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Parcharidou E, Dücker R, Beffa R. Genome-wide study of glutathione transferases and their regulation in flufenacet susceptible and resistant black-grass (Alopecurus myosuroides Huds.). PEST MANAGEMENT SCIENCE 2024; 80:3035-3046. [PMID: 38323683 DOI: 10.1002/ps.8012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/24/2024] [Accepted: 02/02/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND Glutathione transferases (GSTs) are enzymes with a wide range of functions, including herbicide detoxification. Up-regulation of GSTs and their detoxification activity enables the grass weed black-grass (Alopecurus myosuroides Huds.) to metabolize the very-long-chain fatty acid synthesis inhibitor flufenacet and other herbicides leading to multiple herbicide resistance. However, the genomic organization and regulation of GSTs genes is still poorly understood. RESULTS In this genome-wide study the location and expression of 115 GSTs were investigated using a recently published black-grass genome. Particularly, the most abundant GSTs of class tau and phi were typically clustered and often followed similar expression patterns but possessed divergent upstream regulatory regions. Similarities were found in the promoters of the most up-regulated GSTs, which are located next to each other in a cluster. The binding motif of the E2F/DP transcription factor complex in the promoter of an up-regulated GST was identical in susceptible and resistant plants, however, adjacent sequences differed. This led to a stronger binding of proteins to the motif of the susceptible plant, indicating repressor activity. CONCLUSIONS This study constitutes the first analysis dealing with the genomic investigation of GST genes found in black-grass and their transcriptional regulation. It highlights the complexity of the evolution of GSTs in black-grass, their duplication and divergence over time. The large number of GSTs allows weeds to detoxify a broad spectrum of herbicides. Ultimately, more research is needed to fully elucidate the regulatory mechanisms of GST expression. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
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Affiliation(s)
- Evlampia Parcharidou
- Division of Plant Pathology and Crop Protection, Georg-August University Göttingen, Göttingen, Germany
| | - Rebecka Dücker
- Division of Plant Pathology and Crop Protection, Georg-August University Göttingen, Göttingen, Germany
| | - Roland Beffa
- Senior Scientist Consultant, Liederbach am Taunus, Germany
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Rai D, Pattnaik B, Bangaru S, Tak J, Kumari J, Verma U, Vadala R, Yadav G, Dhaliwal RS, Kumar S, Kumar R, Jain D, Luthra K, Chosdol K, Palanichamy JK, Khan MA, Surendranath A, Mittal S, Tiwari P, Hadda V, Madan K, Agrawal A, Guleria R, Mohan A. microRNAs in exhaled breath condensate for diagnosis of lung cancer in a resource-limited setting: a concise review. Breathe (Sheff) 2023; 19:230125. [PMID: 38351949 PMCID: PMC10862127 DOI: 10.1183/20734735.0125-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 11/30/2023] [Indexed: 02/16/2024] Open
Abstract
Lung cancer is one of the common cancers globally with high mortality and poor prognosis. Most cases of lung cancer are diagnosed at an advanced stage due to limited diagnostic resources. Screening modalities, such as sputum cytology and annual chest radiographs, have not proved sensitive enough to impact mortality. In recent years, annual low-dose computed tomography has emerged as a potential screening tool for early lung cancer detection, but it may not be a feasible option for developing countries. In this context, exhaled breath condensate (EBC) analysis has been evaluated recently as a noninvasive tool for lung cancer diagnosis. The breath biomarkers also have the advantage of differentiating various types and stages of lung cancer. Recent studies have focused more on microRNAs (miRNAs) as they play a key role in tumourigenesis by regulating the cell cycle, metastasis and angiogenesis. In this review, we have consolidated the current published literature suggesting the utility of miRNAs in EBC for the detection of lung cancer.
