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Jiang H, Bai W, Yang Y, Zhou G, Li J, Li X, Wan X, Shao J. Biliverdin alleviates cerebral ischemia-reperfusion injury by regulating the P4hb/MAPK/mTOR pathway to inhibit autophagy. Cell Signal 2025; 132:111815. [PMID: 40258578 DOI: 10.1016/j.cellsig.2025.111815] [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: 01/22/2025] [Revised: 03/26/2025] [Accepted: 04/14/2025] [Indexed: 04/23/2025]
Abstract
BACKGROUND Biliverdin (BV) exhibits anti-inflammatory and antioxidative effects. Autophagy activation is crucial in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). This study aimed to investigate whether BV could ameliorate CIRI by regulating autophagy. METHODS A middle cerebral artery occlusion-reperfusion (MCAO/R) model in Sprague-Dawley (SD) rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in PC12 cells were employed to explore the neuroprotective effects of BV and its underlying mechanisms. In these rats, once BV was administered post-MCAO/R, its treatment efficacy and underlying mechanisms were evaluated through behavioral, morphological, and molecular analyses. Alternatively, for PC12 cells, following successful OGD/R modeling, BV, autophagy activator rapamycin, prolyl 4-hydroxylase beta (P4hb) knockdown or overexpression, and the specific inhibitors of three classic autophagy pathways were applied. Cell viability (using CCK8 assay), Calcein/PI staining, autophagosome staining (using MDC assay), reverse transcription quantitative polymerase chain reaction, and western blot were subsequently carried out to investigate the mechanisms by which BV ameliorates CIRI. RESULTS BV alleviated CIRI by inhibiting autophagy. Further investigation suggested that BV downregulated P4hb expression. In vitro experiments showed that P4hb knockdown reduced autophagy in post-CIRI cells, while its overexpression reversed the effects of BV. Rescue experiments indicated that MAPK pathway inhibitors counteracted the effects of P4hb overexpression on autophagy post-CIRI. CONCLUSION BV improves CIRI by regulating the P4hb/MAPK/mTOR signaling pathway to inhibit autophagy, offering a novel therapeutic strategy for ischemic stroke.
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Affiliation(s)
- Huan Jiang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China
| | - Wenya Bai
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China
| | - Yuan Yang
- Department of Anesthesiology, Second Affiliated Hospital of Kunming Medical University, 650000 Kunming, Yunnan Province, China
| | - Guilin Zhou
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China
| | - Junjie Li
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China
| | - Xuelian Li
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China
| | - Xiaohong Wan
- Department of Anesthesiology, Second Affiliated Hospital of Kunming Medical University, 650000 Kunming, Yunnan Province, China.
| | - Jianlin Shao
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China.
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Yang S, Jiang Y, Yang Z. Hypoxia-associated genes as predictors of outcomes in gastric cancer: a genomic approach. Front Immunol 2025; 16:1553477. [PMID: 40129974 PMCID: PMC11931070 DOI: 10.3389/fimmu.2025.1553477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
Objective To investigate the effects of hypoxia-related genes in stomach adenocarcinoma (STAD) and construct an excellent prognostic model. Methods RNA expression data and clinical details were retrieved from the TCGA and GEO database dataset. scRNA-seq analysis was conducted on primary gastric cancer samples from GSE183904. Cellular hypoxia status was predicted using the CHPF software. WGCNA and GO-BP/KEGG enrichment of module genes analyses were performed to identify gene modules associated with hypoxia and biological pathway enrichment. A prognostic model was developed employing the LassoCox algorithm. GES-1, AGS, BGC823, and MGC803 cell lines were obtained for qRT-PCR analysis to identify the expression of model genes. Results Single-cell atlas within STAD delineated that most of neoplastic cells, fibroblasts, endothelial cells, and myeloid cells were hypoxic. Further analysis of neoplastic cell subpopulations identified four hypoxic subpopulations (H1-H4) and four non-hypoxic subpopulations (N1-N4), with H1 subpopulation had the highest degree of hypoxia. The prognostic model constructed by five H1-specific transcription factors EHF, EIF1AD, GLA, KEAPI, and MAGED2, was demonstrated efficacy in predicting overall survival (OS), with significantly worse OS in high-risk patients. qRT-PCR analysis determined the higher expression level of five H1-specific transcription factors in gastric cancer cell lines than that in normal gastric epithelial cell line. Conclusion Hypoxia exerts a profound influence on STAD due to the overexpression of hypoxic cellular subpopulations-specific transcription factors EHF, EIF1AD, GLA, KEAPI, and MAGED2. The novel prognostic model developed by these hypoxia-associated genes presents a novel approach to risk stratification, exhibiting an excellent prognostic value for STAD patients.
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Affiliation(s)
- Shuo Yang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuhao Jiang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhonghua Yang
- Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, China
- NHC Key Laboratory of Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, China
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Nam S, Lee Y. HIF1A protein expression is correlated with clinical features in gastric cancer: an updated systematic review and meta-analysis. Sci Rep 2024; 14:13736. [PMID: 38877062 PMCID: PMC11178933 DOI: 10.1038/s41598-024-63019-6] [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: 04/13/2023] [Accepted: 05/23/2024] [Indexed: 06/16/2024] Open
Abstract
To elucidate the correlation of HIF1A with clinicopathologic characteristics in patients with gastric cancer (GC), we conducted a systematic review and meta-analysis. We searched PubMed, Embase and Web of Science for studies on GC and HIF1A, covering studies published until January 31st, 2022. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for clinical characteristics based on high and low HIF1A protein levels. We used random-effects and fixed-effects meta-analysis methods to determine mean effect sizes of ORs and evaluated publication heterogeneity with τ2, I2, and Q values. Additionally, we generated funnel plots to inspect publication bias. Our meta-analysis included 20 publications with 3416 GC patients to estimate the association between high or low HIF1A expression and clinical characteristics. Positive HIF1A expression was significantly associated with T stage progression (OR: 2.46; 95% CI 1.81-3.36; P < 0.01), TNM stage progression (OR: 2.50; 95% CI 1.61-3.87; P < 0.01), lymph node metastasis (OR: 2.06; 95% CI 1.44-2.94; P < 0.01), undifferentiated status (OR: 1.83; 95% CI 1.45-2.32; P < 0.01), M stage progression (OR: 2.34; 95% CI 1.46-3.77; P < 0.01), Borrmann stage progression (OR: 1.48; 95% CI 1.02-2.15; P = 0.04), larger tumor size (OR: 1.27; 95% CI 1.06-1.52; P < 0.01), vascular invasion (OR: 1.94; 95% CI 1.38-2.72; P < 0.01), and higher vascular endothelial growth factor (VEGF) protein expression (OR: 2.61; 95% CI 1.79-3.80; P < 0.01) in our meta-analysis. GC Patients highly expressing HIF1A protein might be prone to tumor progression, poorly differentiated GC cell types, and a high VEGF expression.
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Affiliation(s)
- Seungyoon Nam
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon, 21999, Republic of Korea.
- Department of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, 38-13, 3Beon-gil Dokjeom-ro, Namdong-gu, Incheon, 21565, Republic of Korea.
| | - Yeeun Lee
- Department of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, 38-13, 3Beon-gil Dokjeom-ro, Namdong-gu, Incheon, 21565, Republic of Korea
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Li SH, Li Y, Zhang MJ, An Q, Tao JN, Wang XH. Interaction Between Hypoxia-Inducible Factor 1-alpha Gene Polymorphism and Helicobacter pylori Infection on Gastric Cancer in a Chinese Tibetan Population. Biochem Genet 2024:10.1007/s10528-024-10776-8. [PMID: 38767822 DOI: 10.1007/s10528-024-10776-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 03/07/2024] [Indexed: 05/22/2024]
Abstract
To investigate the impact of four single nucleotide polymorphisms (SNPs) of the HIF1α gene and its interaction with Helicobacter pylori (H. pylori) infection on susceptibility to gastric cancer (GC).Logistic regression was used to test the relationship between four SNPs of HIF1α gene and the susceptibility of GC. A generalized multifactor dimensionality reduction (GMDR) model was used to assess the HIF1α gene-H. pylori infection interaction.Logistic regression analysis indicated that both the rs11549465-CT genotype and the T allele were associated with an increased risk of GC, adjusted OR (95% CI) were 1.63 (1.09-2.20) (CT vs. CC) and 1.70 (1.13-2.36) (T vs. C), respectively. We also found that both the rs11549467-A allele and rs11549467-GA genotype were associated with an increased risk of GC, and adjusted OR (95% CI) were 2.21 (1.61-2.86) (GA vs. GG), 2.13 (1.65-2.65) (A vs. G), respectively. However, no statistically significant impact of rs2057482 or rs1957757 on risk of GC was found. The GMDR model indicated a statistically significant two-dimensional model combination (including rs11549467 and H. pylori infection). The selected model had testing balanced accuracy of 0.60 and the best cross-validation consistencies of 10/10 (p = 0.0107). Compared with H. pylori infection negative participants with rs11549467-GG genotype, H. pylori positive participants with the rs11549467-GA genotype had the highest GC risk, the OR (95% CI) was 3.04 (1.98-4.12).The rs11549467-A allele and rs11549467-GA genotype was associated with increased GC risk. Additionally, the gene-environment interaction between HIF-1α-rs11549467 and H. pylori infection was also correlated with an increased risk of GC.
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Affiliation(s)
- Su-Hua Li
- Department of Gastroenterology, The Affiliated Hospital of Qinghai University, 29 Tongren Road, Xining, 810001, Qinghai, China.
| | - Yan Li
- Department of Gastroenterology, The Affiliated Hospital of Qinghai University, 29 Tongren Road, Xining, 810001, Qinghai, China
| | - Meng-Jun Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qinghai University, 29 Tongren Road, Xining, 810001, Qinghai, China
| | - Qi An
- Department of Gastroenterology, The Affiliated Hospital of Qinghai University, 29 Tongren Road, Xining, 810001, Qinghai, China
| | - Jia-Nan Tao
- Department of Gastroenterology, The Affiliated Hospital of Qinghai University, 29 Tongren Road, Xining, 810001, Qinghai, China
| | - Xue-Hong Wang
- Department of Gastroenterology, The Affiliated Hospital of Qinghai University, 29 Tongren Road, Xining, 810001, Qinghai, China
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Feng D, Wang J, Li D, Wu R, Tuo Z, Yu Q, Ye L, Miyamoto A, Yoo KH, Wang C, Cheng Y, Ye X, Zhang C, Wei W. Targeting Prolyl 4-Hydroxylase Subunit Beta (P4HB) in Cancer: New Roads to Travel. Aging Dis 2023; 15:2369-2380. [PMID: 38029391 PMCID: PMC11567247 DOI: 10.14336/ad.2023.1126] [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: 10/12/2023] [Accepted: 11/26/2023] [Indexed: 12/01/2023] Open
Abstract
Prolyl 4-hydroxylase subunit beta (P4HB) can catalyze the formation, breakage and rearrangement of disulfide bonds through two thioredoxin domains, which is important for the maintenance of oxidizing environment in endoplasmic reticulum. Recently, P4HB has been demonstrated its oncogenic role of tumorigenesis and development in cancers. Therefore, we comprehensively deciphered P4HB in human cancer from various aspects, including pan-cancer analysis and narrative summary. We also provided some possible interacted molecules and the top 10 predicted drugs targeting P4HB to contribute to future research. We proposed that P4HB was a potential target and brought new therapeutic opportunities for cancer patients.
