109761 were promising treatments for CRC.
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Affiliation(s)
- Mengdi Yang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, shanghai, China
| | - Dan Li
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyuan Jiang
- Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China
| | - Changcan Li
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Suyuan Ji
- School of Life Sciences, Xiamen Univeristy, Xiamen, Fujian, China
| | - Jing Sun
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, shanghai, China
| | - Yujie Chang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, shanghai, China
| | - Shunyi Ruan
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, shanghai, China
| | - Zhiyu Wang
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, shanghai, China
| | - Rui Liang
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueyu Dai
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Zhao
- Shanghai Jiao Tong University Affiliated Sixth People's Hospital, shanghai, China
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16
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Yang H, Zhou S, Lan D, Bin Y, Bao W, Wang M, Huang F, Peng Z. The expression of Slit2 and Robo1 increased during retinoic acid syndrome in acute promyelocytic leukemia and impacted differentiated cell migration. Transl Oncol 2022; 18:101370. [PMID: 35182953 PMCID: PMC8857660 DOI: 10.1016/j.tranon.2022.101370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/25/2022] [Accepted: 02/10/2022] [Indexed: 11/25/2022] Open
Abstract
The upregulation of Robo1 and Slit2 was first found in APL patients. The positive correlation between Robo1/Slit2 and retinoic acid syndrome was first demonstrated. It was demonstrated for the first time that Slit2 induces the migration of differentiated cells. Slit2 did not inhibit il8-induced differentiated cell migration. Retinoic acid syndrome (RAS) is a serious complication developed during the induction therapy of acute promyelocytic leukemia (APL). Cytokines and differentiated cells migration play important roles in the development of RAS. Slit guidance ligand 2 (Slit2) and roundabout 1 (Robo1) involve in cell migration. Our study aimed to investigate the expression of Slit2 and Robo1 in APL and check whether they affected promyelocytes migration. 62 cases of newly diagnosed APL patients were involved and received all-trans retinoic acid (ATRA) and arsenic trioxide as induction therapy. Bone marrow cells (BMCs) were obtained on days 0 and 28, and promyelocytes and plasma were collected from day 1 to day 21. The expression of Robo1 in promyelocytes, and that of Slit2 and cytokines, including IL-8,IL-1β and others, in serum were monitored. 20 healthy individuals donated their cells as control. Of the 62 APL patients, 16 (25.81%) patients developed RAS. The expression of Robo1, Slit2 and IL-8 increased significantly with the development of RAS. In the 16 patients with RAS, levels of Slit2, Robo1 and IL-8 were higher during the development of RAS than before or after the RAS (P < 0.05). RhSlit2-N and rhIL-8 induced cells migration, and the migration induced by IL-8 was not inhibited by rhSlit2-N. Elevated Slit2 and Robo1 levels might be useful markers for the diagnosis and treatment of RAS. The levels of Slit2, Robo1 and IL-8 showed a positive correlation with the severity of RAS. Slit2 and IL-8 promoted the migration of differentiated cells.
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Affiliation(s)
- Haiyan Yang
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Shengsheng Zhou
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Dong Lan
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yehong Bin
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Wenguang Bao
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Man Wang
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Fengxiang Huang
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Zhigang Peng
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
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Cao Y, Chen Y, Wang P, Lu J, Han X, She J. Network pharmacology and experimental validation to explore the molecular mechanisms of Bushen Huoxue for the treatment of premature ovarian insufficiency. Bioengineered 2021; 12:10345-10362. [PMID: 34753385 PMCID: PMC8810062 DOI: 10.1080/21655979.2021.1996317] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/15/2021] [Accepted: 10/16/2021] [Indexed: 11/03/2022] Open
Abstract
Bushen Huoxue (BSHX) has been applied in clinical traditional Chinese medicine treatment, and has definitive clinical efficacy in the treatment of Premature Ovarian Insufficiency (POI) in China. However, little is known of the underlying mechanism of BSHX. The purpose of this paper is to study the pharmacological mechanisms of BSHX acting on POI based on a pharmacology and experimental validation. The pharmacological database of chinese medicine system and analysis platform (TCMSP) were used to search the effective active ingredients and potential action targets of BSHX. Drugbank, Online Mendelian Inheritance in Man (OMIM), Genecards, and Disgenet databases were used to obtain relevant targets of POI. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and the visual network of protein-protein interaction network were constructed by FunRich3.1. Pymol software, and Auto Dock tools 1.5.6 were used for molecular docking. Murine model of POI was used to further investigate the mechanism of BSHX against on POI. Finally, 127 active compounds were collected from TCMSP database, and 215 active targets were identified. There were 1366 targets related to POI and 99 targets of BSHX for the treatment of POI. Quercetin, kaempferol, and stigmasterol were recognized as the most effective compounds corresponding to targets. The top three genes according to degree value are TP53, Akt1, and VEGFA. Further, the results of GO and KEGG enrichment analysis revealed that those core targets were mainly enriched on TRAIL and TGF-β receptor signaling. The results of molecular docking showed that stigmasterol had good binding ability to Akt1. Moreover, experimental validation suggests that BSHX significantly Increased the expression of TGF-β1 and Smad2/3, regulating the release of serum sex hormones, which include Follicular stimulating hormone (FSH), Estradiol (E2), and Antimullerin hormone (AMH).
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Affiliation(s)
- Ying Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Chen
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Department of Obstetrics and Gynecology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Peijuan Wang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Department of Obstetrics and Gynecology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Jialin Lu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xuan Han
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingyao She
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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18
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Cheng L, Wang X, Ma X, Xu H, Yang Y, Zhang D. Effect of dihydromyricetin on hepatic encephalopathy associated with acute hepatic failure in mice. PHARMACEUTICAL BIOLOGY 2021; 59:557-564. [PMID: 33982639 PMCID: PMC8128201 DOI: 10.1080/13880209.2021.1917625] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
CONTEXT Hepatic encephalopathy (HE) is a complex neuropsychiatric disease caused by liver failure. Dihydromyricetin (DMY) is a traditional medicine used to treat liver injury. OBJECTIVE To investigate the effects of dihydromyricetin (DMY) on hepatic encephalopathy associated with acute hepatic failure mice models established by thioacetamide (TAA) exposure. MATERIALS AND METHODS Female BALB/c mouse were randomly divided into control, DMY, TAA, and TAA + DMY groups (n = 8). The first two groups were intraperitoneally injected with saline or 5 mg/kg DMY, respectively. The last two groups were injected with 600 mg/kg TAA to establish HE models, and then the mice in the last group were treated with 5 mg/kg DMY. Neurological and cognition functions were evaluated 24 and 48 h after injection. Mice were sacrificed after which livers and brains were obtained for immunoblot and histopathological analysis, while blood was collected for the analysis of liver enzymes. RESULTS In the TAA + DMY group, ALT and AST decreased to 145.31 ± 12.88 U/L and 309.51 ± 25.92 U/L, respectively, whereas ammonia and TBIL decreased to 415.67 ± 41.91 μmol/L and 3.31 ± 0.35 μmol/L, respectively. Moreover, MDA decreased to 10.74 ± 3.97 nmol/g, while SOD and GST increased to 398.69 ± 231.30 U/g and 41.37 ± 21.84 U/g, respectively. The neurological score decreased to 2.87 ± 0.63, and the number of GFAP-positive cells decreased to 41.10 ± 1.66. Furthermore, the protein levels of TNF-α, IL-6, and GABAA in the cortex decreased. CONCLUSIONS We speculate that DMY can serve as a novel treatment for HE.
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Affiliation(s)
- Long Cheng
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Xiaoying Wang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Xueni Ma
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Huimei Xu
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Yifan Yang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Dekui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
- CONTACT Dekui Zhang Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou730030, People’s Republic of China
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19
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Li K, Wu R, Zhou M, Tong H, Luo KQ. Desmosomal proteins of DSC2 and PKP1 promote cancer cells survival and metastasis by increasing cluster formation in circulatory system. SCIENCE ADVANCES 2021; 7:eabg7265. [PMID: 34586853 PMCID: PMC8480931 DOI: 10.1126/sciadv.abg7265] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 08/09/2021] [Indexed: 06/13/2023]
Abstract
To study how cancer cells can withstand fluid shear stress (SS), we isolated SS-resistant breast and lung cancer cells using a microfluidic circulatory system. These SS-resistant cells showed higher abilities to form clusters, survive in circulation, and metastasize in mice. These SS-resistant cells expressed 4.2- to 5.3-fold more desmocollin-2 (DSC2) and plakophilin-1 (PKP1) proteins. The high expression of DSC2 and PKP1 facilitated cancer cells to form clusters in circulation, and also activated PI3K/AKT/Bcl-2–mediated pathway to increase cell survival. The high levels of DSC2 and PKP1 are also important for maintaining high expression of vimentin, which stimulates fibronectin/integrin β1/FAK/Src/MEK/ERK/ZEB1–mediated metastasis. Moreover, higher levels of DSC2 and PKP1 were detected in tumor samples from patients with breast and lung cancer, and their high expression was correlated with lower overall survival and worse disease progression. DSC2 and PKP1 may serve as new biomarkers for detecting and targeting metastatic circulating tumor cells.