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Affiliation(s)
- Divyanjali Rai
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Bijay Pattnaik
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Sunil Bangaru
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Jaya Tak
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Jyoti Kumari
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Umashankar Verma
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Rohit Vadala
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Geetika Yadav
- Indian Council of Medical Research, New Delhi, India
| | | | - Sunil Kumar
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Rakesh Kumar
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Deepali Jain
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Kalpana Luthra
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Kunzang Chosdol
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | | | - Maroof Ahmad Khan
- Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
| | - Addagalla Surendranath
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Mittal
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Pawan Tiwari
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Vijay Hadda
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Karan Madan
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Anurag Agrawal
- Trivedi School of Biosciences, Ashoka University, Sonipat, India
| | - Randeep Guleria
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Anant Mohan
- Breathomics in Respiratory Diseases Lab, Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
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Nakashiro KI, Tokuzen N, Saika M, Shirai H, Kuribayashi N, Goda H, Uchida D. MicroRNA-1289 Functions as a Novel Tumor Suppressor in Oral Squamous Cell Carcinoma. Cancers (Basel) 2023; 15:4138. [PMID: 37627167 PMCID: PMC10452613 DOI: 10.3390/cancers15164138] [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: 07/10/2023] [Revised: 08/01/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Recently, numerous tumor-suppressive microRNAs (TS-miRs) have been identified in human malignancies. Here, we attempted to identify novel TS-miRs in oral squamous cell carcinoma (OSCC). First, we transfected human OSCC cells individually with 968 synthetic miRs mimicking human mature miRs individually, and the growth of these cells was evaluated using the WST-8 assay. Five miR mimics significantly reduced the cell growth rate by less than 30%, and the miR-1289 mimic had the most potent growth inhibitory effect among these miRs. Subsequently, we assessed the in vivo growth-inhibitory effects of miR-1289 using a mouse model. The administration of the miR-1289 mimic-atelocollagen complex significantly reduced the size of subcutaneously xenografted human OSCC tumors. Next, we investigated the expression of miR-1289 in OSCC tissues using reverse transcription-quantitative PCR. The expression level of miR-1289 was significantly lower in OSCC tissues than in the adjacent normal oral mucosa. Furthermore, 15 genes were identified as target genes of miR-1289 via microarray and Ingenuity Pathway Analysis (IPA) microRNA target filtering. Among these genes, the knockdown of magnesium transporter 1 (MAGT1) resulted in the most remarkable cell growth inhibition in human OSCC cells. These results suggested that miR-1289 functions as a novel TS-miR in OSCC and may be a useful therapeutic tool for patients with OSCC.
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Affiliation(s)
- Koh-ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon 791-0295, Japan; (N.T.); (M.S.); (H.S.); (N.K.); (H.G.); (D.U.)
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Gao X, Yang X, He F, Liu X, Liu D, Yuan X. Downregulation of microRNA‑494 inhibits cell proliferation in lung squamous cell carcinoma via the induction of PUMA‑α‑mediated apoptosis. Exp Ther Med 2023; 25:242. [PMID: 37153893 PMCID: PMC10160919 DOI: 10.3892/etm.2023.11941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 01/16/2023] [Indexed: 05/10/2023] Open
Abstract
Increased evidence has shown that abnormal microRNA (miRNA) plays pivotal roles in numerous types of cancer. However, their expression, function and mechanism in lung squamous cell carcinoma (LSCC) remains to be fully elucidated. The aim of the present study was to investigate the suppressive role of miR-494 in LSCC progression and elucidate its regulatory mechanism. By analyzing expression profiles of miRNAs in LSCC tissues using miRNA microarray, it was revealed that miR-494 was significantly upregulated in 22 pairs of LSCC tissues. Subsequently, reverse transcription-quantitative PCR was performed to determine the expression of miR-494 and p53-upregulated-modulator-of-apoptosis-α (PUMA-α). Western blot analysis was conducted to examine protein levels. Dual-luciferase reporter assay was used to confirm the binding between miR-494 and PUMA-α. Annexin V-fluoresceine isothiocyanate/propidium iodide staining and CCK-8 assays were employed to determine cell apoptosis and cell viability, respectively. It was also revealed that miR-494 was highly expressed in LSCC cell lines compared with that in 16HBE cells. Further experiments confirmed that knockdown of miR-494 reduced cell viability and induced LSCC apoptosis. Bioinformatics analysis predicted that miR-494 could potentially target PUMA-α; also known as Bcl-2-binding component 3, a pro-apoptotic factor, and an inverse correlation between the expression of miR-494 and PUMA-α mRNA levels in LSCC tissues was found. Furthermore, PUMA-α inhibition could reverse the promoting effect of miR-494 knockdown on apoptosis in LSCC cells. Taken together, these findings demonstrated that miR-494 functions as an oncogene by targeting PUMA-α in LSCC, and miR-494 may serve as a novel therapeutic target for treating LSCC.