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Affiliation(s)
- Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
- Chengdu Basebio Company, China.
| | - Jie Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Zhouting Tuo
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
| | - Qingxin Yu
- Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang, China.
| | - Luxia Ye
- Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
| | - Akira Miyamoto
- Department of Rehabilitation, West Kyushu University, Japan.
| | - Koo Han Yoo
- Department of Urology, Kyung Hee University, South Korea.
| | | | | | - Xing Ye
- Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Chi Zhang
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
| | - Wuran Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
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Wang F, Yu Z, Liu X, Hu F, Liu X, Fu X, Liu Y, Zou Z. A meta-analysis and bioinformatics analysis of P4HB expression levels in the prognosis of cancer patients. Pathol Res Pract 2023; 245:154474. [PMID: 37119730 DOI: 10.1016/j.prp.2023.154474] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 04/10/2023] [Accepted: 04/18/2023] [Indexed: 05/01/2023]
Abstract
BACKGROUND P4HB (prolyl 4-hydroxylase, beta polypeptide) is a human chromosomal gene that encodes an endoplasmic reticulum (ER) molecular chaperone protein with oxidoreductase, chaperone and isomerase activities. Recent studies indicated that P4HB may have clinical significance, with elevated P4HB expression reported in cancer patients, but its impact on tumor prognosis is not yet clear. To our knowledge, this is the first meta-analysis to show an association between P4HB expression and the prognosis of various cancers. METHODS We conducted a systematic literature search in the PubMed, PubMed Central, Web of Science, Embase, CNKI, Wanfang and Weipu databases, followed by a quantitative meta-analysis using Stata SE14.0 and R statistics software 4.2.1. The hazard ratio (HR) and relative risk (RR) were analyzed to evaluate the relationships of P4HB expression levels with overall survival (OS), disease-free survival (DFS), and clinicopathological parameters of cancer patients. Subsequently, P4HB expression in various cancer types was validated using the Gene Expression Profiling Interactive Analysis (GEPIA) online database. RESULTS Ten articles containing the data of 4121 cancer patients were included in the analysis, and a significant correlation of high P4HB expression with apparently shorter OS was found (HR, 1.90; 95% CI, 1.50-2.40; P < 0.01), while there was no significant correlation with gender (RR, 1.06; 95% CI, 0.91-1.22; P = 0.084), or age. Additionally, GEPIA online analysis revealed significant upregulation of P4HB in 13 types of cancer. Among them, P4HB overexpression was associated with shorter OS in 9 and worse DFS in 11 cancer types. CONCLUSIONS Upregulation of P4HB is correlated with worse prognosis in various cancers, which could provide new ideas for the development of P4HB-related diagnostic biomarkers and new therapeutic targets.
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Affiliation(s)
- Feiyang Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China; The First School of Clinical Medicine of Nanchang University, Jiangxi Medical College of Nanchang University, No.461 Bayi Avenue, Nanchang 330000, Jiangxi, People's Republic of China
| | - Zhixiang Yu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China
| | - Xiaohan Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China; The Second School of Clinical Medicine of Nanchang University, Jiangxi Medical College of Nanchang University, No.461 Bayi Avenue, Nanchang 330000, Jiangxi, People's Republic of China
| | - Feng Hu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China; The First School of Clinical Medicine of Nanchang University, Jiangxi Medical College of Nanchang University, No.461 Bayi Avenue, Nanchang 330000, Jiangxi, People's Republic of China
| | - Xiangjun Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China
| | - Xinyi Fu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China; The First School of Clinical Medicine of Nanchang University, Jiangxi Medical College of Nanchang University, No.461 Bayi Avenue, Nanchang 330000, Jiangxi, People's Republic of China
| | - Yan Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China; The Second School of Clinical Medicine of Nanchang University, Jiangxi Medical College of Nanchang University, No.461 Bayi Avenue, Nanchang 330000, Jiangxi, People's Republic of China
| | - Zhenhong Zou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi, People's Republic of China.
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Zhang L, Shi B, Hu M, Qian L. HIF-1α and Caspase-3 expression in aggressive papillary thyroid carcinoma. World J Surg Oncol 2022; 20:353. [PMID: 36329448 PMCID: PMC9635136 DOI: 10.1186/s12957-022-02815-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 10/16/2022] [Indexed: 11/06/2022] Open
Abstract
Background Tumor cells adapt to hypoxia by regulating transcription factors that involved in regulation of metabolism, angiogenesis, cell proliferation, and apoptosis. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1), consisting of HIF-1α and HIF-1β subunits, acts as a key transcription factor mediating the adaptive cellular responses. Caspase-3 is a key apoptosis-related protease that plays a role in tumor growth and development. Studies have shown that caspase-3 could be regulated by HIF-1α under pathological conditions. Therefore, HIF-1α and caspase-3 expression may be related to the poor prognosis of tumors. In this study, we analyzed the possible relationships between these two signaling factors in correlation with the clinical behavior of PTC. Methods We detected the expression levels of HIF-1α and caspase-3 in 70 samples of PTC and para-cancerous tissues (control group) by immunohistochemistry (IHC). Furthermore, various clinicopathological parameters were assessed to determine their correlations with HIF-1α and caspase-3 expressions. Results First, HIF-1α and caspase-3 expressions (60% and 37.1%, respectively) increased significantly in the PTC samples as compared to normal tissues (2.9% for both HIF-1α and caspase-3) (p < 0.05) as determined by IHC. Second, although there was no significant difference between the expression of HIF-1α and caspase-3 in regard to gender, age distribution, tumor size, lymph node metastasis, and BRAFV600E mutation (all p > 0.05), HIF-1α and caspase-3 expressions were associated with capsule invasion and cell subtypes of PTC (p < 0.05). The percent positivity of caspase-3 expression in tall-cell variant (TCV) was the highest (63.6%). Third, HIF-1α expression was positively correlated with that of caspase-3 (rs = 0.326; p < 0.05). Conclusions Overexpression of HIF-1α and caspase-3 is associated with carcinogenesis. These factors might serve as promising predictors of aggressive PTC. These findings also suggest their potential as therapeutic targets.
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Affiliation(s)
- Lili Zhang
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Baixue Shi
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Mingyang Hu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Linxue Qian
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Sun M, Qi S, Wu M, Xia W, Xiong H. Calreticulin as a prognostic biomarker and correlated with immune infiltrate in kidney renal clear cell carcinoma. Front Genet 2022; 13:909556. [PMID: 36338983 PMCID: PMC9633671 DOI: 10.3389/fgene.2022.909556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 10/05/2022] [Indexed: 01/29/2024] Open
Abstract
Background: Calreticulin (CALR) has been investigated in several malignant diseases and is associated with immune-cell infiltration. However, the prognostic value of CALR in kidney renal clear cell carcinoma (KIRC) is still unknown. Methods: Based on the computational analysis, data from 530 KIRC cases and 72 normal kidney samples from The Cancer Genome Atlas (TGCA-KIRC) database were analyzed in this study. The expression of CALR mRNA in pan-cancer and immune infiltrates was analyzed using the Tumor Immune Estimation Resource (TIMER) database. The CALR protein expression was obtained from the UALCAN and Human Protein Atlas (HPA) databases. Survival, functional, and statistical analyses were conducted using R software. Results: The CALR expression was higher in KIRC cases than in normal kidneys. A high CALR expression was correlated with TNM stage, pathological stage, and histological grade. Kaplan-Meier survival analysis showed that a high CALR expression was associated with poor overall survival, disease-specific survival, and progression-free interval. Gene set enrichment analysis (GSEA) indicated that CALR was enriched in IL-6 and IL-2 signaling, interferon signaling, TNF signaling, inflammatory response, apoptosis, and the p53 pathway. CALR is correlated with immune-infiltrating cells. A significant correlation was observed between CALR expression and immunomodulators. Conclusion: We identified CALR as a prognostic biomarker of KIRC. Meanwhile, the CALR expression associated with immune infiltration indicated that CALR might be a potential immunotherapy target for patients with KIRC.
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Affiliation(s)
| | | | | | | | - Hao Xiong
- Department of Hematology and Oncology, Wuhan Children’s Hospital, Tongji Medical College, HUST, Wuhan, China
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Piao H, Fu L, Wang Y, Liu Y, Wang Y, Meng X, Yang D, Xiao X, Zhang J. A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression. J Exp Clin Cancer Res 2022; 41:174. [PMID: 35562774 PMCID: PMC9107227 DOI: 10.1186/s13046-022-02366-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/17/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood. METHODS Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment. RESULTS Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient's pessimistic outcome. CONCLUSION Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.
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Affiliation(s)
- Haiyan Piao
- grid.412449.e0000 0000 9678 1884Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning China
| | - Lingfeng Fu
- grid.274841.c0000 0001 0660 6749Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 Japan
- grid.274841.c0000 0001 0660 6749Gastrointestinal Cancer Biology, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuxin Wang
- grid.417404.20000 0004 1771 3058Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- grid.274841.c0000 0001 0660 6749Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | - Yang Liu
- grid.412467.20000 0004 1806 3501Department of Oncology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004 Liaoning China
| | - Yue Wang
- grid.412449.e0000 0000 9678 1884Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning China
| | - Xiangyu Meng
- grid.412449.e0000 0000 9678 1884Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning China
| | - Dong Yang
- grid.412449.e0000 0000 9678 1884Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning China
| | - Xiang Xiao
- Shanghai Yanji Biomedical Technology, Shanghai, China
| | - Jun Zhang
- grid.274841.c0000 0001 0660 6749Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556 Japan
- grid.274841.c0000 0001 0660 6749Gastrointestinal Cancer Biology, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
- grid.412449.e0000 0000 9678 1884Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning China
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10
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Bakker EY, Fujii M, Krstic-Demonacos M, Demonacos C, Alhammad R. Protein disulfide isomerase A1‑associated pathways in the development of stratified breast cancer therapies. Int J Oncol 2022; 60:16. [PMID: 35014681 PMCID: PMC8776328 DOI: 10.3892/ijo.2022.5306] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/07/2021] [Indexed: 11/18/2022] Open
Abstract
The oxidoreductase protein disulfide isomerase A1 (PDIA1) functions as a cofactor for many transcription factors including estrogen receptor α (ERα), nuclear factor (NF)-κB, nuclear factor erythroid 2-like 2 (NRF2) and regulates the protein stability of the tumor suppressor p53. Taking this into account we hypothesized that PDIA1, by differentially modulating the gene expression of a diverse subset of genes in the ERα-positive vs. the ERα-negative breast cancer cells, might modify dissimilar pathways in the two types of breast cancer. This hypothesis was investigated using RNA-seq data from PDIA1-silenced MCF-7 (ERα-positive) and MDA-MB-231 (ERα-negative) breast cancer cells treated with either interferon γ (IFN-γ) or etoposide (ETO), and the obtained data were further analyzed using a variety of bioinformatic tools alongside clinical relevance assessment via Kaplan-Meier patient survival curves. The results highlighted the dual role of PDIA1 in suppressing carcinogenesis in the ERα(+) breast cancer patients by negatively regulating the response to reactive oxygen species (ROS) and promoting carcinogenesis by inducing cell cycle progression. In the ERα(−) breast cancer patients, PDIA1 prevented tumor development by modulating NF-κB and p53 activity and cell migration and induced breast cancer progression through control of cytokine signaling and the immune response. The findings reported in this study shed light on the differential pathways regulating carcinogenesis in ERα(+) and ERα(−) breast cancer patients and could help identify therapeutic targets selectively effective in ERα(+) vs. ERα(−) patients.