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Affiliation(s)
- Koukou Li
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Renfei Wu
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Muya Zhou
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Haibo Tong
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Kathy Q. Luo
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR, China
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20
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Hu M, Li Z, Qiu J, Zhang R, Feng J, Hu G, Ren J. CKS2 (CDC28 protein kinase regulatory subunit 2) is a prognostic biomarker in lower grade glioma: a study based on bioinformatic analysis and immunohistochemistry. Bioengineered 2021; 12:5996-6009. [PMID: 34494924 PMCID: PMC8806895 DOI: 10.1080/21655979.2021.1972197] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Gliomas account for the highest cases of primary brain malignancies. Whereas previous studies have demonstrated the roles of CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) in various cancer types, its functions in lower grade gliomas (LGGs) remain elusive. This study aimed to profile the expression and functions of CKS2 in LGG. Multiple online databases such as The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), Gene Expression Profiling Interactive Analysis 2nd edition (GEPIA2), Tumor Immune Estimation Resource 2nd edition (TIMER2.0) as well as Gene Expression Omnibus (GEO) were used in this study. Immunohistochemistry (IHC) was performed to evaluate CKS2 protein expression. Our data demonstrated upregulation of CKS2 in LGG tissues at both mRNA and protein level, especially in grade III gliomas. Similarly, there was increased expression of CKS2 in isocitrate dehydrogenase 1 (IDH1) wildtype gliomas. In addition, increased DNA copy number and DNA hypomethylation might be associated with the upregulation of the CKS2 in LGG. Using the Kaplan–Meier survival analysis and the Cox regression analysis, CKS2 was shown to be independently associated with poor prognosis of LGG patients. Receiver operating characteristic (ROC) analysis revealed that CKS2 could effectively predict the 1-, 3- and 5-year survival rates of LGG patients. Enrichment analyses revealed that CKS2 was mainly involved in the regulation of the cell cycle in LGG. Taken together, our study demonstrated that CKS2 might be a candidate prognostic biomarker for LGG and could predict the survival rates of LGG patients. Abbreviations: LGG: lower grade glioma; CKS2: CDC28 protein kinase regulatory subunit 2; TCGA: The Cancer Genome Atlas; CGGA: the Chinese Glioma Genome Atlas; GEO: Gene Expression Omnibus; GEPIA: Gene Expression Profiling Interactive Analysis; TIMER: Tumor Immune Estimation Resource; IHC: immunohistochemistry; qRT-PCR: quantitative real-time polymerase chain reaction; PBS: phosphate buffered saline; DAB: diaminobenzidine tetrachloride; OS: overall survival; CAN: copy number alteration; IDH: Isocitrate dehydrogenase; GSEA: Gene Set Enrichment Analysis; DEG: differentially expressed gene; KEGG: Kyoto encyclopedia of genes and genomes; GO: Gene ontology; BP: biological process; CC: cellular component; MF: molecular function; NES: normalized enrichment score; NOM: nominal; FDR: false discovery rate
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Affiliation(s)
- Menglong Hu
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Zongkuo Li
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jinhuan Qiu
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Ruizhen Zhang
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junkai Feng
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Guiming Hu
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jingli Ren
- Department of Pathology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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21
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Gao H, Tang P, Ni K, Zhu L, Chen S, Zheng Y, Wan Y. Inhibition of Kelch-like epichlorohydrin-related protein 1 promotes the progression and drug resistance of lung adenocarcinoma. PeerJ 2021; 9:e11908. [PMID: 34466284 PMCID: PMC8380428 DOI: 10.7717/peerj.11908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022] Open
Abstract
Background Lung cancer is a common malignant carcinoma of respiratory system with high morbidity and mortality. Kelch-like epichlorohydrin-related protein 1 (Keap1), a member of the BTB-Kelch protein family, has been reported as an important molecule in several cancers. However, its potential role in tumor is still controversial. Here we aim to clarify the effect of Keap1 on the biological characteristics and chemotherapy resistance in lung adenocarcinoma (LUAD). Methods Immunohistochemistry was conducted to compare Keap1 expression in lung adenocarcinoma tissues and matched non-cancerous tissues, and the correlation between Keap1 expression and clinicopathological features was analyzed. Subsequently, the stable A549 and H1299 cell lines with Keap1 knockdown or overexpression were constructed using lentivirus. The roles of Keap1 on the cell proliferation, migration, invasion and drug resistance were investigated by colony formation assay, cell proliferation assay, wound scratch test, transwell invasion assay and drug sensitivity assay, respectively. Results Keap1 was lowly expressed in tumor tissues compared to matched non-cancerous tissues, and its expression was correlated with TNM stage and lymph node metastasis. Early stage (I) tumors without lymph node metastasis had higher levels of Keap1 expression compared with late-stage tumors (II, III) with the presence of lymphatic metastasis. Colony formation assays showed that Keap1 knockdown promoted the proliferation of A549 and H1299 cells, and the cell growth curves further confirmed this feature. In contrast, wound scratch and transwell invasion experiments showed that Keap1 overexpression inhibited cell migration and invasive malignancy. The IC50 for cisplatin and paclitaxel were significantly increased by Keap1 knockdown in A549 and H1299 cell lines. Conclusion Keap1 knockdown promotes tumor cell growth, proliferation, invasion, metastasis and chemotherapy resistance in LUAD. It may be a potential tumor marker to guide the staging and treatment of lung cancer.
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Affiliation(s)
- Hong Gao
- Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Peipei Tang
- Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an, Jiangsu, China
| | - Kejie Ni
- Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Lun Zhu
- Department of Pathology, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Song Chen
- Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huai'an, Jiangsu, China
| | - Yulong Zheng
- Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Yufeng Wan
- Department of Respiratory Diseases, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
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22
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Liu C, Wu P, Zhang A, Mao X. Advances in Rodent Models for Breast Cancer Formation, Progression, and Therapeutic Testing. Front Oncol 2021; 11:593337. [PMID: 33842308 PMCID: PMC8032937 DOI: 10.3389/fonc.2021.593337] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/27/2021] [Indexed: 01/01/2023] Open
Abstract
Breast cancer is a highly complicated disease. Advancement in the treatment and prevention of breast cancer lies in elucidation of the mechanism of carcinogenesis and progression. Rodent models of breast cancer have developed into premier tools for investigating the mechanisms and genetic pathways in breast cancer progression and metastasis and for developing and evaluating clinical therapeutics. Every rodent model has advantages and disadvantages, and the selection of appropriate rodent models with which to investigate breast cancer is a key decision in research. Design of a suitable rodent model for a specific research purpose is based on the integration of the advantages and disadvantages of different models. Our purpose in writing this review is to elaborate on various rodent models for breast cancer formation, progression, and therapeutic testing.
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Affiliation(s)
- Chong Liu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Pei Wu
- Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ailin Zhang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiaoyun Mao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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23
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Wang CL, Tang Y, Li M, Xiao M, Li QS, Yang L, Li X, Yin L, Wang YL. Analysis of Mono-ADP-Ribosylation Levels in Human Colorectal Cancer. Cancer Manag Res 2021; 13:2401-2409. [PMID: 33737837 PMCID: PMC7965690 DOI: 10.2147/cmar.s303064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/25/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Colorectal cancer remains a major public health problem with high morbidity and mortality rates. In the search for the mechanisms of colorectal cancer occurrence and development, increasing attention has been focused on epigenetics. The overall level of Mono-ADP-ribosylation, an epigenetic, has not been investigated now. The aim of our study was to analysis of the overall level of mono-ADP-ribosylation in colorectal cancer. METHODS Immunohistochemistry was used to investigate the level of mono-ADP-ribosylation in colorectal cancer and normal colorectal adjacent tissue from 64 CRC patients. The data of patient demographic, clinical and pathological characteristics were acquired and analyzed. RESULTS Mono-ADP-ribosylation was present in both colorectal adenocarcinoma and normal colorectal tissue. The overall level of mono-ADP-ribosylation in colorectal cancer was significantly higher than that in normal colorectal adjacent tissue. In the nucleus, the majority of samples in the high-level group were colorectal adenocarcinoma (55/64), but the opposite was true for normal colorectal tissues (7/32). In particular, increases in the level of mono-ADP-ribosylation in the cytoplasm of colorectal cancer cells was associated with a greater invasion depth of the tumor. CONCLUSION The increased level of mono-ADP-ribosylation in colorectal cancer enhances tumor invasion, which suggests that mono-ADP-ribosylation is involved in the development of colorectal cancer and may become a new direction to solve the problem of colorectal cancer.
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Affiliation(s)
- Chuan-Ling Wang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Yi Tang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Ming Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Ming Xiao
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Qing-Shu Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Lian Yang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Xian Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Ling Yin
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Ya-Lan Wang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
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24
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Yuan SP, Li CX, Qin S, Wen J, Zhang XB, Tian X, Zhu CY, Li T, Huang JP, Zheng XH. High expression of disabled homolog 2-interacting protein contributes to tumor development and proliferation in cutaneous squamous cell carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1131. [PMID: 33240980 PMCID: PMC7576015 DOI: 10.21037/atm-20-5067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Disabled homolog 2-interacting protein (DAB2IP), a Ras GTPase-activating protein, is downregulated in several cancers. Its depletion is involved in tumor cell proliferation, apoptosis, and metastasis, as well as epithelial–mesenchymal transition. The present study aimed to explore the potential role of DAB2IP in cutaneous squamous cell carcinoma (cSCC) and provide a theoretical basis for the diagnosis and targeted therapy of cSCC. Methods The clinicopathological features of DAB2IP expression in cSCC were analyzed by immunohistochemistry, and the effects of DAB2IP on SCL-1 cell behavior were determined via genetic interference in vitro. SCL-1 cell lines that exhibited reduced expression of DAB2IP and a scrambled shRNA control were constructed using a lentivirus vector-based shRNA technique. RNA extraction, reverse transcription-quantitative PCR (RT-qPCR), MTT assay, colony formation test, cell cycle analysis, apoptosis test, transwell assay, wound-healing assay, in vitro invasive assay were used in this study. Results The immunohistochemical results demonstrated that the expression of DAB2IP was higher in cSCC tissues than in soft fibroma. The level of DAB2IP expression was associated with the degree of malignancy and the depth of tumor infiltration; however, it had no association with patients’ sex, tumor size, location, or phenotype. The results of the MTT, cell cycle, apoptosis, and invasion experiments demonstrated that knockdown of DAB2IP inhibited the viability and invasion of SCL-1 cells in vitro. Conclusions High expression of DAB2IP may contribute to the development and proliferation of cSCC.
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Affiliation(s)
- Shao-Ping Yuan
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Dermatology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Chang-Xing Li
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Si Qin
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Dermatology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Ju Wen
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Dermatology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Xi-Bao Zhang
- Guangzhou Institute of Dermatology, Guangzhou, China
| | - Xin Tian
- Guangzhou Institute of Dermatology, Guangzhou, China
| | - Chao-Ying Zhu
- Guangzhou Panyu Station for Chronic Disease Control, Guangzhou, China
| | - Ting Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Department of Dermatology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Jin-Ping Huang
- Department of Dermatology, Guangdong Second Provincial General Hospital, Guangzhou, China
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Xie X, Zhang J, Shi Z, Liu W, Hu X, Qie C, Chen W, Wang Y, Wang L, Jiang J, Liu J. The Expression Pattern and Clinical Significance of the Immune Checkpoint Regulator VISTA in Human Breast Cancer. Front Immunol 2020; 11:563044. [PMID: 33250890 PMCID: PMC7673447 DOI: 10.3389/fimmu.2020.563044] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 10/07/2020] [Indexed: 11/30/2022] Open
Abstract
Background Immunotherapies targeting CTLA-4 and PD-1 have elicited promising responses in a variety of cancers. However, the relatively low response rates warrant the identification of additional immunosuppressive pathways. V domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in antitumor immunity and is a valuable target in cancer immunotherapy. Methods Here, we used single-cell RNA-seq to analyze the gene expression levels of 14897 cells from a breast cancer sample and its paired 7,320 normal cells. Then, we validated the protein expression of immune checkpoint molecules (VISTA, PD-1, PD-L1, TIGIT, TIM3, and LAG3) in 324 human breast cancer samples by immunohistochemistry and quantitative immunofluorescence (QIF) approaches. Results Single cell RNA-seq results show a higher level of immune checkpoint VISTA expression in breast cancer tissue compared to adjacent normal tissue. We also found that VISTA expressed highest in breast cancer tissue than other immune-checkpoints. Immunohistochemical results showed that VISTA was detected with a membranous/cytoplasmic staining pattern in intratumoral immune cells and breast cancer cells. Additionally, VISTA was positively correlated with pathological grade, lymph node status and the levels of PD-1 according to the chi-square test or Fisher’s test. Furthermore, VISTA expression was higher in CD68+ tumor-associated macrophages (TAMs) than in CD4+ T cells, CD8+ cytotoxic T cells or CD20+ B cells. Conclusions These findings therefore support the immunoregulatory role of VISTA in breast cancer and indicate that targeting VISTA may benefit breast cancer immunotherapy.