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Affiliation(s)
- Xinyuan Gao
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China
| | - Xiaohua Yang
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China
| | - Fengzhen He
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China
| | - Xue Liu
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China
| | - Ding Liu
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Xiaomei Yuan
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan 453100, P.R. China
- Correspondence to: Professor Xiaomei Yuan, Department of Respiratory and Critical Care, The First Affiliated Hospital of Xinxiang Medical College, 88 Jiankang Road, Weihui, Xinxiang, Henan 453100, P.R. China
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Zeng P, Wang F, Long X, Cao Y, Wen F, Li J, Luo Z. CPEB2 enhances cell growth and angiogenesis by upregulating ARPC5 mRNA stability in multiple myeloma. J Orthop Surg Res 2023; 18:384. [PMID: 37231521 DOI: 10.1186/s13018-023-03835-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/06/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND The process of multiple myeloma (MM) is the result of the combined action of multiple genes. This study aims to explore the role and mechanism of cytoplasmic polyadenylation element binding protein2 (CPEB2) in MM progression. METHODS The mRNA and protein expression levels of CPEB2 and actin-related protein 2/3 complex subunit 5 (ARPC5) were assessed by quantitative real-time PCR and western blot analysis. Cell function was determined by cell counting kit 8 assay, soft-agar colony formation assay, flow cytometry and tube formation assay. Fluorescent in situ hybridization assay was used to analyze the co-localization of CPEB2 and ARPC5 in MM cells. Actinomycin D treatment and cycloheximide chase assay were performed to assess the stability of ARPC5. The interaction between CPEB2 and ARPC5 was confirmed by RNA immunoprecipitation assay. RESULTS CPEB2 and ARPC5 mRNA and protein expression levels were upregulated in CD138+ plasma cells from MM patients and cells. CPEB2 downregulation reduced MM cell proliferation, angiogenesis, and increased apoptosis, while its overexpression had an opposite effect. CPEB2 and ARPC5 were co-localized at cell cytoplasm and could positively regulate ARPC5 expression by mediating its mRNA stability. ARPC5 overexpression reversed the suppressive effect of CPEB2 knockdown on MM progression, and it knockdown also abolished CPEB2-promoted MM progression. Besides, CPEB2 silencing also reduced MM tumor growth by decreasing ARPC5 expression. CONCLUSION Our results indicated that CPEB2 increased ARPC5 expression through promoting its mRNA stability, thereby accelerating MM malignant process.
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Affiliation(s)
- Piaorong Zeng
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Fujue Wang
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Xingxing Long
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Yixiong Cao
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Feng Wen
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Junjun Li
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Zeyu Luo
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, No.69, Chuanshan Road, Hengyang, 421001, Hunan Province, People's Republic of China.