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Affiliation(s)
- Emyr Yosef Bakker
- School of Medicine, University of Central Lancashire, Preston, Lancashire PR1 2HE, UK
| | - Masayuki Fujii
- Department of Biological and Environmental Chemistry, Faculty of Humanity Oriented Science and Engineering, Kindai University, Iizuka, Fukuoka 820‑8555, Japan
| | | | - Constantinos Demonacos
- Faculty of Biology Medicine and Health, School of Health Science, Division of Pharmacy and Optometry, University of Manchester, Manchester M13 9PT, UK
| | - Rashed Alhammad
- Faculty of Biology Medicine and Health, School of Health Science, Division of Pharmacy and Optometry, University of Manchester, Manchester M13 9PT, UK
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11
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Hypoxia associated lncRNA HYPAL promotes proliferation of gastric cancer as ceRNA by sponging miR-431-5p to upregulate CDK14. Gastric Cancer 2022; 25:44-63. [PMID: 34247316 DOI: 10.1007/s10120-021-01213-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is a common malignant solid tumor that is characterized by high hypoxia. The transcription of genes associated with hypoxia affects tumor occurrence and development. Long non-coding RNAs (lncRNAs) have been reported to play important roles in cancer development. In this study, we screened for differentially expressed ncRNAs (non-coding RNA) and mRNAs between hypoxia-inducible factor-1 (HIF-1α) knockdown GC cells and scrambled GC cells. Microarray data revealed that HIF-1α regulated the expression of LINC01355 (Hypoxia Yield Proliferation Associated LncRNA, HYPAL). HYPAL was found to be significantly upregulated in GC cells and tissues and was correlated with poor GC prognosis. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays revealed that HIF-1α promoted HYPAL expression by binding the promoter region. A regulatory network for the competing endogenous RNA (ceRNA) was constructed using bioinformatics tools. Mechanistic studies revealed that HYPAL acted as a ceRNA of miR-431-5p to regulate CDK14 expression. Carcinogenic effects of HYPAL were evaluated in vitro and in vivo. The HIF-1α/HYPAL/miR-431-5p/CDK14 (Cyclin-dependent kinase 14) axis activated the Wnt/β-catenin signaling pathway and induced GC cell proliferation while inhibiting apoptosis. In conclusion, HYPAL is a potential molecular target for GC therapy.
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12
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Abd Allah M, Soliman A. Evaluation of prolyl-4-hydroxylase subunit beta and special AT-rich region-binding protein-1 immunoexpression in bladder transitional-cell carcinoma. EGYPTIAN JOURNAL OF PATHOLOGY 2022; 42:28. [DOI: 10.4103/egjp.egjp_7_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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13
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Arjmand MH, Moradi A, Rahimi HR, Es-haghi A, Akbari A, Hadipanah MR, Afshar J, Mehrad-Majd H. Prognostic value of HIF-1α in digestive system malignancies: evidence from a systematic review and meta-analysis. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2022; 15:108-119. [PMID: 35845307 PMCID: PMC9275741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/27/2022] [Indexed: 11/08/2022]
Abstract
Aim This meta-analysis aimed to evaluate the association of HIF-1α expression with clinicopathological features and overall survival (OS) of patients with digestive system malignancies. Background Numerous studies have demonstrated that hypoxia-inducible factor-1α (HIF-1α) is abnormally expressed in various solid tumors. However, the clinicopathological features and prognostic value of HIF-1α expression in patients with digestive system malignancies remain controversial. Methods A literature search in PubMed, Web of Science, and Scopus databases was performed to identify all relevant studies published in English until 15 October 2020. The pooled effect was calculated to evaluate the association between HIF-1α expression and clinicopathological features and overall survival in cancer patients. Pooled odds ratios (ORs) or hazard ratios (HRs) with a 95% confidence interval (CI) were calculated using fixed- or random-effects model based on between-study heterogeneity. Results A total of 44 eligible studies with 5,964 patients were included. The pooled results indicated a positive association of HIF-1α overexpression with poor overall survival (OS) (HR=1.990, 95% CI: 1.615-2.453, p<0.001) and disease-free survival (DFS) (HR=1.90, 95% CI: 1.084-3.329, p=0.043). Meta-analysis results showed that HIF-1α level expression was significantly associated with positive lymph node metastasis (OR=1.869, 95% CI: 1.488-2.248, p<0.001), distance metastasis (OR=2.604, 95% CI: 1.500-4.519, p<0.001), tumor stage (OR=1.801, 95% CI: 1.437-2.257, p<0.001) and tumor size (OR=1.392. 95% CI: 1.068-1.815, p=0.014). Conclusion This meta-data suggest that HIF-1α expression might serve as an independent prognostic marker and a promising therapeutic target in patients with digestive system malignancies.
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Affiliation(s)
- Mohammad-Hassan Arjmand
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Ali Moradi
- Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid-Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Es-haghi
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Hadipanah
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jalil Afshar
- Department of Biochemistry, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Hassan Mehrad-Majd
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Wu P, Xiang T, Wang J, Lv R, Ma S, Yuan L, Wu G, Che X. Identification of immunization-related new prognostic biomarkers for papillary renal cell carcinoma by integrated bioinformatics analysis. BMC Med Genomics 2021; 14:241. [PMID: 34620162 PMCID: PMC8499437 DOI: 10.1186/s12920-021-01092-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 09/21/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Despite papillary renal cell carcinoma (pRCC) being the second most common type of kidney cancer, the underlying molecular mechanism remains unclear. Targeted therapies in the past have not been successful because of the lack of a clear understanding of the molecular mechanism. Hence, exploring the underlying mechanisms and seeking novel biomarkers for pursuing a precise prognostic biomarker and appropriate therapies are critical. MATERIAL AND METHODS In our research, the differentially expressed genes (DEGs) were screened from the TCGA and GEO databases, and a total of 149 upregulated and 285 downregulated genes were sorted. This was followed by construction of functional enrichment and protein-protein interaction (PPI) network, and then the top 15 DEGs were selected for further analysis. The P4HB gene was chosen as our target gene by repetitively validating multiple datasets, and higher levels of P4HB expression predicted lower overall survival (OS) in patients with pRCC. RESULTS We found that P4HB not only connects with immune cell infiltration and co-expression with PD-1, PD-L2, and CTLA-4, but also has a strong connection with the newly discovered hot gene, TOX. CONCLUSION We speculate that P4HB is a novel gene involved in the progression of pRCC through immunomodulation.
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Affiliation(s)
- Ping Wu
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Tingting Xiang
- Department of Rehabilitation, Liguang Rehabilitation Hospital of Dalian Development Zone, Dalian, 116600, China
| | - Jing Wang
- Department of Neurobiology, Harbin Medical University, Harbin, 150086, China
| | - Run Lv
- Department of Anesthesiology, Dalian Medical University, Dalian, 116044, China
| | - Shaoxin Ma
- Department of Anesthesiology, Dalian Medical University, Dalian, 116044, China
| | - Limei Yuan
- Department of Anesthesiology, Dalian Medical University, Dalian, 116044, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
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15
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Zhou HC, Xin-Yan Yan, Yu WW, Liang XQ, Du XY, Liu ZC, Long JP, Zhao GH, Liu HB. Lactic acid in macrophage polarization: The significant role in inflammation and cancer. Int Rev Immunol 2021; 41:4-18. [PMID: 34304685 DOI: 10.1080/08830185.2021.1955876] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Metabolite lactic acid has always been regarded as a metabolic by-product rather than a bioactive molecule. Recently, this view has changed since it was discovered that lactic acid can be used as a signal molecule and has novel signal transduction functions both intracellular and extracellular, which can regulate key functions in the immune system. In recent years, more and more evidence has shown that lactic acid is closely related to the metabolism and polarization of macrophages. During inflammation, lactic acid is a regulator of macrophage metabolism, and it can prevent excessive inflammatory responses; In malignant tumors, lactic acid produced by tumor tissues promotes the polarization of tumor-associated macrophages, which in turn promotes tumor progression. In this review, we examined the relationship between lactic acid and macrophage metabolism. We further discussed how lactic acid plays a role in maintaining the homeostasis of macrophages, as well as the biology of macrophage polarization and the M1/M2 imbalance in human diseases. Potential methods to target lactic acid in the treatment of inflammation and cancer will also be discussed so as to provide new strategies for the treatment of diseases.
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Affiliation(s)
- Hai-Cun Zhou
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Xin-Yan Yan
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China
| | - Wen-Wen Yu
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Xiao-Qin Liang
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Xiao-Yan Du
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China
| | - Zhi-Chang Liu
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
| | - Jian-Ping Long
- Department of Breast Surgery, Gansu Maternal and Child Health Care Hospital, Lanzhou, Gansu Province, P. R. China
| | - Guang-Hui Zhao
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, P. R. China
| | - Hong-Bin Liu
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, P.R. China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, P.R.China
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16
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Mao R, Liu K, Zhao N, Guo P, Wu Y, Wang Z, Liu Y, Zhang T. Clinical significance and prognostic role of an immune-related gene signature in gastric adenocarcinoma. Aging (Albany NY) 2021; 13:17734-17767. [PMID: 34247148 PMCID: PMC8312416 DOI: 10.18632/aging.203266] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 05/11/2021] [Indexed: 12/13/2022]
Abstract
Limited progress has been made in the treatment of gastric adenocarcinoma (GAC) in recent years, but the potential of immunotherapy in GAC is worthy of consideration. The purpose of this study was to develop a reliable, personalized signature based on immune genes to predict the prognosis of GAC. Here, we identified two groups of patients with significantly different prognoses by performing unsupervised clustering analysis of The Cancer Genome Atlas (TCGA) database based on 881 immune genes. The immune signature was constructed with a training set composed of 350 GAC samples from the TCGA and subsequently validated with 431 samples from GSE84437, 432 samples from GSE26253, and 145 GAC samples from real-time quantitative reverse transcription polymerase chain reaction data. This classification system can also be used to predict prognosis in different clinical subgroups. Further analysis suggested that high-risk patients were characterized by low immune scores, distinctive immune cell proportions, different immune checkpoint profiles, and a low tumor mutational burden. Ultimately, the signature was identified as an independent prognostic factor. In general, the signature can accurately predict recurrence and overall survival in patients with GAC and may serve as a powerful prognostic tool to further optimize cancer immunotherapy.