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Affiliation(s)
- Xiaoxue Xie
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Junying Zhang
- Clinical Cancer Research Center, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhongyuan Shi
- Department of Pathology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China
| | - Wanmei Liu
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Xinlei Hu
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Chenxin Qie
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Wenting Chen
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Yan Wang
- Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Li Wang
- Department of Translational Hematology and Oncology Research (THOR), Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Jingwei Jiang
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Jun Liu
- Jiangsu Key Lab of Drug Screening, China Pharmaceutical University, Nanjing, China
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Meng C, Qian Y, Zhang C, Liu H, Mu X, Zhang A. IKKε deficiency inhibits acute lung injury following renal ischemia reperfusion injury. Mol Med Rep 2020; 22:4213-4220. [PMID: 33000218 PMCID: PMC7533469 DOI: 10.3892/mmr.2020.11532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023] Open
Abstract
Renal ischemia reperfusion injury (IRI) after surgery may promote acute lung injury (ALI) by inducing an inflammatory response. However, the underlying molecular mechanism is still unclear. Studies have reported that inhibitor of κB kinase (IKK)ε primarily regulates inflammation and cell proliferation. The present study aimed to investigate the regulatory role of IKKε in ALI in mice, in order to provide an experimental basis for preventing ALI following surgery-induced renal IRI. C57BL/6J wild-type (WT) and IKKε knockout (IKKε−/−) mice underwent bilateral renal pedicle occlusion. The plasma creatinine concentration, urea nitrogen level and lung wet-to-dry ratio were measured at baseline, and at 24 and 48 h after declamping. The histological localization and protein levels of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10, were analyzed in lung tissues. Subsequently, the interactions between IKKε and components of the nuclear factor (NF)-κB pathway were studied. The results of the present study demonstrated that the IKKε−/− groups displayed similar renal function but less pulmonary edema compared with that of the WT groups. The levels of proinflammatory factors in the lungs were significantly upregulated in WT mice compared with those in IKKε−/− mice after IRI surgery. The NF-κB pathway components and downstream factors were substantially upregulated in the WT groups after acute ischemic kidney injury, and these effects were significantly inhibited in the IKKε−/− groups. Based on these data, the present study hypothesized that IKKε may serve a negative role in kidney-lung crosstalk after renal IRI and may be a novel target for the treatment of patients with renal IRI.
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Affiliation(s)
- Chao Meng
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
| | - Yi Qian
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Cui Zhang
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
| | - Han Liu
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
| | - Xinwei Mu
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
| | - Aiping Zhang
- Department of Cardiothoracic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210001, P.R. China
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27
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Yang M, Wang A, Li C, Sun J, Yi G, Cheng H, Liu X, Wang Z, Zhou Y, Yao G, Wang S, Liang R, Li B, Li D, Zhao H. Methylation-Induced Silencing of ALDH2 Facilitates Lung Adenocarcinoma Bone Metastasis by Activating the MAPK Pathway. Front Oncol 2020; 10:1141. [PMID: 32850324 PMCID: PMC7406638 DOI: 10.3389/fonc.2020.01141] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 06/05/2020] [Indexed: 01/11/2023] Open
Abstract
Bone metastasis (BM) dramatically reduces the quality of life and life expectancy in lung adenocarcinoma (LUAD) patients. There is an urgent need to identify potential biomarkers for application in the treatment of this deadly disease. We compared patient BM, LUAD, and para-LUAD tissues using proteomic analysis and identified aldehyde dehydrogenase 2 (ALDH2), which can detoxify acetaldehyde to acetic acid, as one of the key regulators in lung tumor metastasis. Both the mRNA and protein levels of ALDH2 were significantly lower in tumor tissues than in normal tissues and were lowest in BM tissues with increased migratory capacity. Also, ALDH2 was upregulated following treatment with 5-azacitidine, a DNA methyltransferase inhibitor, in H1299, H460, and HCC827 cells. Further, we identified a potential methylated CpG island 3, with the longest methylated CpG island area in ALDH2, and performed bisulfite genomic sequencing of these sites. An average of 78.18% of the sites may be methylated in CpG island 3. Knockdown of DNA (cytosine-5)-methyltransferase 3A (DNMT3A) and methylated CpG binding protein 4 (MBD4) upregulated ALDH2 expression. ALDH2 functions as a mitogen-activated protein kinase (MAPK) upstream to inhibit cell proliferation and migration, promote cell apoptosis, and alter the epithelial–mesenchymal transition (EMT) by elevating E-cadherin and attenuating vimentin. Cell proliferation and migration were inhibited after the addition of the JNK inhibitor SP600125. In the multivariate analysis, M stage (p = 0.003), ALDH2 (p = 0.008), and phospho-c-Jun N-terminal kinase (p-JNK) (p = 0.027) expression were independent prognostic factors for overall survival in patients with BM. In vivo experiments also showed that ALDH2 expression could suppress tumor formation. In summary, we found that ALDH2 expression is a prognostic factor for BM in LUAD and that DNMT3A and MBD4 repression of ALDH2 via a MAPK-dependent pathway alters the EMT process, indicating that these proteins could act as potential biomarkers or therapeutic targets for LUAD metastasis.
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Affiliation(s)
- Mengdi Yang
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - AiTing Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changcan Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jing Sun
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gang Yi
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Cheng
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyu Wang
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yiyi Zhou
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Guangyu Yao
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Shuai Wang
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Rui Liang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Zhao
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Yin M, Xiong Y, Huang L, Liu G, Yu Z, Zhao Y, Zhao J, Zhang Y, Lian T, Huang J, Liang D, Zeng J, Ni J. Circulating follicular helper T cells and subsets are associated with immune response to hepatitis B vaccination. Hum Vaccin Immunother 2020; 17:566-574. [PMID: 32614645 DOI: 10.1080/21645515.2020.1775457] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Around 5-10% of healthy vaccinees lack or produce an inadequate antibody response following receipt of a standard hepatitis B vaccination regimen. Studying immune response to hepatitis B vaccination could promote researches of immunological events contributing to this poor response. To address this, we investigated follicular helper T (Tfh) cells and firstly demonstrated similar kinetics between circulating Tfh (cTfh) cells and Tfh cells derived from mice spleen after hepatitis B vaccination. And cTfh cells were positively associated with anti-HBs at one week after vaccination (D7). Furthermore, we found PBMCs stimulated by HBsAg showed preferential activation of CXCR3- Tfh cells subsets in vitro. The expression of transcription factor BCL6 in CD4+ T cell significantly differed between D7 and four weeks after vaccination (D28). However, dynamic curve of CD19+ B cells tended to rise then fall but no significant trends were observed. Our findings revealed a decrease in cTfh cells and subset skewing contribute to reduced antibody responses in immune response to hepatitis B vaccination, which indicated the importance of Tfh cell in facilitating the optimization of vaccine efficacy.
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Affiliation(s)
- Mingjuan Yin
- Department of Preventive Medicine, Guangdong Medical University , Dongguan, China.,Maternal and Child Research Institute, Women and Children's Hospital Affiliated to Guangdong Medical University (Shunde District Maternal and Child Health Hospital) , Foshan, China
| | - Yongzhen Xiong
- School Clinic, Guangdong Medical University , Dongguan, China
| | - Lingfeng Huang
- Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
| | - Gang Liu
- Department of Immunization Program, Shenzhen Center for Disease Control and Prevention , Shenzhen, China
| | - Zuwei Yu
- Public Health Office, Dalang Town Community Health Service Center , Dongguan, China
| | - Yi Zhao
- Microbiology and Immunology, Guangdong Medical University , Dongguan, China
| | - Jie Zhao
- Neonatal Department, Shenzhen Maternal and Child Health Hospital Affiliated to Southern Medical University , Shenzhen, China
| | - Yan Zhang
- Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
| | - Tingyu Lian
- Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
| | - Jingxiao Huang
- Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
| | - DongMei Liang
- Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
| | - JinMei Zeng
- Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
| | - Jindong Ni
- Maternal and Child Research Institute, Women and Children's Hospital Affiliated to Guangdong Medical University (Shunde District Maternal and Child Health Hospital) , Foshan, China.,Department of Epidemiology and Biostatistics, Guangdong Medical University , Dongguan, China
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29
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Zhao G, Zhang Y, Zhao Z, Cai H, Zhao X, Yang T, Chen W, Yao C, Wang Z, Wang Z, Han C, Wang H. MiR-153 reduces stem cell-like phenotype and tumor growth of lung adenocarcinoma by targeting Jagged1. Stem Cell Res Ther 2020; 11:170. [PMID: 32375892 PMCID: PMC7201619 DOI: 10.1186/s13287-020-01679-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 03/27/2020] [Accepted: 04/15/2020] [Indexed: 12/15/2022] Open
Abstract
Background Cancer stem cells (CSCs) have been proposed to be responsible for tumor recurrence and chemo-resistance. Previous studies suggested that miR-153 played essential roles in lung cancer. However, the molecular mechanism of miR-153 in regulating the stemness of non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we investigated the role of miR-153 in regulation of the stemness of NSCLC. Methods The stemness property of lung stem cancer cells was detected by sphere formation assay, immunofluorescence, and Western blot. Luciferase reporter assay was performed to investigate the direct binding of miR-153 to the 3′-UTR of JAG1 mRNA. Animal study was conducted to evaluate the effect of miR-153 on tumor growth in vivo. The clinical relevance of miR-153 in NSCLC was evaluated by Rt-PCR and Kaplan-Meier analysis. Results MiR-153 expression was decreased in lung cancer tissues. Reduced miR-153 expression was associated with lung metastasis and poor overall survival of lung cancer patients. Jagged1, one of the ligands of Notch1, is targeted by miR-153 and inversely correlates with miR-153 in human lung samples. More importantly, we found that miR-153 inhibited stem cell-like phenotype and tumor growth of lung adenocarcinoma through inactivating the Jagged1/Notch1 axis. Conclusion MiR-153 suppresses the stem cell-like phenotypes and tumor growth of lung adenocarcinoma by targeting Jagged1 and provides a potential therapeutic target in lung cancer therapy.