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Qu G, Zhang Y, Duan H, Tang C, Yang G, Chen D, Xu Y. ARPC5 is transcriptionally activated by KLF4, and promotes cell migration and invasion in prostate cancer via up-regulating ADAM17 : ARPC5 serves as an oncogene in prostate cancer. Apoptosis 2023; 28:783-795. [PMID: 36881291 DOI: 10.1007/s10495-023-01827-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND Prostate cancer (PCa) is one of the most common cancers in men worldwide. Actin-related protein 2/3 complex subunit 5 (ARPC5) has been validated as a critical regulator in several kinds of human tumors. However, whether ARPC5 is implicated in PCa progression remains largely unknown. METHODS PCa specimens and PCa cell lines were obtained for detecting gene expressions using western blot and quantitative reverse transcriptase PCR (qRT-PCR). PCa cells transfected with ARPC5 shRNA or a disintegrin and metalloprotease 17 (ADAM17) overexpressed plasmids were harvested for assessing cell proliferation, migration and invasion by using cell counting kit-8 (CCK-8), colony formation and transwell assays, respectively. The interaction relationship between molecules was testified with chromatin immunoprecipitation and luciferase reporter assay. Xenograft mice model was conducted for confirming the role of ARPC5/ADAM17 axis in vivo. RESULTS Upregulated ARPC5 was observed in PCa tissues and cells, as well as forecasted poor prognosis of PCa patients. Depletion of ARPC5 inhibited PCa cell proliferation, migration and invasion. Krüppel-like factor 4 (KLF4) was identified to be a transcriptional activator of ARPC5 via binding with its promoter region. Furthermore, ADAM17 served as a downstream effector of ARPC5. ADAM17 overexpression overturned ARPC5 knockdown-induced repressive impacts on PCa progression in vitro and in vivo. CONCLUSION Collectively, ARPC5 was activated by KLF4 and upregulated ADAM17 to promote PCa progression, which might act as a promising therapeutic target and prognostic biomarker for PCa.
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Affiliation(s)
- GenYi Qu
- Department of Urology, ZhuZhou central hospital, No. 116, Changjiang South Road, Tianyuan District, ZhuZhou, 412000, Hunan Province, P.R. China
| | - YuLong Zhang
- Department of Urology, ZhuZhou central hospital, No. 116, Changjiang South Road, Tianyuan District, ZhuZhou, 412000, Hunan Province, P.R. China
| | - HongTao Duan
- Department of Ultrasound, ZhuZhou central hospital, ZhuZhou, 412000, Hunan Province, P.R. China
| | - Cheng Tang
- Department of Urology, ZhuZhou central hospital, No. 116, Changjiang South Road, Tianyuan District, ZhuZhou, 412000, Hunan Province, P.R. China
| | - Guang Yang
- Department of Urology, ZhuZhou central hospital, No. 116, Changjiang South Road, Tianyuan District, ZhuZhou, 412000, Hunan Province, P.R. China
| | - Dan Chen
- Department of Urology, ZhuZhou central hospital, No. 116, Changjiang South Road, Tianyuan District, ZhuZhou, 412000, Hunan Province, P.R. China
| | - Yong Xu
- Department of Urology, ZhuZhou central hospital, No. 116, Changjiang South Road, Tianyuan District, ZhuZhou, 412000, Hunan Province, P.R. China.
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Huang S, Sun L, Hou P, Liu K, Wu J. A comprehensively prognostic and immunological analysis of actin-related protein 2/3 complex subunit 5 in pan-cancer and identification in hepatocellular carcinoma. Front Immunol 2022; 13:944898. [PMID: 36148220 PMCID: PMC9485570 DOI: 10.3389/fimmu.2022.944898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/15/2022] [Indexed: 11/24/2022] Open
Abstract
Background Actin-related protein 2/3 complex subunit 5 (ARPC5) is one of the members of actin-related protein 2/3 complex and plays an important role in cell migration and invasion. However, little is known about the expression pattern, prognosis value, and biological function of ARPC5 in pan-cancer. Thus, we focus on ARPC5 as cut point to explore a novel prognostic and immunological biomarker for cancers. Methods The public databases, including TCGA, GTEx, and UCEC, were used to analyze ARPC5 expression in pan-cancer. The Human Protein Atlas website was applied to obtain the expression of ARPC5 in different tissues, cell lines, and single-cell types. Univariate Cox regression analysis and Kaplan–Meier analysis were used to explore the prognosis value of ARPC5 in various cancers. Spearman’s correlation analysis was performed to investigate the association between ARPC5 expression and tumor microenvironment scores, immune cell infiltration, immune-related genes, TMB, MSI, RNA modification genes, DNA methyltransferases, and tumor stemness. Moreover, qPCR, Western blot, and immunohistochemistry were carried out to examine the differential expression of ARPC5 in HCC tissues and cell lines. CCK8, EdU, flow cytometry, wound-healing assays, and transwell assays were conducted to explore its role in tumor proliferation, apoptosis, migration, and invasion among HCC cells. Results