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Affiliation(s)
- Rui Mao
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University and The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610031, China.,Affiliated Hospital of Southwest Jiaotong University, Chengdu 610036, China
| | - Kehao Liu
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University and The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610031, China
| | - Nana Zhao
- Department of Operating Room, The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Pengsen Guo
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University and The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610031, China
| | - Yingxin Wu
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University and The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610031, China
| | - Zheng Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yanjun Liu
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University and The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610031, China.,Affiliated Hospital of Southwest Jiaotong University, Chengdu 610036, China
| | - Tongtong Zhang
- Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University and The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu 610031, China.,Affiliated Hospital of Southwest Jiaotong University, Chengdu 610036, China.,Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China
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17
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Shi R, Gao S, Zhang J, Xu J, Graham LM, Yang X, Li C. Collagen prolyl 4-hydroxylases modify tumor progression. Acta Biochim Biophys Sin (Shanghai) 2021; 53:805-814. [PMID: 34009234 DOI: 10.1093/abbs/gmab065] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Indexed: 12/12/2022] Open
Abstract
Collagen is the main component of the extracellular matrix. Hydroxylation of proline residues on collagen, catalyzed by collagen prolyl 4-hydroxylase (C-P4H), is essential for the stability of the collagen triple helix. Vertebrate C-P4H is an α2β2 tetramer with three isoenzymes differing in the catalytic α-subunits, which are encoded by P4HA1, P4HA2, and P4HA3 genes. In contrast, β-subunit is encoded by a single gene P4HB. The expressions of P4HAs and P4HB are regulated by multiple cellular factors, including cytokines, transcription factors, and microRNAs. P4HAs and P4HB are highly expressed in many tumors and participate in cancer progression. Several inhibitors of P4HAs and P4HB have been confirmed to have anti-tumor effects, suggesting that targeting C-P4H is a feasible strategy for cancer treatment. Here, we summarize recent progresses on the function and expression of regulatory mechanisms of C-P4H in cancer progression and point out the potential development of therapeutic strategies in targeting C-P4H in the future.
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Affiliation(s)
- Run Shi
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| | - Shanshan Gao
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| | - Jie Zhang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
| | - Jiang Xu
- Department of Stomatology, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi 832008, China
| | - Linda M Graham
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Xiaowen Yang
- Department of the First Abdominal Surgery, The Affiliated Tumor Hospital of Nanchang University, Jiangxi Cancer Center, Nanchang 330029, China
| | - Chaoyang Li
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 510095, China
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18
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Zhao Q, Xie J, Xie J, Zhao R, Song C, Wang H, Rong J, Yan L, Song Y, Wang F, Xie Y. Weighted correlation network analysis identifies FN1, COL1A1 and SERPINE1 associated with the progression and prognosis of gastric cancer. Cancer Biomark 2021; 31:59-75. [PMID: 33780362 DOI: 10.3233/cbm-200594] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most deadliest tumours worldwide, and its prognosis remains poor. OBJECTIVE This study aims to identify and validate hub genes associated with the progression and prognosis of GC by constructing a weighted correlation network. METHODS The gene co-expression network was constructed by the WGCNA package based on GC samples and clinical data from the TCGA database. The module of interest that was highly related to clinical traits, including stage, grade and overall survival (OS), was identified. GO and KEGG pathway enrichment analyses were performed using the clusterprofiler package in R. Cytoscape software was used to identify the 10 hub genes. Differential expression and survival analyses were performed on GEPIA web resources and verified by four GEO datasets and our clinical gastric specimens. The receiver operating characteristic (ROC) curves of hub genes were plotted using the pROC package in R. The potential pathogenic mechanisms of hub genes were analysed using gene set enrichment analysis (GSEA) software. RESULTS A total of ten modules were detected, and the magenta module was identified as highly related to OS, stage and grade. Enrichment analysis of magenta module indicated that ECM-receptor interaction, focal adhesion, PI3K-Akt pathway, proteoglycans in cancer were significantly enriched. The PPI network identified ten hub genes, namely COL1A1, COL1A2, FN1, POSTN, THBS2, COL11A1, SPP1, MMP13, COMP, and SERPINE1. Three hub genes (FN1, COL1A1 and SERPINE1) were finally identified to be associated with carcinogenicity and poor prognosis of GC, and all were independent risk factors for GC. The area under the curve (AUC) values of FN1, COL1A1 and SERPINE1 for the prediction of GC were 0.702, 0.917 and 0.812, respectively. GSEA showed that three hub genes share 15 common upregulated biological pathways, including hypoxia, epithelial mesenchymal transition, angiogenesis, and apoptosis. CONCLUSION We identified FN1, COL1A1 and SERPINE1 as being associated with the progression and poor prognosis of GC.
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Affiliation(s)
- Qiaoyun Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China.,Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Jun Xie
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China.,Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Jinliang Xie
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Rulin Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Conghua Song
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Huan Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Jianfang Rong
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Lili Yan
- Laboratory of Biochemistry and Molecular Biology, Jiangxi Institute of Medical Sciences, Donghu District, Nanchang, Jiangxi, China
| | - Yanping Song
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Fangfei Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
| | - Yong Xie
- Department of Gastroenterology, First Affiliated Hospital of Nanchang University, Donghu District, Nanchang, Jiangxi, China
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19
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Gao X, Wang Y, Lu F, Chen X, Yang D, Cao Y, Zhang W, Chen J, Zheng L, Wang G, Fu M, Ma L, Song Y, Zhan Q. Extracellular vesicles derived from oesophageal cancer containing P4HB promote muscle wasting via regulating PHGDH/Bcl-2/caspase-3 pathway. J Extracell Vesicles 2021; 10:e12060. [PMID: 33732415 PMCID: PMC7944388 DOI: 10.1002/jev2.12060] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 11/18/2020] [Accepted: 01/05/2021] [Indexed: 02/05/2023] Open
Abstract
Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC) and associated with their poor prognosis. However, its underlying mechanisms remain elusive. Here, we developed an ESCC‐induced cachexia mouse model using human xenograft ESCC cell lines and found that ESCC‐derived extracellular vesicles (EVs) containing prolyl 4‐hydroxylase subunit beta (P4HB) induced apoptosis of skeletal muscle cells. We further identified that P4HB promoted apoptotic response through activating ubiquitin‐dependent proteolytic pathway and regulated the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent antiapoptotic protein Bcl‐2. Additionally, we proved that the P4HB inhibitor, CCF642, not only rescued apoptosis of muscle cells in vitro, but also prevented body weight loss and muscle wasting in ESCC‐induced cachexia mouse model. Overall, these findings demonstrate a novel pathway for ESCC‐induced muscle wasting and advocate for the development of P4HB as a potential intervention target for cachexia in patients with ESCC.
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Affiliation(s)
- Xiaohan Gao
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
| | - Fang Lu
- Department of Ophthalmology West China Hospital Sichuan University Chengdu China
| | - Xu Chen
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Di Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
| | - Yiren Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
| | - Weimin Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
| | - Jie Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
| | - Leilei Zheng
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Guangchao Wang
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Ming Fu
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Liying Ma
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Yongmei Song
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Qimin Zhan
- State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China.,Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing China
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McAleese CE, Choudhury C, Butcher NJ, Minchin RF. Hypoxia-mediated drug resistance in breast cancers. Cancer Lett 2020; 502:189-199. [PMID: 33278499 DOI: 10.1016/j.canlet.2020.11.045] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/23/2020] [Accepted: 11/26/2020] [Indexed: 02/07/2023]
Abstract
Tissue hypoxia in solid tumors is caused by several pathological changes associated with tumor growth, including altered microvasculature structure, increased diffusional distances, and tumor-associated anemia. As the oxygen tension decreases, tumor cells adapt to the limited oxygen supply. Previous studies have shown that such adaptation leads to an aggressive phenotype that is resistant to many anti-cancer therapies. Induction of hypoxia inducible factors (HIFs) mediates many proteomic and genomic changes associated with tumor hypoxia. In breast cancers, HIFs not only predict poor prognosis, but also promote metastasis and drug resistance. Several studies have proposed HIF-1α as a druggable target in drug-resistant breast cancers, leading to the synthesis and development of small molecule inhibitors. Disappointingly, however, none of these small molecule inhibitors have progressed to clinical use. In this review, we briefly discuss the role of HIF-1α in breast cancer drug resistance and summarize the current and future approaches to targeting this transcription factor in breast cancer treatment.
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Affiliation(s)
- Courtney E McAleese
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Chandra Choudhury
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Neville J Butcher
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Rodney F Minchin
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
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Zhang J, Piao HY, Wang Y, Lou MY, Guo S, Zhao Y. Development and validation of a three-long noncoding RNA signature for predicting prognosis of patients with gastric cancer. World J Gastroenterol 2020; 26:6929-6944. [PMID: 33311941 PMCID: PMC7701940 DOI: 10.3748/wjg.v26.i44.6929] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/06/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most frequently diagnosed gastrointestinal cancers throughout the world. Novel prognostic biomarkers are required to predict the prognosis of GC.
AIM To identify a multi-long noncoding RNA (lncRNA) prognostic model for GC.
METHODS Transcriptome data and clinical data were downloaded from The Cancer Genome Atlas. COX and least absolute shrinkage and selection operator regression analyses were performed to screen for prognosis associated lncRNAs. Receiver operating characteristic curve and Kaplan-Meier survival analyses were applied to evaluate the effectiveness of the model.
RESULTS The prediction model was established based on the expression of AC007991.4, AC079385.3, and AL109615.2 Based on the model, GC patients were divided into “high risk” and “low risk” groups to compare the differences in survival. The model was re-evaluated with the clinical data of our center.
CONCLUSION The 3-lncRNA combination model is an independent prognostic factor for GC.