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Affiliation(s)
- Guoli Zhao
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Yueying Zhang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China. .,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China.
| | - Zhonghua Zhao
- Department of Rehabilitation and Physiotherapy, The People's Hospital of Huaiyin, Jinan, 250000, China
| | - Haibo Cai
- Department of Thoracic Surgery, The Affiliated First People's Hospital of Jining Medical University, Jining, 272011, Shandong, China
| | - Xiaogang Zhao
- Department of Thoracic Surgery, The Second Hospital of Shandong University, Jinan, 250000, Shandong, China
| | - Tong Yang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Weijun Chen
- Department of Medical Oncology, Yantaishan Hospital, Yantai, 264000, Shandong, China
| | - Chengfang Yao
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China.,School of Medicine and Life Science, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 250062, Shandong, China
| | - Zhaopeng Wang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
| | - Zhaoxia Wang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
| | - Chen Han
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
| | - Hengxiao Wang
- Institute of Basic Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250062, Shandong, China
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30
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Effect of Berberine from Coptis chinensis on Apoptosis of Intestinal Epithelial Cells in a Mouse Model of Ulcerative Colitis: Role of Endoplasmic Reticulum Stress. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:3784671. [PMID: 32382284 PMCID: PMC7197007 DOI: 10.1155/2020/3784671] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 01/16/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023]
Abstract
The purpose of this study was to verify the effect of berberine (BBR) on endoplasmic reticulum stress (ERS) and apoptosis of intestinal epithelial cells (IECs) in mice with ulcerative colitis (UC). BALB/c mice were randomly divided into five groups as follows: blank control, model, and low-, medium-, and high-dose BBR. A dextran sodium sulfate- (DSS-) induced model of UC was prepared, and the low-, medium-, and high-dose BBR groups were simultaneously gavaged with a BBR suspension for 7 d. Disease activity index (DAI) was assessed, and tissue damage index (TDI) was assessed from colon samples after the last administration. TUNEL assays were used to detect apoptosis of IECs. Immunohistochemistry and/or real-time PCR were applied to determine the expression of GRP78, caspase-12, and caspase-3. In all BBR treatment groups, clinical symptoms of colitis and histopathological damage were significantly reduced. The high-dose BBR group exhibited particularly pronounced decrease (p < 0.01) in both DAI (0.48 ± 0.36) and TDI (1.62 ± 0.64) relative to the model group (1.50 ± 0.65 and 3.88 ± 0.04, respectively). In colon tissues of the model group, the number of apoptotic IECs was significantly increased; the expression of GRP78, caspase-12, and caspase-3 proteins was significantly increased; and the expression of the GRP78 mRNA was upregulated. In low-, medium-, and high-dose BBR groups, the number of apoptotic IECs was significantly reduced. Moreover, GRP78 and caspase-3 expression levels were significantly decreased in the medium- and high-dose BBR groups, caspase-12 expression was significantly decreased in the high-dose BBR group, and the GRP78 mRNA expression level was significantly decreased in the high-dose BBR group. BBR can effectively reduce the rate of IEC apoptosis in UC mice and alleviate the inflammatory response in the colon. The underlying mechanism seems to involve ERS modulation and inhibition of ERS-mediated activation of the caspase-12/caspase-3 apoptosis signaling pathway.
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31
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Yang M, Jiang Z, Yao G, Wang Z, Sun J, Qin H, Zhao H. GALC Triggers Tumorigenicity of Colorectal Cancer via Senescent Fibroblasts. Front Oncol 2020; 10:380. [PMID: 32318333 PMCID: PMC7154132 DOI: 10.3389/fonc.2020.00380] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 03/04/2020] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC)-associated senescent fibroblasts may play a crucial role in tumor progression, but the mechanism remains unclear. In order to solve this complicated problem, we randomly collected 16 patients with CRC, who had been treated with oxaliplatin and capecitabine (XELOX). Hematoxylin-eosin (HE) staining revealed that the tumor-stroma ratio (TSR) of CRC was affected by XELOX treatment. Immunohistochemistry (IHC) and senescence-associated β-galactosidase (SAβG) staining were used to verify a stable model of senescent fibroblasts. IHC analysis showed that high expression levels of galactosylceramidase (GALC) and significant senescence-associated β-galactosidase (SAβG) staining were associated with CRC patient survival. We observed that fibroblasts overexpressing GALC underwent cell cycle arrest. Changes in cell morphology and cell cycle characteristics were accompanied by the upregulation of the p16, p21, and p53 gene, and the downregulation of hTERT expression. In a co-culture system, fibroblasts overexpressing GALC significantly increased the proliferation of CRC cells. Transmission electron microscopy (TEM) analysis confirmed that GALC overexpression fibroblasts co-cultured with CRC caused changes in CRC cell morphology. The aging fibroblast co-culture group (70%) had a higher migration ability. In vivo experiments and transcriptomics analysis were performed to verify the effect of senescent fibroblasts on tumor formation and to identify the potential mechanisms for the above results. We found that a high expression of ATF3 was related to good survival rates. However, a high expression of KIAA0907 was bad for survival rates (p < 0.05). The knockdown of ATF3 can promote cell proliferation, migration, and clonogenic assays, while downregulation of KIAA0907 inhibits cell proliferation, migration, and clonogenic assays. The results demonstrate that senescent fibroblasts with a high level of GALC regulated several aspects of the tumor growth process, including migration and invasion.
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Affiliation(s)
- Mengdi Yang
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhiyuan Jiang
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Guangyu Yao
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhiyu Wang
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jing Sun
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Huanlong Qin
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital Affiliated With Tongji University, Shanghai, China
| | - Hui Zhao
- Department of Internal Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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Lv D, Xing C, Cao L, Zhuo Y, Wu T, Gao N. PD-L1 gene promoter methylation represents a potential diagnostic marker in advanced gastric cancer. Oncol Lett 2020; 19:1223-1234. [PMID: 31966052 PMCID: PMC6956287 DOI: 10.3892/ol.2019.11221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 11/08/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is one of the most prevalent malignant tumors worldwide. Immunological checkpoint inhibitors of the programmed death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling pathway are effective in the treatment of various malignant tumor types, but the potential of such immunotherapeutic techniques for the treatment of gastric cancer is yet to be elucidated. The purpose of the present study was to investigate the methylation of the PD-L1 gene promoter and its clinical significance in advanced gastric cancer, as this may suggest the use of PD-L1 promoter methylation as a novel biomarker for gastric cancer progression. In a total of 70 samples, the methylation rate of the PD-L1 gene promoter region was significantly higher in gastric cancer tissues compared with adjacent tissues. A high level of PD-L1 promoter methylation was associated with lymph node staging, and resulted in poorer prognoses in patients with advanced gastric cancer. A total of 26 patients exhibited highly methylated PD-L1; in this group, the median progression-free survival time of patients receiving platinum/fluorouracil chemotherapy was 4.2 months longer than those receiving paclitaxel/fluorouracil chemotherapy, and the risk of disease progression in patients receiving paclitaxel/fluorouracil chemotherapy was 5.009 times higher compared with patients who received platinum/fluorouracil chemotherapy. Additionally, PD-L1 promoter methylation was significantly correlated with PD-L1 expression, and the progression of advanced gastric cancer. In conclusion, high methylation levels of the PD-L1 promoter region may be a faciliatory mechanism enabling gastric cancer tumorigenesis, and may also represent an independent prognostic factor for chemotherapeutic efficacy in patients with advanced gastric cancer.
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Affiliation(s)
- Dan Lv
- Dalian Medical University, Dalian, Liaoning 116044, P.R. China
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Chengjuan Xing
- Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Lin Cao
- Dalian Medical University, Dalian, Liaoning 116044, P.R. China
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yuejian Zhuo
- Dalian Medical University, Dalian, Liaoning 116044, P.R. China
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Tao Wu
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Na Gao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Fu Y, Chen Y, Huang J, Cai Z, Wang Y. RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis. Am J Physiol Gastrointest Liver Physiol 2020; 318:G352-G360. [PMID: 31869240 DOI: 10.1152/ajpgi.00228.2019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is the most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) coreceptors have been identified to interact with noncanonical Wnt ligand Wnt5a. We, therefore, aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT), such as N-cadherin and E-cadherin, were subjected to correlation analysis with clinicopathological features. Endogenous RYK expression levels were compared in GC cell lines with ascending metastatic potentials followed by stable RYK knockdown. Effect of RYK knockdown on GC cell migration, invasion, and EMT phenotype were assessed in vitro, and on GC tumor growth in vivo in a xenograft rodent model. Particularly, liver metastasis potential of tail vein-injected GC cells was also analyzed following RYK knockdown. RYK was highly correlated with liver metastasis of GC tumors and the expression profiles of EMT markers toward the mesenchymal tendency. RYK expression was also positively correlated with the metastasis potential of GC cells. RYK knockdown not only inhibited migration, invasion, and EMT of GC cells in vitro, but also suppressed tumorigenesis and liver metastasis of GC cells in vivo using the mouse xenograft model. RYK is highly correlated with GC tumorigenesis and potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to GC.NEW & NOTEWORTHY RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to gastric cancer.