ARPC5 expression was upregulated in most cancer types and significantly associated with worse prognosis in KIRC, KIRP, LGG, and LIHC. mRNA expression of ARPC5 showed low tissue and cell specificity in normal tissues, cell lines, and single-cell types. ARPC5 expression was positively correlated with the tumor microenvironment scores, immune infiltrating cells, immune checkpoint–related genes in most cancers. ARPC5 in STAD and BRCA was positively associated with TMB, MSI, and neoantigens. We also discovered that ARPC5 was correlated with the expression of m1A-related genes, m5C-related genes, m6A-related genes, and DNA methyltransferases. In experiment analyses, we found that ARPC5 was significantly highly expressed in HCC tissues and HCC cells. Functionally, silencing ARPC5 dramatically decreased proliferation, migration, and invasion ability of HCC cells. Conclusions ARPC5 expression affects the prognosis of multiple tumors and is closely correlated to tumor immune infiltration and immunotherapy. Furthermore, ARPC5 may function as an oncogene and promote tumor progression in HCC.
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Affiliation(s)
- Shenglan Huang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Liying Sun
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ping Hou
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kan Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianbing Wu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Jianbing Wu,
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Pavlíková L, Šereš M, Breier A, Sulová Z. The Roles of microRNAs in Cancer Multidrug Resistance. Cancers (Basel) 2022; 14:cancers14041090. [PMID: 35205839 PMCID: PMC8870231 DOI: 10.3390/cancers14041090] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/16/2022] [Accepted: 02/20/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary The resistance of neoplastic cells to multiple drugs is a serious problem in cancer chemotherapy. The molecular causes of multidrug resistance in cancer are largely known, but less is known about the mechanisms by which cells deliver phenotypic changes that resist the attack of anticancer drugs. The findings of RNA interference based on microRNAs represented a breakthrough in biology and pointed to the possibility of sensitive and targeted regulation of gene expression at the post-transcriptional level. Such regulation is also involved in the development of multidrug resistance in cancer. The aim of the current paper is to summarize the available knowledge on the role of microRNAs in resistance to multiple cancer drugs. Abstract Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed.
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Affiliation(s)
- Lucia Pavlíková
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
| | - Mário Šereš
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Albert Breier
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia
- Correspondence: (M.Š.); (A.B.); (Z.S.)
| | - Zdena Sulová
- Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská Cesta 9, 84005 Bratislava, Slovakia;
- Correspondence: (M.Š.); (A.B.); (Z.S.)
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ARPC1B Is Associated with Lethal Prostate Cancer and Its Inhibition Decreases Cell Invasion and Migration In Vitro. Int J Mol Sci 2022; 23:ijms23031476. [PMID: 35163398 PMCID: PMC8836051 DOI: 10.3390/ijms23031476] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/26/2022] [Accepted: 01/26/2022] [Indexed: 02/05/2023] Open
Abstract
ARPC1B (Actin Related Protein 2/3 Complex Subunit 1B) has been found to be involved in platelet abnormalities of immune-mediated inflammatory disease and eosinophilia. However, its role in prostate cancer (PCa) has not been established. We characterized the role of ARPC1B in PCa invasion and metastasis and investigated its prognosis using in vitro cellular models and PCa clinical data. Higher immunohistochemistry (IHC) expressions of ARPC1B were observed in localized and castrate resistant PCa (CRPC) vs. benign prostate tissue (p < 0.01). Additionally, 47% of patients with grade group 5 (GG) showed high ARPC1B expression vs. other GG patients. Assessing ARPC1B expression in association with two of the common genetic aberrations in PCa (ERG and PTEN) showed significant association to overall and cause-specific survival for combined assessment of ARPC1B and PTEN, and ARPC1B and ERG. Knockdown of ARPC1B impaired the migration and invasion of PC3 and DU145 PCa cells via downregulation of Aurora A kinase (AURKA) and resulted in the arrest of the cells in the G2/M checkpoint of the cell cycle. Additionally, higher ARPC1B expression was observed in stable PC3-ERG cells compared to normal PC3, supporting the association between ERG and ARPC1B. Our findings implicate the role of ARPC1B in PCa invasion and metastasis in association with ERG and further support its prognostic value as a biomarker in association with ERG and PTEN in identifying aggressive phenotypes of PCa cancer.