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Affiliation(s)
- Jun Zhang
- Department of Gastric Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Hai-Yan Piao
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yue Wang
- Department of Gastric Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Mei-Yue Lou
- Department of Gastroenterological Surgery, Kumamoto University, Graduate School of Medical Sciences, Kumamoto 860-8556, Kumamoto, Japan
| | - Shuai Guo
- Department of Gastric Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yan Zhao
- Department of Gastric Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
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Mao R, Wang Z, Zhang Y, Chen Y, Liu Q, Zhang T, Liu Y. Development and validation of a novel prognostic signature in gastric adenocarcinoma. Aging (Albany NY) 2020; 12:22233-22252. [PMID: 33188157 PMCID: PMC11623975 DOI: 10.18632/aging.104161] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/27/2020] [Indexed: 11/25/2022]
Abstract
Competing endogenous RNA networks have attracted increasing attention in gastric adenocarcinoma (GA). The current study aimed to explore ceRNA-based prognostic biomarkers for GA. RNA expression profiles were downloaded from TCGA and GEO databases. A ceRNA network was constructed based on the most relevant modules in the weighted gene coexpression network analysis. Kaplan-Meier (KM) survival analysis revealed prognosis-related RNAs, which were subjected to the multivariate Cox regression analysis. The predictive accuracy and discriminative ability of the signature were determined by KM analyses, receiver operating characteristic curves and area under the curve values. Ultimately, we constructed a ceRNA network consisting of 55 lncRNAs, 17 miRNAs and 73 mRNAs. Survival analyses revealed 3 lncRNAs (LINC01106, FOXD2-AS1, and AC103702.2) and 3 mRNAs (CCDC34, ORC6, and SOX4) as crucial prognostic factors; these factors were then used to construct a survival specific ceRNA network. Patients with high risk scores exhibited significantly worse overall survival than patients with low risk scores, and the AUC for 5-year survival was 0.801. A total of 112 GA specimens and the GSE84437 dataset were used to successfully validate the robustness of our signature by qRT-PCR. In summary, we developed a prognostic signature for GA, that shows better accuracy than the traditional TNM pathological staging system.
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Affiliation(s)
- Rui Mao
- Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610036, China
| | - Zheng Wang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yuanchuan Zhang
- The Center of Gastrointestinal and Minimally Invasive Surgery, The Third People’s Hospital of Chengdu, Chengdu, 610031, China
| | - YuanYuan Chen
- Department of Pathology, The Third People’s Hospital of Chengdu, Chengdu, 610031, China
| | - Qian Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Tongtong Zhang
- Medical Research Center, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, Sichuan, China
| | - Yanjun Liu
- Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610036, China
- The Center of Gastrointestinal and Minimally Invasive Surgery, The Third People’s Hospital of Chengdu, Chengdu, 610031, China
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Zhang J, Piao HY, Wang Y, Meng XY, Yang D, Zhao Y, Zheng ZC. To Develop and Validate the Combination of RNA Methylation Regulators for the Prognosis of Patients with Gastric Cancer. Onco Targets Ther 2020; 13:10785-10795. [PMID: 33122917 PMCID: PMC7591098 DOI: 10.2147/ott.s276239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 09/16/2020] [Indexed: 12/12/2022] Open
Abstract
Background Gastric cancer (GC) accounts for high mortality. RNA methylation has recently gained interest as markers in specific tumors. This study aimed to uncover the function of the roles of 25 RNA methylation regulators in GC. Methods RNA sequence and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. “STRING” and R were performed to analyze the correlation among the methylase. COX and LASSO were performed to screen for prognostic associated RNA methylation regulators. A prognostic model was established based on the expression of methylase. RT-PCR and immunohistochemistry detected the expression of methylase in GC cells and tissue. Kaplan–Meier curve and Cox analysis were applied to evaluate the effectiveness of the model. Results The prediction model was established based on the expression of m6A RNA methylation regulators FTO (fat mass and obesity-associated) and RBM15 (RNA binding motif protein 15). Based on the model, GC patients were divided into “high risk” and “low risk” groups to compare the differences in survival. The model was re-evaluated with the clinical data of our center. Conclusion The two-methylase combination model was an independent prognostic factor of GC.
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Affiliation(s)
- Jun Zhang
- Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
| | - Hai-Yan Piao
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
| | - Yue Wang
- Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
| | - Xiang-Yu Meng
- Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
| | - Dong Yang
- Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
| | - Yan Zhao
- Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
| | - Zhi-Chao Zheng
- Gastric Cancer Department, Liaoning Province Cancer Hospital & Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province 110042, People's Republic of China
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Stojak M, Milczarek M, Kurpinska A, Suraj-Prazmowska J, Kaczara P, Wojnar-Lason K, Banach J, Stachowicz-Suhs M, Rossowska J, Kalviņš I, Wietrzyk J, Chlopicki S. Protein Disulphide Isomerase A1 Is Involved in the Regulation of Breast Cancer Cell Adhesion and Transmigration via Lung Microvascular Endothelial Cells. Cancers (Basel) 2020; 12:cancers12102850. [PMID: 33023153 PMCID: PMC7601413 DOI: 10.3390/cancers12102850] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/29/2020] [Accepted: 09/30/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer cell cross-talk with the host endothelium plays a crucial role in metastasis, but the underlying mechanisms are still not fully understood. We studied the involvement of protein disulphide isomerase A1 (PDIA1) in human breast cancer cell (MCF-7 and MDA-MB-231) adhesion and transendothelial migration. For comparison, the role of PDIA1 in proliferation, migration, cell cycle and apoptosis was also assessed. Pharmacological inhibitor, bepristat 2a and PDIA1 silencing were used to inhibit PDIA1. Inhibition of PDIA1 by bepristat 2a markedly decreased the adhesion of breast cancer cells to collagen type I, fibronectin and human lung microvascular endothelial cells. Transendothelial migration of breast cancer cells across the endothelial monolayer was also inhibited by bepristat 2a, an effect not associated with changes in ICAM-1 expression or changes in cellular bioenergetics. The silencing of PDIA1 produced less pronounced anti-adhesive effects. However, inhibiting extracellular free thiols by non-penetrating blocker p-chloromercuribenzene sulphonate substantially inhibited adhesion. Using a proteomic approach, we identified that β1 and α2 integrins were the most abundant among all integrins in breast cancer cells as well as in lung microvascular endothelial cells, suggesting that integrins could represent a target for PDIA1. In conclusion, extracellular PDIA1 plays a major role in regulating the adhesion of cancer cells and their transendothelial migration, in addition to regulating cell cycle and caspase 3/7 activation by intracellular PDIA1. PDIA1-dependent regulation of cancer-endothelial cell interactions involves disulphide exchange and most likely integrin activation but is not mediated by the regulation of ICAM-1 expression or changes in cellular bioenergetics in breast cancer or endothelial cells.
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Affiliation(s)
- Marta Stojak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland; (M.S.); (A.K.); (J.S.-P.); (P.K.); (K.W.-L.)
| | - Magdalena Milczarek
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.M.); (J.B.); (M.S.-S.); (J.R.)
| | - Anna Kurpinska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland; (M.S.); (A.K.); (J.S.-P.); (P.K.); (K.W.-L.)
| | - Joanna Suraj-Prazmowska
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland; (M.S.); (A.K.); (J.S.-P.); (P.K.); (K.W.-L.)
| | - Patrycja Kaczara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland; (M.S.); (A.K.); (J.S.-P.); (P.K.); (K.W.-L.)
| | - Kamila Wojnar-Lason
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland; (M.S.); (A.K.); (J.S.-P.); (P.K.); (K.W.-L.)
- Department of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland
| | - Joanna Banach
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.M.); (J.B.); (M.S.-S.); (J.R.)
| | - Martyna Stachowicz-Suhs
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.M.); (J.B.); (M.S.-S.); (J.R.)
| | - Joanna Rossowska
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.M.); (J.B.); (M.S.-S.); (J.R.)
| | - Ivars Kalviņš
- Laboratory of Carbofunctional Compounds, Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia;
| | - Joanna Wietrzyk
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.M.); (J.B.); (M.S.-S.); (J.R.)
- Correspondence: (J.W.); (S.C.)
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 30-348 Krakow, Poland; (M.S.); (A.K.); (J.S.-P.); (P.K.); (K.W.-L.)
- Department of Pharmacology, Jagiellonian University Medical College, 31-531 Krakow, Poland
- Correspondence: (J.W.); (S.C.)
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Wang X, Bai Y, Zhang F, Yang Y, Feng D, Li A, Yang Z, Li D, Tang Y, Wei X, Wei W, Han P. Targeted Inhibition of P4HB Promotes Cell Sensitivity to Gemcitabine in Urothelial Carcinoma of the Bladder. Onco Targets Ther 2020; 13:9543-9558. [PMID: 33061438 PMCID: PMC7532080 DOI: 10.2147/ott.s267734] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 08/15/2020] [Indexed: 02/05/2023] Open
Abstract
Background Bladder cancer (BC) is a common malignancy worldwide that accounts for 3% of global cancer diagnoses. Chemotherapy resistance limits the therapeutic effect of chemotherapeutic agents in patients with BC. Prolyl 4-hydroxylase, beta polypeptide (P4HB) is an endoplasmic reticulum (ER) chaperone that is upregulated in bladder cancer tissues (The Cancer Genome Atlas, TCGA datasets). Knockdown or suppression of P4HB exerts anticancer activity and sensitizes cells to chemotherapy in various types of cancer. Purpose We aimed to investigate whether the inhibition of P4HB enhances the anticancer efficacy of gemcitabine (GEM) in BC cells and to study the underlying molecular mechanisms. Patients and Methods The P4HB mRNA expression levels of 411 BC patients from the TCGA database and P4HB expression level of eighty BC paraffin-embedded samples detected by immunohistochemistry (IHC) staining were used for clinical feature and prognostic analyses. Bioinformatics analysis was utilized for the mechanistic investigation. Highly P4HB-expressed BC cell lines (T24 and 5637) treated with P4HB inhibitor (Bacitracin, BAC) were used to study the effects of BAC on the sensitivity of BC cells to GEM and the potential mechanism. P4HB inhibition experiments were performed in highly P4HB-expressed BC cells, and cell viability, colony formation, cell cycle, reactive oxygen species (ROS), apoptosis and pathway proteins were assessed in T24 and 5637 cells. Results Western blot analysis showed that P4HB expression was significantly higher in BC tissues than in paired normal tissues. IHC showed that patients with high P4HB expression had a poorer overall survival (OS) rate than those with low P4HB expression. Furthermore, increased P4HB expression was demonstrated to be an independent prognostic marker for BC. Functionally, P4HB inhibition by BAC decreased the cell proliferation ability in vitro. Moreover, BAC treatment sensitized BC cells to GEM. Molecular mechanism analysis indicated that inhibition of P4HB by BAC treatment enhanced the anticancer effects of GEM through increasing cellular ROS content and promoting cell apoptosis and PERK/eIF2α/ATF4/CHOP signaling. Conclusion High P4HB expression was significantly correlated with poor prognosis in BC patients. Inhibition of P4HB by BAC decreased the cell proliferation ability and sensitized BC cells to GEM by activating apoptosis and the PERK/eIF2α/ATF4/CHOP pathways.