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Affiliation(s)
- Yongan Fu
- Department of Gastrointestinal Surgery, Quanzhou First Affiliated Hospital to Fujian Medical University, Quanzhou, Fujian, China
| | - Yilin Chen
- Department of General Surgery, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Jinghua Huang
- Department of Gastrointestinal Surgery, Quanzhou First Affiliated Hospital to Fujian Medical University, Quanzhou, Fujian, China
| | - Zongda Cai
- Department of Gastrointestinal Surgery, Quanzhou First Affiliated Hospital to Fujian Medical University, Quanzhou, Fujian, China
| | - Yangqiang Wang
- Department of Gastrointestinal Surgery, Quanzhou First Affiliated Hospital to Fujian Medical University, Quanzhou, Fujian, China
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Protective effect of Saccharomyces boulardii on intestinal mucosal barrier of dextran sodium sulfate-induced colitis in mice. Chin Med J (Engl) 2020; 132:1951-1958. [PMID: 31335471 PMCID: PMC6708699 DOI: 10.1097/cm9.0000000000000364] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background: The effect and mechanism of Saccharomyces boulardii (Sb) in inflammatory bowel disease are unclear. The objective of the study was to evaluate the impact of Sb on intestinal mucosal barrier and intestinal flora in a colitis mouse model. Methods: Forty C57BL/6J male mice were randomly assigned to five groups: normal control group (A), pathologic control group (B), Sb treatment group (C), mesalazine treatment group (D), and Sb combined with mesalazine treatment group (E). Colitis was induced by the addition of 2.5% (wt/vol) dextran sodium sulfate (DSS) in the drinking water ad libitum for 7 days. The general condition, weight change, stool property, and bloody stool level of mice were observed to evaluate the disease activity index. The expression of zona occludens-1 (ZO-1) and occludin in intestinal tissue were measured by immunohistochemistry. The level of tumor necrosis factor-α (TNF-α) and interleukin (IL)-8 in plasma was measured by enzyme linked immunosorbent assay. Inter-cellular tight junctions were observed by transmission electron microscopy. The feces and intestinal contents were collected sterilely, and intestinal flora was analyzed by 16S rRNA sequencing. Results: Compared with group B, Sb reduced the disease activity index and histological score of group C (disease activity index: group B 2.708 ± 0.628, group C 1.542 ± 0.616, PBC = 0.005; histological score: group B 9.875 ± 3.271, group C 4.750 ± 1.832, PBC = 0.005) in DSS-induced colitis in mice. Sb exerted a protect effect on the expression of ZO-1 (group B 2.075 ± 1.176, group C 4.225 ± 1.316, PBC = 0.019) and occludin (group B 2.200 ± 0.968, group C 3.525 ± 1.047, PBC = 0.023). Compared with group B, Sb decreased the level of TNF-α and IL-8 of group C (TNF-α: group B 716.323 ± 44.691 ng/L, group C 521.740 ± 90.121 ng/L, PBC = 0.001; IL-8: group B 128.992 ± 11.475 pg/mL, group C 106.283 ± 15.906 pg/mL, PBC = 0.012). Treatment with Sb preserved the tight junctions and ameliorated microvilli and inter-cellular space. Treatment with Sb also showed its own characteristics: a higher percentage of Bacteroidetes and a lower percentage of Firmicutes, with significant differences or a significant trend. The proportion of the S24-7 family was increased significantly in the Sb treatment group. Conclusions: Sb shows an anti-inflammatory effect and has a protective effect on the intestinal mucosal mechanical barrier. Sb may up-regulate the abundance of family S24-7 specifically, and maybe a mechanism underlying its function.
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Yu S, Yi M, Xu L, Qin S, Li A, Wu K. CXCL1 as an Unfavorable Prognosis Factor Negatively Regulated by DACH1 in Non-small Cell Lung Cancer. Front Oncol 2020; 9:1515. [PMID: 31998654 PMCID: PMC6966305 DOI: 10.3389/fonc.2019.01515] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/16/2019] [Indexed: 12/25/2022] Open
Abstract
Background: Interaction between cancer cells with microenvironment is essential for cancer progression, therapeutic resistance and prognosis. Chemokine CXCL1 shows variable roles in the development of cancers. DACH1 has been considered as a tumor suppressor and represses the expressions of several chemokines. The relationship between CXCL1 and DACH1 in non-small cell lung cancer (SCLC) deserves further investigation. Methods: Immunohistochemistry staining was performed on tumor tissue microarrays from lung cancer patients to detect CXCL1 protein. The CXCL1 concentration in the serum of adenocarcinoma patients was measured by ELISA. The CXCL1 protein secreted by cancer cell lines was detected by SearchLight proteome array and human cytokine antibody array. The meta-analysis of CXCL1 expression form public databases was performed and correlation between CXCL1 and DACH1 was analyzed. Moreover, the association between clinicopathological features and prognosis with CXCL1 and DACH1 was analyzed by tissue array and KM-plotter from public database. Results: The protein abundance of CXCL1 in lung cancer tissues was significantly higher than that in adjacent normal tissues. CXCL1 was closely related to TNM stage, tumor size, and lymph node metastasis and predicted worse overall survival in adenocarcinoma. The level of CXCL1 in the peripheral blood of adenocarcinoma patients also significantly elevated and positively related with clinical stage. The meta-analysis demonstrated that CXCL1 mRNA level was increased in lung cancer tissues and high level of CXCL1 indicated tumor progression in lung adenocarcinoma. In addition, public database analyses showed that CXCL1 negatively correlated with DACH1. Stable overexpressing DACH1 in cultured lung cancer cells remarkably decreased CXCL1 protein. Moreover, ectopic expression of DACH1 significantly inhibited the expression of CXCL1, Ki67, and cyclin D1 in tumor tissues compared with A549 cells with empty vector. Survival analysis showed that high CXCL1 and low DACH1 indicated poor overall survival and progression-free survival. Conclusion: CXCL1 is closely associated with tumor progression and poor survival. DACH1 significantly inhibits the expression of CXCL1 and indicates good prognosis. Therefore, combined detection of CXCL1 and DACH1 could more precisely predict prognosis of lung adenocarcinoma.
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Affiliation(s)
- Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linping Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Shuang Qin
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Anping Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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Qin S, Yi M, Jiao D, Li A, Wu K. Distinct Roles of VEGFA and ANGPT2 in Lung Adenocarcinoma and Squamous Cell Carcinoma. J Cancer 2020; 11:153-167. [PMID: 31892982 PMCID: PMC6930396 DOI: 10.7150/jca.34693] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 09/26/2019] [Indexed: 01/03/2023] Open
Abstract
Background: Vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (ANGPT2) are key mediators in angiogenesis. The expression and clinical significance of VEGFA and ANGPT2 have been investigated in lung cancer, but the results are controversial. The specific roles of VEGFA and ANGPT2 in adenocarcinoma (ADC) and squamous cell carcinoma (SQC) are still not fully understood. To characterize it, we conducted the current study. Materials and Methods: The relationships between clinic-pathological characteristics and the protein expressions of VEGFA and ANGPT2 were analyzed on tissue microarrays by immunohistochemistry (IHC) staining. Then public databases were used to evaluate the association of VEGFA and ANGPT2 mRNA expressions with clinic-pathological parameters and prognosis. Cobalt chloride (CoCl2) was adopted to mimic a hypoxic microenvironment and western blot was used to detect the expression of hypoxia inducible factor-1α (HIF-1α), VEGFA and ANGPT2 in lung cancer cell lines. Results: IHC staining revealed that the expressions of VEGFA and ANGPT2 were enriched in lung cancer tissues compared with normal tissues. Additionally, both VEGFA and ANGPT2 protein levels were significantly associated with the tumor size and lymph node metastasis only in ADC, not SQC. More importantly, increased VEGFA and ANGPT2 protein levels were negatively correlated with overall survival (OS) of ADC individuals. Meta-analyses of 22 gene expression omnibus (GEO) databases of lung cancer implicated that patients with higher VEGFA and ANGPT2 mRNA expressions tended to have advanced stage in ADC rather than SQC. Kaplan-Meier plot analyses further verified that high levels of VEGFA and ANGPT2 mRNA were associated with poor survival only in ADC. Moreover, the combination of VEGFA and ANGPT2 could more precisely predict prognosis in ADC. In hypoxia-mimicking conditions, induced expression of HIF-1α unregulated VEGFA and ANGPT2 proteins abundance. Conclusion: Our results showed hypoxia upregulated the protein levels of VEGFA and ANGPT2 in lung cancer cell lines, and the roles of VEGFA and ANGPT2 were distinct in ADC and SQC. Combined detections of VEGFA and ANGPT2 may be valuable prognostic biomarkers for ADC and double block of VEGFA and ANGPT2 may improve therapeutic outcome.
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Affiliation(s)
- Shuang Qin
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dechao Jiao
- Department of Interventional Radiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Anping Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
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Zhang Y, Wu X, Kai Y, Lee CH, Cheng F, Li Y, Zhuang Y, Ghaemmaghami J, Chuang KH, Liu Z, Meng Y, Keswani M, Gough NR, Wu X, Zhu W, Tzatsos A, Peng W, Seto E, Sotomayor EM, Zheng X. Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer. JCI Insight 2019; 4:129344. [PMID: 31852841 DOI: 10.1172/jci.insight.129344] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 11/13/2019] [Indexed: 12/12/2022] Open
Abstract
Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer. Indeed, most of the lung-enriched genes identified in our analysis have known or suspected roles in lung cancer. We focused on the gene encoding neuron-derived neurotrophic factor (NDNF), which had not yet been associated with lung cancer. We determined that NDNF was preferentially expressed in the normal adult lung and that its expression was decreased in human lung adenocarcinoma and a mouse model of this cancer. Higher expression of NDNF was associated with better clinical outcome of patients with lung adenocarcinoma. Purified NDNF inhibited proliferation of lung cancer cells, whereas silencing NDNF promoted tumor cell growth in culture and in xenograft models. We determined that NDNF is downregulated through DNA hypermethylation near CpG island shores in human lung adenocarcinoma. Furthermore, the lung cancer-related DNA hypermethylation sites corresponded to the methylation sites that occurred in tissues with low NDNF expression. Thus, by analyzing the tissue-specific secretome, we identified a tumor-suppressive factor, NDNF, which is associated with patient outcomes in lung adenocarcinoma.