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Cao M, Tian K, Sun W, Xu J, Tang Y, Wu S. MicroRNA-141-3p inhibits the progression of oral squamous cell carcinoma via targeting PBX1 through the JAK2/STAT3 pathway. Exp Ther Med 2022; 23:97. [PMID: 34976139 PMCID: PMC8674974 DOI: 10.3892/etm.2021.11020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 07/23/2021] [Indexed: 02/07/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC), which is the most common epithelial malignant neoplasm in the head and neck, is characterized by local infiltration and metastasis of lymph nodes. The five-year survival rate of OSCC remains low despite the advances in clinical methods. miR-141-3p has been shown to activate or inhibit tumorigenesis. However, the effects of miR-141-3p on invasion and migration of OSCC remain unclear. The present study aimed to evaluate the effects of miR-141-3p on invasion, proliferation, and migration in oral squamous cell carcinoma (OSCC). Reverse transcription quantitative PCR, western blotting and immunohistochemistry were used to detect microRNA(miR)-141-3p and pre-B-cell leukaemia homeobox-1 (PBX1) expression in OSCC tissues and cell lines. The luciferase reporter assay was used to detect targets of miR-141-3p in OSCC. MTT, Transwell and wound healing assays were used to determine the cell proliferation and invasive and migratory abilities, respectively. Expression of constitutive phosphorylated (p)-Janus kinase 2 (JAK2) and p-signal transducer and activator of transcription 3 (STAT3) was detected using western blotting in tissues and cells. miR-141-3p expression was decreased in OSCC tissues and cells, while PBX1 protein expression was increased compared with non-cancerous controls. The result from the dual-luciferase reporter assay revealed that PBX1 was the direct target of miR-141-3p in OSCC tissues. Furthermore, miR-141-3p overexpression and PBX1 knockdown could reduce cell invasion, proliferation and migration, and inhibit the JAK2/STAT3 pathway; however, miR-141-3p downregulation had the opposite effects. In addition, silencing of PBX1 using small interfering RNA could weaken the effects of miR-141-3p inhibitor on JAK2/STAT3 pathway and cell progression in CAL27 cells. In summary, the findings from this study indicated that miR-141-3p upregulation could inhibit OSCC cell invasion, proliferation and migration, by targeting PBX1 via the JAK2/STAT3 pathway.