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Affiliation(s)
- Xiaoming Wang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Yunjin Bai
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Facai Zhang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Yubo Yang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Dechao Feng
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Ao Li
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Zhiqiang Yang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Dengxiong Li
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Yin Tang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Xin Wei
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Wuran Wei
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
| | - Ping Han
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People's Republic of China
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Lyu L, Xiang W, Zheng F, Huang T, Feng Y, Yuan J, Zhang C. Significant Prognostic Value of the Autophagy-Related Gene P4HB in Bladder Urothelial Carcinoma. Front Oncol 2020; 10:1613. [PMID: 32903592 PMCID: PMC7438560 DOI: 10.3389/fonc.2020.01613] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/24/2020] [Indexed: 01/01/2023] Open
Abstract
While hundreds of consistently altered autophagy-related genes (ARGs) have been identified in cancers, their prognostic value in bladder urothelial carcinoma (BUC) remains unclear. In the present study, we collected 232 ARGs from the Human Autophagy Database (HADb), and identified 37 differentially expressed ARGs in BUC based on The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis based on the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that among the 37 differentially expressed ARGs, prolyl 4-hydroxylase, beta polypeptide (P4HB), and regulator of G protein signaling 19 (RGS19) were significantly negatively correlated with overall survival (OS) and disease-free survival (DFS). Overexpression of P4HB and RGS19 in BUC was further validated using independent data sets, including those from the Oncomine and Gene Expression Omnibus (GEO) databases. cBioPortal and UALCAN analyses indicated that altered P4HB and RGS19 mRNA expression was significantly associated with mutations and clinical characteristics (nodal metastasis and cancer stage). Moreover, co-expression network analysis and gene set enrichment analysis (GSEA) predicted that the potential functions of P4HB and RGS19 are involved in the endoplasmic reticulum (ER) stress response, cytokine-mediated signaling pathway and inflammatory response. More importantly, multivariate Cox proportional hazards regression analysis demonstrated that P4HB, but not RGS19, is an independent and unfavorable BUC biomarker based on clinical characteristics (age, gender, cancer stage, and pathological TNM stage). Finally, we validated that the mRNA and protein expression levels of P4HB were upregulated in four bladder cancer cell lines (T24, J82, EJ, and SW780) and found that knockdown of P4HB dramatically inhibited the invasion and proliferation of bladder cancer cells. In summary, our study screened ARGs and identified P4HB as a biomarker that can predict the progression and prognosis of BUC and may provide a better understanding of the autophagy regulatory mechanisms involved in BUC.
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Affiliation(s)
- Lei Lyu
- Department of Urology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Xiang
- Department of Urology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Fuxin Zheng
- Department of Urology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Huang
- Department of Urology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Feng
- Department of Pathology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jingdong Yuan
- Department of Urology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Chuanhua Zhang
- Department of Urology, Wuhan No.1 Hospital, Huazhong University of Science and Technology, Wuhan, China
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27
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Huang B, Zhou Z, Liu J, Wu X, Li X, He Q, Zhang P, Tang X. The role of monoamine oxidase A in HPV-16 E7-induced epithelial-mesenchymal transition and HIF-1α protein accumulation in non-small cell lung cancer cells. Int J Biol Sci 2020; 16:2692-2703. [PMID: 32792865 PMCID: PMC7415426 DOI: 10.7150/ijbs.46966] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/23/2020] [Indexed: 12/19/2022] Open
Abstract
Our previous studies have found that human papillomavirus (HPV)-16 E7 oncoprotein promotes epithelial-mesenchymal transition (EMT) and hypoxia-inducible factor-1α (HIF-1α) protein accumulation in non-small cell lung cancer (NSCLC) cells and monoamine oxidase A (MAOA) is highly expressed in NSCLC tissues. Here, we further explored the role of MAOA in HPV-16 E7-induced EMT and HIF-1α protein accumulation in A549 and NCI-H460 NSCLC cells. Our results showed that HPV-16 E7 enhanced MAOA expression in NSCLC cells. Additionally, MAOA knockout inhibited HPV-16 E7-induced migration, invasion, and EMT, and significantly reduced HPV-16 E7-induced ROS generation and HIF-1α protein accumulation via promoting its degradation. Furthermore, MAOA knockout suppressed HPV-16 E7-induced ERK1/2 activation. In vivo, MAOA knockout inhibited tumor growth, metastasis, and the expression of EMT-related markers and HIF-1α proteins induced by HPV-16 E7 in NCI-H460 NSCLC subcutaneous xenograft and in situ intrapulmonary models of nude mice. Taken together, our findings provide evidence that MAOA plays a key role in EMT and HIF-1α protein accumulation induced by HPV-16 E7 in NSCLC cells, suggesting that MAOA may be a potential therapeutic target for HPV-related NSCLC.
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Affiliation(s)
- Bingyu Huang
- Institute of Biochemistry and Molecular Biology, Collaborative innovation center for antitumor active substance research and development, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Zhiyuan Zhou
- Institute of Biochemistry and Molecular Biology, Collaborative innovation center for antitumor active substance research and development, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Jiao Liu
- Institute of Biochemistry and Molecular Biology, Collaborative innovation center for antitumor active substance research and development, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xin Wu
- Marine Medical Research Institute of Guangdong Zhanjiang, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Xiangyong Li
- Institute of Biochemistry and Molecular Biology, Collaborative innovation center for antitumor active substance research and development, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Zhanjiang 524023, P.R. China
| | - Qiang He
- Institute of Plastic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, P.R. China
| | - Peihua Zhang
- Institute of Plastic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, P.R. China
| | - Xudong Tang
- Institute of Biochemistry and Molecular Biology, Collaborative innovation center for antitumor active substance research and development, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Zhanjiang 524023, P.R. China.,Marine Medical Research Institute of Guangdong Zhanjiang, Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, P.R. China
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Dai J, Jiang L, Qiu L, Shao Y, Shi P, Li J. WHSC1 Promotes Cell Proliferation, Migration, and Invasion in Hepatocellular Carcinoma by Activating mTORC1 Signaling. Onco Targets Ther 2020; 13:7033-7044. [PMID: 32801739 PMCID: PMC7398890 DOI: 10.2147/ott.s248570] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 07/05/2020] [Indexed: 12/16/2022] Open
Abstract
Background Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1) plays key regulatory roles in cancer development and progression. However, its specific functions and potential mechanisms of action remain to be described in hepatocellular carcinoma (HCC). Materials and Methods WHSC1 expression in HCC was evaluated using The Cancer Genome Atlas and verified in HCC tissues and cell lines using qRT-PCR, Western blotting, and immunohistochemistry. Functional assays were performed to explore the role of WHSC1 in HCC progression. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, immunofluorescence, and immunohistochemistry were conducted to evaluate the interaction between WHSC1 and prolyl 4-hydroxylase subunit beta (P4HB). Pathway enrichment was performed using gene set enrichment analysis. Results WHSC1 was markedly overexpressed in HCC tissues and cell lines. The level of expression was strongly associated with adverse clinicopathological characteristics. Survival analyses revealed that WHSC1 upregulation predicted poor overall survival and higher recurrence rates in patients with HCC. Functional studies revealed that WHSC1 significantly stimulated HCC proliferation, migration, and invasion in vitro and in vivo. WHSC1 was shown to interact with P4HB to stimulate P4HB expression and subsequently activate mTOR1 signaling. Conclusion We determined the oncogenic role of WHSC1 in HCC, via P4HB interaction, which activates mTOR1 signaling, and identified WHSC1 as a promising therapeutic target for HCC.
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Affiliation(s)
- Jingjing Dai
- Department of Infectious Diseases, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Longfeng Jiang
- Department of Infectious Diseases, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Lei Qiu
- Department of General Surgery, The Second People's Hospital of Lianyungang, Lianyungang, Jiangsu, People's Republic of China
| | - Yuyun Shao
- Department of Infectious Diseases, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Ping Shi
- Department of Infectious Diseases, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People's Republic of China
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Zhang T, Piao HY, Guo S, Zhao Y, Wang Y, Zheng ZC, Zhang J. LncRNA PCGEM1 enhances metastasis and gastric cancer invasion through targeting of miR-129-5p to regulate P4HA2 expression. Exp Mol Pathol 2020; 116:104487. [PMID: 32622013 DOI: 10.1016/j.yexmp.2020.104487] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 06/18/2020] [Accepted: 06/18/2020] [Indexed: 12/23/2022]
Abstract
AIM Aberrantly expressed long non-coding RNAs (lncRNAs) are critical instigators of gastric cancer (GC) progression and metastasis. The ceRNA (competing endogenous RNAs) network is well-known in modulating tumor pathological and physiological processes. This research aims to determine the more effective molecular mechanisms of lncRNA PCGEM1 (prostate cancer gene expression marker 1). METHODS Bioinformatics database and Ago2-RIP were performed to predict and verify the potential targets of lncRNA PCGEM1. Both gain- and loss-of-function experiments were carried out to dissect the biological functions of RNAs. Fluorescence in situ hybridization, dual-luciferase reporter assays, western blot, and real-time PCR (RT-PCR) experiments were utilized to determine the pathophysiological pathways of competitive endogenous RNAs (ceRNAs). RESULTS GC cells expressed high levels of cytoplasmic PCGEM1. Loss-of-function experiments displayed that the silencing of PCGEM1 suppressed metastatic and invasive cell qualities. PCGEM1 was also found to have associations with miR-129-5p. Subsequently, luciferase reporter and RIP experiments, together with RT-PCR, verified that PCGEM1 functioned as a ceRNA of P4HA2 (Prolyl 4-Hydroxylase Subunit Alpha 2) via sponging miR-129-5p to up-regulate P4HA2 expression. Finally, the rescue assays determined that P4HA2 overexpression rescued the inhibited cell invasion and metastasis caused by PCGEM1 down-regulation. CONCLUSION These findings found that an over-expression of PCGEM1 in GC acts as a miR-129-5p sponge, leading to higher levels of P4HA2. The PCGEM1/miR-129-5p/P4HA2 axis was confirmed to possess a crucial role in GC metastasis and invasion, suggesting its utility as a potential diagnostic and therapeutic biomarker.
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Affiliation(s)
- Tao Zhang
- Gastric Cancer Department, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China
| | - Hai-Yan Piao
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China
| | - Shuai Guo
- Gastric Cancer Department, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China
| | - Yan Zhao
- Gastric Cancer Department, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China
| | - Yue Wang
- Gastric Cancer Department, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China
| | - Zhi-Chao Zheng
- Gastric Cancer Department, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China
| | - Jun Zhang
- Gastric Cancer Department, Liaoning Cancer Hospital & Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province 110042, China.