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Affiliation(s)
- Ya Zhang
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Xuefeng Wu
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Yan Kai
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Department of Physics, George Washington University Columbian College of Arts and Sciences, Washington, DC, USA
| | - Chia-Han Lee
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.,Department of Biochemistry and Molecular Medicine
| | - Fengdong Cheng
- GW Cancer Center and.,Division of Hematology and Oncology, Department of Medicine, and
| | - Yixuan Li
- GW Cancer Center and.,Department of Biochemistry and Molecular Medicine
| | - Yongbao Zhuang
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Javid Ghaemmaghami
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Kun-Han Chuang
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Zhuo Liu
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Yunxiao Meng
- GW Cancer Center and.,Department of Biochemistry and Molecular Medicine
| | - Meghana Keswani
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Nancy R Gough
- Center for Translational Medicine, Department of Surgery, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Xiaojun Wu
- Department of Pathology, Johns Hopkins Sibley Memorial Hospital, Washington, DC, USA.,Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Wenge Zhu
- GW Cancer Center and.,Department of Biochemistry and Molecular Medicine
| | - Alexandros Tzatsos
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Weiqun Peng
- GW Cancer Center and.,Department of Physics, George Washington University Columbian College of Arts and Sciences, Washington, DC, USA
| | - Edward Seto
- GW Cancer Center and.,Department of Biochemistry and Molecular Medicine
| | - Eduardo M Sotomayor
- GW Cancer Center and.,Division of Hematology and Oncology, Department of Medicine, and
| | - Xiaoyan Zheng
- GW Cancer Center and.,Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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Chen JX, Yi XJ, Gu PL, Gao SX. The role of KDR in intrauterine adhesions may involve the TGF-β1/Smads signaling pathway. ACTA ACUST UNITED AC 2019; 52:e8324. [PMID: 31596310 PMCID: PMC6787948 DOI: 10.1590/1414-431x20198324] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/30/2019] [Indexed: 01/10/2023]
Abstract
The aim of this study was to investigate the role of kinase-insert domain-containing receptor (KDR) in intrauterine adhesions (IUA) and its mechanism. The Case group consisted of 92 patients diagnosed with IUA, and the Control group included 86 patients with uterine septum who had normal endometrium verified with an uteroscope. In addition, 50 rats were randomly assigned into Control, Sham, Model, NC-siRNA, and KDR-siRNA groups. Rats in the Model, NC-siRNA, and KDR-siRNA groups were induced by uterine curettage and lipopolysaccharide (LPS) treatment to establish the IUA model. Then, immunohistochemistry was applied for detection of VEGF and KDR expression, HE staining was used for observation of the endometrial morphology and gland counting, Masson staining for measurement of the degree of endometrial fibrosis, and qRT-PCR and western blot for the expression of KDR, VEGF, MMP-9, as well as TGF-β1/Smads pathway-related proteins. Compared with the Control group, the mRNA and protein expressions of KDR were significantly higher in IUA endometrial tissues, and the expression of KDR was positively correlated to the severity of IUA. In addition, the injection of si-KDR increased the number of endometrial glands, reduced the area of fibrosis, inhibited mRNA and protein expression of KDR and VEGF, up-regulated the expression of MMP-9 and Smad7, and decreased the expression level of TGF-β1, p-Smad2, p-Smad3, and Smad4 in rats with IUA. Highly-expressed KDR was related to patients' severity of IUA, and silencing KDR may prevent the occurrence and development of IUA via TGF-β1/Smads signaling pathway and up-regulating the expression of MMP-9.
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Affiliation(s)
- Jian Xia Chen
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong, China
| | - Xi Juan Yi
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong, China
| | - Pei Ling Gu
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong, China
| | - Shan Xia Gao
- Department of Reproductive Medicine, Linyi Central Hospital, Linyi City, Shandong, China
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Huang W, Zhao S, Xu W, Zhang Z, Ding X, He J, Liang W. Presence of intra-tumoral CD61+ megakaryocytes predicts poor prognosis in non-small cell lung cancer. Transl Lung Cancer Res 2019; 8:323-331. [PMID: 31555508 DOI: 10.21037/tlcr.2019.08.23] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Lung is a reservoir for megakaryocytes (MKs). The relationship between intra-tumoral MKs and non-small cell lung cancer (NSCLC) is unknown. We investigate relationship between high intra-tumoral MKs with the recurrence of NSCLC. Methods The tissue sections of 629 patients with resected NSCLC were stained with hematoxylin, anti-CD61, anti-CD34 and stromal cell-derived factor-1 (SDF-1). CD61+ giant cells localized in CD34+ capillaries were identified as MKs. The impact of MKs and preoperative platelet count on disease-free survival (DFS) was investigated. Results Overall, 18.9% of patients were positive for the presence of MKs. In univariate analysis, the median DFS of the MK+ group was shorter than the median DFS of the MK- group (69.1 vs. 80.5 months; P=0.021). Multivariate analysis indicated that MKs in tumor tissue was an unfavorable prognostic factor for DFS (HR 1.351, P=0.065), the impact of which was more significant in non-squamous cell carcinoma (NSCC) (HR 1.710, P=0.008) and in patients with N0 (HR 1.883, P=0.009). Although systemic platelet count of the MK+ group was significantly higher than the MK- group (270.6×109 vs. 243.6×109/L, P=0.007), the stratified subgroup DFS curves (P=0.003) showed that the effect of MKs on prognosis was independent of the blood platelet count. Conclusions Our results demonstrate that CD61+ MKs in tumor tissue predict unfavorable prognosis in NSCLC.
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Affiliation(s)
- Weizhe Huang
- Department of Thoracic Surgery, the First Affiliated Hospital, Medical College of Shantou University, Shantou 515041, China.,Department of Thoracic Surgery/Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.,Guangzhou Institute of Respiratory Disease & Health, Guangzhou 510120, China.,China State Key Laboratory and National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Shen Zhao
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wei Xu
- Guangzhou KingMed Center for Clinical Laboratory Co. Ltd., Guangzhou 510000, China
| | - Zhikui Zhang
- Guangzhou KingMed Center for Clinical Laboratory Co. Ltd., Guangzhou 510000, China
| | - Xiangdong Ding
- Guangzhou KingMed Center for Clinical Laboratory Co. Ltd., Guangzhou 510000, China
| | - Jianxing He
- Department of Thoracic Surgery/Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.,Guangzhou Institute of Respiratory Disease & Health, Guangzhou 510120, China.,China State Key Laboratory and National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Wenhua Liang
- Department of Thoracic Surgery/Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.,Guangzhou Institute of Respiratory Disease & Health, Guangzhou 510120, China.,China State Key Laboratory and National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
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Zhang SL, Zhu HY, Zhou BY, Chu Y, Huo JR, Tan YY, Liu DL. Histone deacetylase 6 is overexpressed and promotes tumor growth of colon cancer through regulation of the MAPK/ERK signal pathway. Onco Targets Ther 2019; 12:2409-2419. [PMID: 31118659 PMCID: PMC6498393 DOI: 10.2147/ott.s194986] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 03/01/2019] [Indexed: 12/14/2022] Open
Abstract
Purpose: To investigate the expression of histone deacetylase 6 (HDAC6) in colon cancer and its role in colon cancer cell growth and migration. Materials and methods: We detected the expression of HDAC6 in a colon cancer tissue chip using immunochemical staining, and analyzed the difference in HDAC6 expression between cancer and adjacent noncancerous tissues. Then, we explored the relationship between HDAC6 expression and patients’ clinicopathological characteristics and prognoses. In adidition, the role of HDAC6 in colon cancer cell growth and migration, as well as its potential related signal pathway, through HDAC6 knockdown was explored. Results: The immunochemical score of HDAC6 expression was higher in cancer tissue than in the adjacent noncancerous tissue (4.54 vs 3.08, P<0.005); similarly, as well as the rate of high HDAC6 expression was higher in cancer tissue than in the adjacent noncancerous tissue (71.1% vs 40.9%, P<0.001). Patients showing high HDAC6 expression had a shorter overall survival time. Additionally, Cox regression analysis showed that high HDAC6 expression was an independent risk factor for poor prognosis. HDAC6 knockdown decreased cell viability, colony formation, and number of migrated colon cancer cells (HCT116 and HT29); the expression of p-MEK, p-ERK, and p-AKT was also decreased, but had no influence on MEK, ERK, and AKT expression. Conclusion: HDAC6 is highly expressed in colon cancer and associated with a poor prognosis. HDAC6 knockdown inhibits colon cancer cell growth and migration, partly through the MAPK/ERK pathway.
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Affiliation(s)
- Shi-Lan Zhang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Hong-Yi Zhu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Bing-Yi Zhou
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Yi Chu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Ji-Rong Huo
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - Yu-Yong Tan
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
| | - De-Liang Liu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
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Li W, Wang Y, Tan S, Rao Q, Zhu T, Huang G, Li Z, Liu G. Overexpression of Epidermal Growth Factor Receptor (EGFR) and HER-2 in Bladder Carcinoma and Its Association with Patients' Clinical Features. Med Sci Monit 2018; 24:7178-7185. [PMID: 30296252 PMCID: PMC6190725 DOI: 10.12659/msm.911640] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND The aim of this study was to determine the expression of EGFR/HER-2 and investigate their association with patients' clinical features in bladder transitional cell carcinoma (BTCC). MATERIAL AND METHODS Immunohistochemistry was utilized in our study to explore the expression of EGFR/HER-2 of 56 human bladder cancer samples and 10 normal bladder samples. RESULTS EGFR and HER-2 expressions were both significantly higher in bladder transitional cell carcinoma (BTCC) than that in non-cancer bladder samples; the EGFR positivity rate was 55.4% among BTCC samples and 37.5% for HER-2a. A statistically significant correlation was also present between the increasing EGFR or HER-2 expression levels and the clinical stages, pathologic grades, and tumor recurrence. The expression level of EGFR increased along with higher clinical stages and pathologic grades of BTCC, and the obviously increased expression of HER-2 was statistically associated with clinical stages and tumor recurrence. In addition, the expression level of HER-2 increased along with the higher clinical stage of BTCC. EGFR expression and HER-2 levels were positively associated in BTCC samples. CONCLUSIONS Our findings demonstrate that high EGFR and HER-2 expressions are dramatically increased in the BTCC tissues and are closely related to the clinical stages, pathologic grades, and tumor recurrence. Therefore, the evaluation of EGFR and HER-2 expression in BTCC may contribute to identifying patients who are at increased risk of disease progression and recurrence.
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Affiliation(s)
- Wei Li
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
| | - Youquan Wang
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
| | - Shubo Tan
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
| | - Qishuo Rao
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
| | - Tian Zhu
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
| | - Guo Huang
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
| | - Zhuo Li
- Department of Urology, Hunan Provincial People's Hospital, Changsha, Hunan, China (mainland)
| | - Guowen Liu
- Department of Surgery, The Second Hospital, University of South China, Hengyang, Hunan, China (mainland)
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Bai X, Yi M, Xia X, Yu S, Zheng X, Wu K. Progression and prognostic value of ECT2 in non-small-cell lung cancer and its correlation with PCNA. Cancer Manag Res 2018; 10:4039-4050. [PMID: 30319288 PMCID: PMC6167987 DOI: 10.2147/cmar.s170033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Purpose Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor, which is involved in cell division regulation and cell cycle modulation. Recent evidence indicates that ECT2 is overexpressed in many human cancers. However, the exact prognostic value of ECT2 in lung cancer has not been elucidated. Patients and methods In the current study, we performed correlation and prognosis analyses using public databases and conducted immunohistochemical staining in tissue microarrays, using samples from 204 lung cancer patients with survival data. Results We found that the expression of ECT2 was markedly increased in lung cancer tissues compared with normal tissues. Moreover, we demonstrated that the expression of ECT2 was related to tumor cell differentiation degree, TNM stage, lymph node metastasis, and prognosis in non-small-cell lung cancer (NSCLC). A correlation analysis indicated that ECT2 levels were significantly correlated with proliferating cell nuclear antigen (PCNA) levels in NSCLC. Furthermore, Kaplan–Meier analyses revealed that high ECT2 expression was associated with unfavorable overall survival (OS) and progression-free survival (PFS) in NSCLC patients. Conclusion Taken together, these results indicate that the overexpression of ECT2 contributes to tumor invasion and progression, suggesting that ECT2 is a potential prognostic marker for NSCLC patients.