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Zhu Z, He A, Lv T, Xu C, Lin L, Lin J. Overexpression of P4HB is correlated with poor prognosis in human clear cell renal cell carcinoma. Cancer Biomark 2020; 26:431-439. [PMID: 31640086 DOI: 10.3233/cbm-190450] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prolyl 4-hydroxylase, beta polypeptide (P4HB) protein has been found to be associated with tumorigenesis in many types of tumor, However, the relationship between P4HB and clear cell renal cell carcinoma (ccRCC) has not been clarified. In this study, we focus on the correlation between P4HB expression and ccRCC. Through the Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, our database and immunohistochemical (IHC) staining. Compared with adjacent normal tissues, both the mRNA and protein levels of P4HB in ccRCC tissues were enhanced. The Kaplan-Meier survival analysis showed that high expression of P4HB is correlated with poor prognosis in both TCGA database and our own database. Multivariate survival analysis and Univariate analysis showed that P4HB expression and age are significantly correlative with poor prognose. All the results indicated that P4HB is correlated with poor prognosis in human clear cell renal cell carcinoma.
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Affiliation(s)
- Zhenpeng Zhu
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Department of Urology, Peking University First Hospital, Beijing, China
| | - Anbang He
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,Department of Urology, Peking University First Hospital, Beijing, China
| | - Tongde Lv
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China
| | - Chunru Xu
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China
| | - Lanruo Lin
- Capital Medical University, Beijing, China
| | - Jian Lin
- Department of Urology, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China
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Piao HY, Guo S, Wang Y, Zhang J. Exosome-transmitted lncRNA PCGEM1 promotes invasive and metastasis in gastric cancer by maintaining the stability of SNAI1. Clin Transl Oncol 2020; 23:246-256. [PMID: 32519176 DOI: 10.1007/s12094-020-02412-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 05/25/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Clinically, hypoxia is associated with increased distant metastasis and poor survival in gastric cancer (GC). In this study, we set out from the cellular interaction to further explain the molecular mechanism of invasion in GC cells under hypoxic conditions. METHODS Gastric cancer cells were cultured under 1% O2 (hypoxia-cultured gastric cancer cells, HGC) and 20% O2 condition (normoxic-cultured gastric cancer cells, NGC). NGC was co-cultured with HGC-medium. Scrape and Transwell were used to evaluate invasion and migration. Exosomes from GC were extracted by ultracentrifugation. Electron microscopy images, western-blot used to analyze the size distributions and the number of exosomes. RESULTS HGC-medium induced NGC dissociated. Long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was specifically expressed in HGC exosomes. HGC-derived PCGEM1-riched exosomes could promote the invasion and migration of NGC. On the mechanism, PCGEM1 maintained stability and reduced the degradation of SNAI1, which could induce the epithelial-mesenchymal transition of GC. CONCLUSION LncRNA PCGEM1 was overexpressed in GC cells. And part of the PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and migration of other GC cells. We considered PCGEM1 might act as a "scaffold" combined with SNAI1 and prompt the invasion and migration of GC.
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Affiliation(s)
- H-Y Piao
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China
| | - S Guo
- Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China
| | - Y Wang
- Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China
| | - J Zhang
- Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China.
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D'Aniello C, Patriarca EJ, Phang JM, Minchiotti G. Proline Metabolism in Tumor Growth and Metastatic Progression. Front Oncol 2020; 10:776. [PMID: 32500033 PMCID: PMC7243120 DOI: 10.3389/fonc.2020.00776] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/21/2020] [Indexed: 12/15/2022] Open
Abstract
Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist therapy. Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-essential amino acids in this complex scenario. Here we discuss the impact of proline metabolism in cancer development and progression, with particular emphasis on the enzymes involved in proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how proline availability influences collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby proline availability generates a cycle based on collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic cancers.
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Affiliation(s)
- Cristina D'Aniello
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy
| | - Eduardo J. Patriarca
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy
| | - James M. Phang
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD, United States
| | - Gabriella Minchiotti
- Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy
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Xie L, Li H, Zhang L, Ma X, Dang Y, Guo J, Liu J, Ge L, Nan F, Dong H, Yan Z, Guo X. Autophagy-related gene P4HB: a novel diagnosis and prognosis marker for kidney renal clear cell carcinoma. Aging (Albany NY) 2020; 12:1828-1842. [PMID: 32003756 PMCID: PMC7053637 DOI: 10.18632/aging.102715] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 01/02/2020] [Indexed: 12/14/2022]
Abstract
Autophagy can protect cells and organisms from stressors such as nutrient deprivation, and is involved in many pathological processes including human cancer. Therefore, it is necessary to investigate the role of autophagy-related genes (ARGs) in cancer. In this study, we investigated the gene expression of 222 ARGs in 1048 Kidney Renal Clear Cell Carcinoma (KIRC) cases, from 5 independent cohorts. The gene expression of ARGs were first evaluated in the The Cancer Genome Atlas (TCGA) by Recevier Operating Characteristic (ROC) analysis to select potential biomarkers with extremely high ability in KIRC detection (AUC≥0.85 and p<0.0001). Then in silico procedure progressively leads to the selection of two genes in a three rounds of validation performed in four human KIRC-patients datasets including two independent Gene Expression Omnibus (GEO) datasets, Oncomine dataset and Human Protein Atlas dataset. Finally, only P4HB (Prolyl 4-hydroxylase, beta polypeptide) gene was experimentally validated by RT-PCR between control kidney cells and cancer cells. Following univariate and multivariate analyses of TCGA-KIRC clinical data showed that P4HB expression is an independent prognostic indicator of unfavorable overall survival (OS) for KIRC patients. Based on these findings, we proposed that P4HB might be one potential novel KIRC diagnostic and prognostic biomarker at both mRNA and protein levels.
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Affiliation(s)
- Longxiang Xie
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Huimin Li
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Lu Zhang
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Xiaoyu Ma
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Yifang Dang
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Jinshuai Guo
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Jiahao Liu
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Linna Ge
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Fangmei Nan
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Huan Dong
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Zhongyi Yan
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Xiangqian Guo
- Department of Predictive Medicine, Institute of Biomedical Informatics, Cell Signal Transduction Laboratory, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
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Piao HY, Guo S, Wang Y, Zhang J. Exosomal Long Non-Coding RNA CEBPA-AS1 Inhibits Tumor Apoptosis and Functions as a Non-Invasive Biomarker for Diagnosis of Gastric Cancer. Onco Targets Ther 2020; 13:1365-1374. [PMID: 32110038 PMCID: PMC7034294 DOI: 10.2147/ott.s238706] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/25/2020] [Indexed: 12/27/2022] Open
Abstract
AIM Traditional non-invasive diagnostic markers for gastric cancer (GC) exhibit insufficient sensitivity and specificity. Circulating exosomes are clinically useful non-invasive biomarkers for tumor diagnosis. In addition to their potential role in cancer biology, circulating long non-coding RNAs (lncRNAs) are a new class of promising cancer biomarkers. In the present study, we aimed to identify lncRNAs in circulating exosomes with potential as biomarkers for GC detection. METHODS We compared the expression of CEBPA-AS1 between GC cells and gastric epithelial cells. The biological function of exosomal CEBPA-AS1 was determined by cell phenotype experiments and rescue assays. We also compared the expression of CEBPA-AS1 in cancerous tissue from GC patients and corresponding adjacent normal tissues, as well as the expression of CEBPA-AS1 in plasma exosomes of GC patients and healthy controls. Diagnostic accuracy was assessed by the receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULTS CEBPA-AS1 was highly expressed in both GC cells and in exosomes secreted by GC cells. In addition, CEBPA-AS1-containing exosomes secreted by GC cells could promote cell proliferation and inhibit apoptosis, thereby inducing the malignant behavior of GC cells. The level of CEBPA-AS1 was also significantly increased in tissues and plasma exosomes of GC patients. Stability tests showed that most plasma CEBPA-AS1 was encased in exosomes, thus avoiding degradation by RNases. We evaluated the diagnostic accuracy of exosome-derived CEBPA-AS1. The AUC value of CEBPA-AS1 in discriminating GC patients from healthy controls was 0.824, which was higher than the diagnostic accuracy of other traditional tumor biomarkers. CONCLUSION CEBPA-AS1-containing exosomes secreted from GC cells could promote cell proliferation, inhibit apoptosis, and induce GC progression, indicating that exosomal CEBPA-AS1 is involved in cell-to-cell communication in GC carcinogenesis. Exosomal CEBPA-AS1 is a promising new biomarker for clinical diagnosis of GC.
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Affiliation(s)
- Hai-yan Piao
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province110042, People’s Republic of China
| | - Shuai Guo
- Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province110042, People’s Republic of China
| | - Yue Wang
- Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province110042, People’s Republic of China
| | - Jun Zhang
- Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang City, Liaoning Province110042, People’s Republic of China
- Correspondence: Jun Zhang Gastric Cancer Department, Liaoning Province Cancer Hospital and Institute (Cancer Hospital of China Medical University), No. 44 Xiaoheyan Road, Dadong District, Shenyang City, Liaoning Province110042, People’s Republic of ChinaTel +86-18900917948Fax +86-24-2431-5679 Email
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Ding X, Huang R, Zhong Y, Cui N, Wang Y, Weng J, Chen L, Zang M. CTHRC1 promotes gastric cancer metastasis via HIF-1α/CXCR4 signaling pathway. Biomed Pharmacother 2019; 123:109742. [PMID: 31855733 DOI: 10.1016/j.biopha.2019.109742] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/16/2019] [Accepted: 11/29/2019] [Indexed: 12/18/2022] Open
Abstract
Metastasis is the main cause of gastric cancer (GC) related death and the underlying mechanisms still remain unclear. Collagen triple helix repeat containing 1 (CTHRC1) protein is known to be involved in tissue remodeling processes and closely associated with carcinogenesis and metastasis in solid tumors, but the functional role of CTHRC1 and its underlying mechanism with tumor metastasis in GC have not been fully illuminated. In the present study, CTHRC1 was highly expressed in tumor tissues and associated with poor prognosis of GC according to TCGA and GEO database. Functional studies revealed that CTHRC1 overexpression in GC significantly increased cell migration and invasion capacity. However, the promoting effects were abolished subsequent to silencing of CXCR4. In addition, CTHRC1 increased CXCR4 expression through upregulating HIF-1α expression, which eventually contributed to the promotion of cell migration and invasion. Inhibiting HIF-1α expression decreased CXCR4 expression and suppressed cell migration and invasion in GC. These results substantiated our hypothesis that HIF-1α/CXCR4 signaling pathway mediated the promoting effect of CTHRC1 on cell migration and invasion in GC.
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Affiliation(s)
- Xusheng Ding
- Department of Gastric Cancer Surgery, Fudan University, Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of General Surgery of Changzheng Hospital Affiliated to Naval Military Medical University, Fengyang Road, Shanghai, 200003, China; Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Ruijin Er Road, Shanghai 200025, China
| | - Renhong Huang
- Department of General Surgery of Changzheng Hospital Affiliated to Naval Military Medical University, Fengyang Road, Shanghai, 200003, China
| | - Yiming Zhong
- Department of General Surgery of Changzheng Hospital Affiliated to Naval Military Medical University, Fengyang Road, Shanghai, 200003, China; Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Ruijin Er Road, Shanghai 200025, China
| | - Na Cui
- Department of Pathology of Changzheng Hospital Affiliated to Naval Military Medical University, Fengyang Road, Shanghai, 200003, China
| | - Yifei Wang
- Department of Cardiothoracic Surgery of Changzheng Hospital Affiliated to Naval Military Medical University, Fengyang Road, Shanghai, 200003, China
| | - Junyong Weng
- Department of Gastric Cancer Surgery, Fudan University, Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Li Chen
- Department of Gastric Cancer Surgery, Fudan University, Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Mingde Zang
- Department of Gastric Cancer Surgery, Fudan University, Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Ruijin Er Road, Shanghai 200025, China.
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Zhu B, Pan S, Liu J, Wang S, Ni Y, Xiao L, Wei Q, Peng Y, Ding Z, Zhao W. HIF-1α forms regulatory loop with YAP to coordinate hypoxia-induced adriamycin resistance in acute myeloid leukemia cells. Cell Biol Int 2019; 44:456-466. [PMID: 31617641 DOI: 10.1002/cbin.11246] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/13/2019] [Indexed: 12/13/2022]
Abstract
Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia-inducible factor 1α (HIF-1α) by CdCl2 can make AML cells re-susceptibile to ADR even under hypoxia. Moreover, HIF-1α is overexpressed and plays an important role in ADR-resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF-1α can significantly upregulate yes-associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF-1α stability but also promote HIF-1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF-1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin-based chemotherapy in AML.
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Affiliation(s)
- Bin Zhu
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Shaoying Pan
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Juanjuan Liu
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Suli Wang
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Ying Ni
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Linlin Xiao
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Quhao Wei
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - You Peng
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Zhiyong Ding
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
| | - Wenli Zhao
- Department of Hematology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University South Branch, i.e. Shanghai Fengxian District Central Hospital, Shanghai, 201499, China
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Circulating long non-coding RNA PCGEM1 as a novel biomarker for gastric cancer diagnosis. Pathol Res Pract 2019; 215:152569. [DOI: 10.1016/j.prp.2019.152569] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/15/2019] [Accepted: 07/26/2019] [Indexed: 01/16/2023]
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P4HB, a Novel Hypoxia Target Gene Related to Gastric Cancer Invasion and Metastasis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9749751. [PMID: 31467922 PMCID: PMC6699373 DOI: 10.1155/2019/9749751] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 03/10/2019] [Indexed: 12/15/2022]
Abstract
Gastric cancer (GC) is a common tumor-associated lethal disease, and invasiveness and metastasis are primary challenges in its clinical treatment. Hypoxia microenvironment cannot be ignored in the process of metastasis. Hypoxia inducible factor-1α (HIF-1α) is the core component of the hypoxia signaling pathway. The aim of this study was to identify potential hub genes and signaling pathways associated with HIF-1α. We explored the invasiveness- and metastasis-associated phenotype of GC via bioinformatics analysis and molecular studies. Differentially expressed genes (DEGs) were identified in GC cells and HIF-1α-knockdown GC cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and a protein-protein interaction (PPI) network was constructed. Hub genes were identified via centrality analysis and Molecular Complex Detection (MCODE) module analysis. The findings suggested that prolyl 4-hydroxylase beta polypeptide (P4HB) has strong associations with HIF-1α. Further, we observed that HIF-1α and P4HB were upregulated in SGC-7901 and BGC-823 cells. In addition, inhibition of HIF-1α expression reduced invasion and metastasis in GC cells; this effect was partially reversed by P4HB overexpression. Our results confirm that P4HB plays a significant role in the regulatory network of HIF-1α. Therefore, HIF-1α and P4HB may be considered potential biomarkers of GC.
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Shi L, Wu Z, Miao J, Du S, Ai S, Xu E, Feng M, Song J, Guan W. Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K-AKT-mTOR signaling. Mol Biol Cell 2019; 30:2527-2534. [PMID: 31339445 PMCID: PMC6743355 DOI: 10.1091/mbc.e19-03-0136] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The accumulation of adenosine in the tumor microenvironment is associated with tumor progression in many cancers. However, whether adenosine is involved in gastric cancer (GC) metastasis and progression, and the underlying molecular mechanism, is largely unclear. In this study, we find that GC tissues and cell lines had higher A2aR levels than nontumor gastric tissues and cell lines. A2aR expression correlated positively with TNMstage, and associated with poor outcomes. Adenosine enhanced the expression of the stemness and epithelial-mesenchymal transition-associated genes by binding to A2aR. A2aR expression on GC cells promoted metastasis in vivo. The PI3K-AKT-mTOR signaling pathway was involved in adenosine-stimulated GC cell migration and invasion. Our results indicate that adenosine promotes GC cell invasion and metastasis by interacting with A2aR to enhance PI3K-AKT-mTOR pathway signaling.
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Affiliation(s)
- Linsen Shi
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, People's Republic of China.,The Affiliated Nanjing Drum Tower Clinical College of Nanjing Medical University, Nanjing 210002, People's Republic of China
| | - Zhaoying Wu
- Xuzhou Medical University, Xuzhou 221006, People's Republic of China
| | - Ji Miao
- Department of Gastrointestinal Surgery, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing 210000, People's Republic of China
| | - Shangce Du
- The Affiliated Nanjing Drum Tower Clinical College of Nanjing Medical University, Nanjing 210002, People's Republic of China
| | - Shichao Ai
- Nanjing University, Nanjing 21000, People's Republic of China
| | - En Xu
- Nanjing University, Nanjing 21000, People's Republic of China
| | - Min Feng
- Department of Gastrointestinal Surgery, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing 210000, People's Republic of China
| | - Jun Song
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, People's Republic of China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou 221006, People's Republic of China
| | - Wenxian Guan
- The Affiliated Nanjing Drum Tower Clinical College of Nanjing Medical University, Nanjing 210002, People's Republic of China.,Department of Gastrointestinal Surgery, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing 210000, People's Republic of China
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Hypoxia-induced LncRNA PCGEM1 promotes invasion and metastasis of gastric cancer through regulating SNAI1. Clin Transl Oncol 2019; 21:1142-1151. [PMID: 30690667 DOI: 10.1007/s12094-019-02035-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 01/08/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Hypoxia is an indispensable factor in the progression of metastasis. Hypoxia inducible factor-1α (HIF-1α), the core element in generating the hypoxia response, induces invasion and metastasis by promoting epithelial-mesenchymal transition (EMT). This study explored the underlying mechanism of hypoxia associated with the invasion and metastasis of gastric cancer (GC). METHODS Six methods were employed to assess the function of the long noncoding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) including gene silencing, RT-PCR, the separation of nuclear and cytoplasmic fractions, scrape motility assay, transwell migration assay, and Western-blot. RESULTS LncRNA PCGEM1 was overexpressed in GC cells and tissues, and was induced by hypoxia in GC cells. Additional experiments confirmed that the knockdown of PCGEM1 significantly repressed the invasion and metastasis of GC cells. SNAI1, a key transcription factor of EMT, was regulated by PCGEM1. Overexpression of SNAI1 rescued the inhibition of PCGEM1-knockdown during the invasion and metastasis of GC cells. In addition, PCGEM1 and SNAI1 jointly affected the biomarkers of EMT. CONCLUSION Our findings indicated that PCGEM1 is a hypoxia-responsive lncRNA, and contributes to the invasion and metastasis of GC. The potential mechanism is attributed to the regulation of EMT by PCGEM1 and its influence on the expression of SNAI1.
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Zhang J, Wu Y, Jin HY, Guo S, Dong Z, Zheng ZC, Wang Y, Zhao Y. Prognostic value of sorting nexin 10 weak expression in stomach adenocarcinoma revealed by weighted gene co-expression network analysis. World J Gastroenterol 2018; 24:4906-4919. [PMID: 30487700 PMCID: PMC6250920 DOI: 10.3748/wjg.v24.i43.4906] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/17/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To detect significant clusters of co-expressed genes associated with tumorigenesis that might help to predict stomach adenocarcinoma (SA) prognosis.
METHODS The Cancer Genome Atlas database was used to obtain RNA sequences as well as complete clinical data of SA and adjacent normal tissues from patients. Weighted gene co-expression network analysis (WGCNA) was used to investigate the meaningful module along with hub genes. Expression of hub genes was analyzed in 362 paraffin-embedded SA biopsy tissues by immunohistochemical staining. Patients were classified into two groups (according to expression of hub genes): Weak expression and over-expression groups. Correlation of biomarkers with clinicopathological factors indicated patient survival.
RESULTS Whole genome expression level screening identified 6,231 differentially expressed genes. Twenty-four co-expressed gene modules were identified using WGCNA. Pearson’s correlation analysis showed that the tan module was the most relevant to tumor stage (r = 0.24, P = 7 × 10-6). In addition, we detected sorting nexin (SNX)10 as the hub gene of the tan module. SNX10 expression was linked to T category (P = 0.042, χ2 = 8.708), N category (P = 0.000, χ2 = 18.778), TNM stage (P = 0.001, χ2 = 16.744) as well as tumor differentiation (P = 0.000, χ2 = 251.930). Patients with high SNX10 expression tended to have longer disease-free survival (DFS; 44.97 mo vs 33.85 mo, P = 0.000) as well as overall survival (OS; 49.95 vs 40.84 mo, P = 0.000) in univariate analysis. Multivariate analysis showed that dismal prognosis could be precisely predicted clinicopathologically using SNX10 [DFS: P = 0.014, hazard ratio (HR) = 0.698, 95% confidence interval (CI): 0.524-0.930, OS: P = 0.017, HR = 0.704, 95%CI: 0.528-0.940].
CONCLUSION This study provides a new technique for screening prognostic biomarkers of SA. Weak expression of SNX10 is linked to poor prognosis, and is a suitable prognostic biomarker of SA.
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Affiliation(s)
- Jun Zhang
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yue Wu
- Department of Emergency, Sheng Jing Hospital of China Medical University, Shenyang 110042, Liaoning Province, China
| | - Hao-Yi Jin
- Pancreatic and Thyroid Surgery Department, Sheng Jing Hospital of China Medical University, Shenyang 110042, Liaoning Province, China
| | - Shuai Guo
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Zhe Dong
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Zhi-Chao Zheng
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yue Wang
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yan Zhao
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
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