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Affiliation(s)
- Xianguang Bai
- Medical School of Pingdingshan University, Pingdingshan, Henan, People's Republic of China,
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China,
| | - Xichao Xia
- Medical School of Pingdingshan University, Pingdingshan, Henan, People's Republic of China,
| | - Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China,
| | - Xinhua Zheng
- Medical School of Pingdingshan University, Pingdingshan, Henan, People's Republic of China,
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China,
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Cao LL, Pei XF, Qiao X, Yu J, Ye H, Xi CL, Wang PY, Gong ZL. SERPINA3 Silencing Inhibits the Migration, Invasion, and Liver Metastasis of Colon Cancer Cells. Dig Dis Sci 2018; 63:2309-2319. [PMID: 29855767 DOI: 10.1007/s10620-018-5137-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 05/24/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To investigate the impact of SERPINA3 on the migration, invasion, and liver metastasis of colon cancer cells. METHODS Immunohistochemical staining was conducted to determine SERPINA3 expression in the cancer and adjacent normal tissues of 131 patients suffering from colon cancer. In vitro experiment, colon cancer cells with low (HT-29P), intermediate (KM-12C), and high (HT-29LMM, KM-12L4) metastatic potential were obtained to examine SERPINA3 expression levels. Besides, quantitative real-time PCR (qRT-PCR) and Western Blot were performed to detect SERPINA3 expression in HT-29LMM and KM-12L4 cells transfected with SERPINA3 siRNA; Wound-healing and Transwell assays to measure cell migration and invasion, respectively; and ELISA to detect MMP-2 and MMP-9 levels. In vivo experiment, mice with liver metastasis of colon cancer were established to observe the effect of SERPINA3 silencing on liver metastasis. Immunohistochemical assay was applied to evaluate the expressions of Serpina3, Mmp-2, Mmp-9, and proliferating cell nuclear antigen (Pcna) in liver metastasis tissues. RESULTS SERPINA3 in colon cancer tissues was higher than in adjacent normal tissues, which was associated with patients' clinicopathological features. Besides, SERPINA3 expression showed a rising trend in low, intermediate, and high metastatic potential colon cancer cells. After KM-12L4 and HT-29LMM cells transfected with SERPINA3 siRNA, the migration and invasive ability of cells, as well as the expression levels of MMP-2 and MMP-9 were all decreased. Moreover, SERPINA3 siRNA could not only reduce live metastasis of mice, but also down-regulate the expression of Mmp-2 and Mmp-9 in liver metastasis tissues. CONCLUSION SERPINA3 silencing could inhibit the migration, invasion, and liver metastasis of colon cancer cells.
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Affiliation(s)
- Long-Lei Cao
- Department of Anal-colorectal Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Renmin Road 1, Jingzhou, 434020, China
| | - Xu-Feng Pei
- Department of Emergency Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Jingzhou, 434020, China
| | - Xu Qiao
- Department of Gastroenterology, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Jingzhou, 434020, China
| | - Jie Yu
- Department of Anal-colorectal Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Renmin Road 1, Jingzhou, 434020, China
| | - Hui Ye
- Department of Anal-colorectal Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Renmin Road 1, Jingzhou, 434020, China
| | - Chang-Lei Xi
- Department of Anal-colorectal Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Renmin Road 1, Jingzhou, 434020, China
| | - Pei-Yun Wang
- Department of Anal-colorectal Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Renmin Road 1, Jingzhou, 434020, China
| | - Zhi-Lin Gong
- Department of Anal-colorectal Surgery, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Renmin Road 1, Jingzhou, 434020, China.
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Jiang C, Tong Z, Fang WL, Fu QB, Gu YJ, Lv TT, Liu DM, Xue W, Lv JW. Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post-menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway. J Cell Biochem 2018; 119:6429-6441. [PMID: 29240250 DOI: 10.1002/jcb.26610] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 12/07/2017] [Indexed: 01/06/2023]
Abstract
The study explores whether miR-139-5p targeting LPAR4 affects epithelial-mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-α. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E-cadherin, N-cadherin, Vimentin, TGF-β1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-β1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-α expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-β1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR-139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway.
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Affiliation(s)
- Chen Jiang
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Zhen Tong
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Wei-Lin Fang
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Qi-Bo Fu
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Yin-Jun Gu
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Ting-Ting Lv
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Dong-Ming Liu
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Wei Xue
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
| | - Jian-Wei Lv
- Department of Urology, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P. R. China
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Banys-Paluchowski M, Fehm T, Janni W, Aktas B, Fasching PA, Kasimir-Bauer S, Milde-Langosch K, Pantel K, Rack B, Riethdorf S, Solomayer EF, Witzel I, Müller V. Elevated serum RAS p21 is an independent prognostic factor in metastatic breast cancer. BMC Cancer 2018; 18:541. [PMID: 29739347 PMCID: PMC5941516 DOI: 10.1186/s12885-018-4282-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 03/21/2018] [Indexed: 01/03/2023] Open
Abstract
Background An important component of the RAS signalling pathway, the RAS p21 oncogene, is frequently hyperactivated in breast cancer. Its expression in tumor tissue has been linked to poor clinical outcome. This study was designed to evaluate the clinical relevance of RAS p21 levels in peripheral blood in a large cohort of metastatic breast cancer patients. Methods Two hundred fifty-one patients with metastatic breast cancer were enrolled in this prospective, multicentre, open-label, non-randomized study. Blood samples were collected before start of first-line or later-line treatment. RAS p21 was determined using a sandwich-type ELISA immunoassay. For the determination of the cutoff, blood samples from age-matched healthy controls were analyzed. A value above 452 pg/ml was regarded as elevated (mean + 2 x SD). In the univariate survival analysis, two other cutoffs were considered as well (50th and 75th percentile of patients, i.e. 229 pg/ml and 320 pg/ml). Circulating tumor cells (CTCs) were detected using the CellSearch system. Results 29 of 251 (12%) patients had RAS p21 levels above the cut-off level of 452 pg/ml. Clinical-pathological parameters, such as hormone receptor and HER2 status, line of therapy and CTC status, did not correlate with RAS p21 levels. Elevated RAS p21 was significantly associated with shorter progression-free and overall survival in the univariate analysis (median PFS: 3.9 months [95%-CI: 1.8–6.0] for patients with elevated RAS p21 levels versus 8.5 months [95%-CI: 7.4–9.5] with non-elevated levels [p = 0.01]; median OS: 7.1 months [95%-CI: 0.3–14.2] versus not reached [p = 0.002], respectively). When RAS p21 cutoffs other than 452 pg/ml were considered, elevated RAS p21 was significantly associated with OS but not with PFS. Classical clinical-pathological factors were included into a multivariate Cox regression analysis. In addition, factors previously shown to influence survival in a univariate analysis, such as serum HER2, CAIX and TIMP1, were included as well. In the multivariate analysis, RAS p21, presence of ≥5 CTCs per 7.5 ml blood, higher grading and higher line of therapy remained independent predictors of shorter OS. Conclusions Metastatic breast cancer patients with elevated levels of circulating RAS p21 have significantly worse clinical outcome. Hypothetically, these patients might benefit from therapeutic strategies targeting RAS pathway. Trial registration Current Controlled Trials ISRCTN59722891 (DETECT); trial registration date: April, 17th 2010; the trial was registered retrospectively.
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Affiliation(s)
| | - Tanja Fehm
- Department of Obstetrics and Gynecology, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Bahriye Aktas
- Department of Obstetrics and Gynecology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Erlangen, Erlangen, Germany
| | - Sabine Kasimir-Bauer
- Department of Obstetrics and Gynecology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Karin Milde-Langosch
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumour Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Brigitte Rack
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Sabine Riethdorf
- Department of Tumour Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Erich-Franz Solomayer
- Department of Gynecology and Obstetrics, Saarland University Hospital, Homburg/Saar, Germany
| | - Isabell Witzel
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Volkmar Müller
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Wang H, Liu H, Min S, Shen Y, Li W, Chen Y, Wang X. CDK16 overexpressed in non-small cell lung cancer and regulates cancer cell growth and apoptosis via a p27-dependent mechanism. Biomed Pharmacother 2018; 103:399-405. [PMID: 29674275 DOI: 10.1016/j.biopha.2018.04.080] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 04/02/2018] [Accepted: 04/10/2018] [Indexed: 12/14/2022] Open
Abstract
Cyclin-dependent kinase 16 (CDK16, PCTAIRE1) expression is upregulated in a wide variety of human malignancies. However, the function(s) of CDK16 in non-small cell lung cancer (NSCLC) remain unknown. Therefore, here we investigated the role of CDK16 in NSCLC. From 43 NSCLC tumors and matching healthy control lung tissues, immunohistochemistry revealed significantly greater CDK16 and phospho-p27Ser10 staining levels in NSCLC samples relative to healthy controls. The NSCLC cell line EKVX was transfected with a control siRNA, a CDK16-siRNA, or CDK16-siRNA + p27-siRNA. We found significantly decreased proliferation levels and significantly increased apoptosis levels in CDK16-silenced NSCLC cells. However, these effects were abrogated in cells treated with both the CDK16-siRNA and the p27-siRNA. In CDK16-silenced NSCLC cells, we found upregulated p27 and downregulated phospho-p27Ser10 protein expression but downregulated ubiquitinated p27 and ubiquitinated phospho-p27Ser10 protein expression. Cycloheximide-treated CDK16-silenced NSCLC cells displayed a much milder reduction in p27 protein expression over time relative to untreated CDK16-silenced NSCLC cells. In summary, CDK16 is significantly upregulated in human NSCLC tumor tissue and plays an oncogenic role in NSCLC cells via promoting cell proliferation and inhibiting apoptosis in a p27-dependent manner. Moreover, CDK16 negatively regulates expression of the p27 via ubiquination and protein degradation.
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Affiliation(s)
- Hongtao Wang
- Department of Immunology, Bengbu Medical College, Bengbu, 233000, Anhui Province, China
| | - Hongli Liu
- Department of Gynecological Oncology, First Affiliated Hospital, Bengbu Medical College, Bengbu, 233000, Anhui Province, China
| | - Shengping Min
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Department of Respiration, First Affiliated Hospital, Bengbu Medical College, No. 287 Changhuai Road, Bengbu, 233000, Anhui Province, China
| | - Yuanbing Shen
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Department of Respiration, First Affiliated Hospital, Bengbu Medical College, No. 287 Changhuai Road, Bengbu, 233000, Anhui Province, China
| | - Wei Li
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Department of Respiration, First Affiliated Hospital, Bengbu Medical College, No. 287 Changhuai Road, Bengbu, 233000, Anhui Province, China
| | - Yuqing Chen
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Department of Respiration, First Affiliated Hospital, Bengbu Medical College, No. 287 Changhuai Road, Bengbu, 233000, Anhui Province, China.
| | - Xiaojing Wang
- Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, Department of Respiration, First Affiliated Hospital, Bengbu Medical College, No. 287 Changhuai Road, Bengbu, 233000, Anhui Province, China.
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Liu Q, Li A, Yu S, Qin S, Han N, Pestell RG, Han X, Wu K. DACH1 antagonizes CXCL8 to repress tumorigenesis of lung adenocarcinoma and improve prognosis. J Hematol Oncol 2018; 11:53. [PMID: 29636079 PMCID: PMC5894143 DOI: 10.1186/s13045-018-0597-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 03/26/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND C-X-C motif ligand 8 (CXCL8), known as a proinflammatory chemokine, exerts multiple effects on the proliferation, invasion, and migration of tumor cells via the autocrine or paracrine manner. Conversely, the human Dachshund homologue 1 (DACH1) is recognized as a tumor suppressor which retards the progression of various cancers. In prostate cancer, it has been demonstrated that DACH1 was negatively correlated with the expression of CXCL8 and able to antagonize the effects of CXCL8 on cellular migration. Herein, we explored the mechanisms by which DACH1 regulated the CXCL8 in non-small cell lung cancer (NSCLC). METHODS Public microarray and Kaplan-Meier plotter datasets were analyzed. Blood serum samples from lung adenocarcinoma (ADC) patients were collected for enzyme-linked immunosorbent assay (ELISA) analysis. Immunohistochemical staining was conducted on tissue microarray. Cell lines with stable expression of DACH1 were established, and relative gene expression was measured by Western blot, ELISA, real-time PCR, and human cytokine array. Correspondingly, cell lines transfected with shDACH1 were established, and relative gene expression was measured by real-time PCR and immunofluorescence array. Functional studies were performed by transwell and xenograft mice models. Luciferase reporter gene assay was applied to measure the regulation of DACH1 on CXCL8. RESULTS Our study indicated that CXCL8 both at the mRNA and protein level was associated with the high tumor burden of ADC. Correlational analyses in ADC cell lines and ADC tissues showed that DACH1 was inversely correlated with CXCL8. Meanwhile, patients with high DACH1 expression and low CXCL8 expression had prolonged time to death and recurrence. Moreover, we verified the inhibitory effects of DACH1 on CXCL8 both in vitro and in vivo. Mechanism studies proved that DACH1 transcriptionally repressed CXCL8 promoter activity through activator protein-1 (AP-1) and nuclear transcription factor-kappa B (NF-κB) sites. CONCLUSIONS Our study proved that CXCL8 acted as an unfavorable factor promoting to tumor progression and poor prognosis of ADC, while DACH1 antagonized CXCL8 to provide a favorable survival of ADC patients. Double detection of DACH1 and CXCL8 may provide a precise information for further evaluating the prognosis of ADC patients.
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Affiliation(s)
- Qian Liu
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Anping Li
- grid.412633.1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China
| | - Shengnan Yu
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Shuang Qin
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Na Han
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
| | - Richard G. Pestell
- Pennsylvania Cancer and Regenerative Medicine Research Center, Wynnewood, PA 19096 USA
| | - Xinwei Han
- grid.412633.1Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 People’s Republic of China
| | - Kongming Wu
- 0000 0004 1799 5032grid.412793.aDepartment of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People’s Republic of China
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Zhong JT, Wang HJ, Yu J, Zhang JH, Wang SF, Yang X, Su W. Correlations of the expressions of c-Jun and Egr-1 proteins with clinicopathological features and prognosis of patients with nasopharyngeal carcinoma. Cancer Biomark 2018; 19:213-220. [PMID: 28269757 DOI: 10.3233/cbm-161710] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study intended to explore the correlation of the expressions of c-Jun and Egr-1 proteins with clinicopathological features and prognosis of patients with nasopharyngeal carcinoma (NPC). From January 2008 to January 2011, 123 NPC patients and 59 patients with chronic rhinitis were enrolled in this study. Fresh NPC and normal nasopharynx tissue specimens were obtained during surgery. Immunohistochemistry (IHC) was adopted to determine the positive expressions of the c-Jun and Egr-1 proteins. A 5-year clinical follow-up was conducted on all NPC patients. The Kaplan-Meier survival curve and Cox regression model were used for survival analysis. Compared with normal nasopharynx tissues, c-Jun expression was up-regulated but Egr-1 expression was down-regulated in NPC tissues. NPC patients with stage T3-T4 or stage III-IV had higher positive rates of c-Jun expression than those with stage T1-T2 or stage I-II. However, the positive rates of Egr-1 expression was higher in patients with stage T1-T2 or stage III-IV than those with stage T3-T4 or stage I-II. The survival rate of NPC patients with high c-Jun expression was lower than those with low/negative c-Jun expression, while the survival rate of NPC patients with high Egr-1 expression was higher than those with low/negative Egr-1 expression. The Cox regression analysis revealed that stage T3-T4, high c-Jun expression, and low Egr-1 expression were risk factors for poor prognosis of NPC patients. In conclusion, our study suggests that the c-Jun and Egr-1 proteins can serve as novel potential biomarkers for the early diagnosis and prognosis prediction of NPC.
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Affiliation(s)
- Jia-Teng Zhong
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Hai-Jun Wang
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, China
| | - Jian Yu
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, China
| | - Jing-Hang Zhang
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, China
| | - Shi-Feng Wang
- Pediatric Rescue Room, Linyi People's Hospital, Linyi, Shandong 276003, China
| | - Xue Yang
- Pediatric Rescue Room, Linyi People's Hospital, Linyi, Shandong 276003, China
| | - Wei Su
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, China.,Clinical Molecular Pathology Diagnosis Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, China
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Yang M, Sun Y, Sun J, Wang Z, Zhou Y, Yao G, Gu Y, Zhang H, Zhao H. Differentially expressed and survival-related proteins of lung adenocarcinoma with bone metastasis. Cancer Med 2018. [PMID: 29522283 PMCID: PMC5911611 DOI: 10.1002/cam4.1363] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Despite recent advances in targeted and immune‐based therapies, the poor prognosis of lung adenocarcinoma (LUAD) with bone metastasis (BM) remains a challenge. First, two‐dimensional gel electrophoresis (2‐DE) was used to identify proteins that were differentially expressed in LUAD with BM, and then matrix‐assisted laser desorption/ionization time of flight mass spectrometry (MALDI‐TOF‐MS) was used to identify these proteins. Second, the Cancer Genome Atlas (TCGA) was used to identify mutations in these differentially expressed proteins and Kaplan–Meier plotter (KM Plotter) was used to generate survival curves for the analyzed cases. Immunohistochemistry (IHC) was used to check the expression of proteins in 28 patients with BM and nine patients with LUAD. Lastly, the results were analyzed with respect to clinical features and patient's follow‐up. We identified a number of matched proteins from 2‐DE. High expression of enolase 1 (ENO1) (HR = 1.67, logrank P = 1.9E‐05), ribosomal protein lateral stalk subunit P2 (RPLP2) (HR = 1.77, logrank P = 2.9e‐06), and NME/NM23 nucleoside diphosphate kinase 2 (NME1‐NME2) (HR = 2.65, logrank P = 3.9E‐15) was all significantly associated with poor survival (P < 0.05). Further, ENO1 was upregulated (P = 0.0004) and calcyphosine (CAPS1) was downregulated (P = 5.34E‐07) in TCGA LUAD RNA‐seq expression data. IHC revealed that prominent ENO1 staining (OR = 7.5, P = 0.034) and low levels of CAPS1 (OR = 0.01, P < 0.0001) staining were associated with BM incidence. Finally, we found that LUAD patients with high expression of ENO1 and RPLP2 had worse overall survival. This is the first instance where the genes ENO1, RPLP2, NME1‐NME2 and CAPS1 were associated with disease severity and progression in LUAD patients with BM. Thus, with this study, we have identified potential biomarkers and therapeutic targets for this disease.
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Affiliation(s)
- Mengdi Yang
- Department of Internal Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Yi Sun
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Jing Sun
- Department of Internal Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Zhiyu Wang
- Department of Internal Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Yiyi Zhou
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Soochow University, Shanghai, 200233, China
| | - Guangyu Yao
- Department of Internal Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Yifeng Gu
- Department of Radiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Huizhen Zhang
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
| | - Hui Zhao
- Department of Internal Oncology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China
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Kongkaew T, Aung WPP, Supanchart C, Makeudom A, Langsa-ard S, Sastraruji T, Chaiyarit P, Krisanaprakornkit S. O
-GlcNAcylation in oral squamous cell carcinoma. J Oral Pathol Med 2018; 47:260-267. [DOI: 10.1111/jop.12680] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2018] [Indexed: 10/18/2022]
Affiliation(s)
- Tassaporn Kongkaew
- Department of Oral and Maxillofacial Surgery; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
| | - Win Pa Pa Aung
- Center of Excellence in Oral and Maxillofacial Biology; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
| | - Chayarop Supanchart
- Department of Oral and Maxillofacial Surgery; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
- Center of Excellence in Oral and Maxillofacial Biology; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
| | - Anupong Makeudom
- Center of Excellence in Oral and Maxillofacial Biology; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
| | - Sarawat Langsa-ard
- Center of Excellence in Oral and Maxillofacial Biology; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
| | - Thanapat Sastraruji
- Center of Excellence in Oral and Maxillofacial Biology; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
| | - Ponlatham Chaiyarit
- Department of Oral Diagnosis; Faculty of Dentistry; Khon Kaen University; Khon Kaen Thailand
- Research Group of Chronic Inflammatory Oral Diseases and Systemic Diseases Associated with Oral Health; Khon Kaen University; Khon Kaen Thailand
| | - Suttichai Krisanaprakornkit
- Center of Excellence in Oral and Maxillofacial Biology; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
- Department of Oral Biology and Diagnostic Sciences; Faculty of Dentistry; Chiang Mai University; Chiang Mai Thailand
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