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Affiliation(s)
- Mingguo Cao
- School of Medicine and Health Sciences, Lishui University, Lishui, Zhejiang 323000, P.R. China
| | - Kebin Tian
- School of Medicine and Health Sciences, Lishui University, Lishui, Zhejiang 323000, P.R. China
| | - Weifeng Sun
- School of Medicine and Health Sciences, Lishui University, Lishui, Zhejiang 323000, P.R. China
| | - Jun Xu
- School of Medicine and Health Sciences, Lishui University, Lishui, Zhejiang 323000, P.R. China
| | - Yu Tang
- School of Medicine and Health Sciences, Lishui University, Lishui, Zhejiang 323000, P.R. China
| | - Shilian Wu
- School of Medicine and Health Sciences, Lishui University, Lishui, Zhejiang 323000, P.R. China
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11
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Ramírez-Salazar EG, Gayosso-Gómez LV, Baez-Saldaña R, Falfán-Valencia R, Pérez-Padilla R, Higuera-Iglesias AL, Vázquez-Manríquez ME, Ortiz-Quintero B. Cigarette Smoking Alters the Expression of Circulating microRNAs and Its Potential Diagnostic Value in Female Lung Cancer Patients. BIOLOGY 2021; 10:biology10080793. [PMID: 34440025 PMCID: PMC8389578 DOI: 10.3390/biology10080793] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 12/29/2022]
Abstract
Simple Summary In this study, we investigated whether circulating microRNA expression levels and their potential diagnostic value are affected by cigarette smoking in lung cancer patients and healthy participants. Our findings support that cigarette smoking affects the reliable identification of circulating miRNAs as diagnostic biomarkers in lung cancer and suggest a smoking-dependent pathogenic role of miR-133a-3p in smokers. Abstract Cigarette smoking is a known risk factor for the development of lung cancer. We investigated whether circulating microRNA expression levels and their potential diagnostic value are affected by cigarette smoking in adenocarcinoma (AD) patients and healthy (H) participants. In total, 71 female AD patients and 91 H individuals were recruited, including 42 AD never-smokers (AD/CS−), 29 AD smokers (AD/CS+), 54 H never-smokers (H/CS−), and 37 H smokers (H/CS+). PCR array (754 microRNAs) and qPCR were performed on sera from the discovery and validation cohorts, respectively. The expression levels of miR-532-5p, miR-25-3p, and miR-133a-3p were significantly higher in adenocarcinoma patients than in healthy participants, independent of their smoking status. Multivariate analysis showed that levels of miR-133a-3p were independently associated with smoking. ROC analysis showed that only miR-532-5p discriminated AD patients from H controls (AUC: 0.745). However, when making comparisons according to cigarette smoking status, miR-532-5p discriminated AD/CS− patients from H/CS− controls with a higher AUC (AUC:0.762); miR-25-3p discriminated AD/CS+ patients from H/CS+ controls (AUC: 0.779), and miR-133a discriminated AD/CS+ patients from H/CS+ controls with the highest AUC of 0.935. Cancer and lung-cancer-enriched pathways were significantly associated with the three miRNAs; in addition, nicotinate/nicotinamide metabolism, inflammation, and pulmonary hypertension were associated with miR-133a-3p. Our findings highlight how cigarette smoking affects the reliable identification of circulating miRNAs as diagnostic biomarkers in lung cancer and suggest a smoking-dependent pathogenic role of miR-133a-3p in smokers.
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Affiliation(s)
- Eric Gustavo Ramírez-Salazar
- Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico;
| | - Luis Vicente Gayosso-Gómez
- Department of Research in Biochemistry, Research Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Renata Baez-Saldaña
- Pneumology-Oncology Service, Instituto Nacional de Enfermedades Respiratorias, Mexico City 14080, Mexico;
| | - Ramcés Falfán-Valencia
- HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Rogelio Pérez-Padilla
- Department of Research in Tobacco and COPD, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Anjarath L. Higuera-Iglesias
- Department of Clinical Epidemiology Research, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - María E. Vázquez-Manríquez
- Department of Pathology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Blanca Ortiz-Quintero
- Department of Research in Biochemistry, Research Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
- Correspondence: ; Tel.: +52-55-54871705
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12
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Huang S, Li D, Zhuang L, Sun L, Wu J. Identification of Arp2/3 Complex Subunits as Prognostic Biomarkers for Hepatocellular Carcinoma. Front Mol Biosci 2021; 8:690151. [PMID: 34307456 PMCID: PMC8299467 DOI: 10.3389/fmolb.2021.690151] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/14/2021] [Indexed: 01/15/2023] Open
Abstract
The actin-related protein 2/3 complex (Arp2/3) is a major actin nucleator that has been widely reported and plays an important role in promoting the migration and invasion of various cancers. However, the expression patterns and prognostic values of Arp2/3 subunits in hepatocellular carcinoma (HCC) remain unclear. In this study, The Cancer Genome Atlas (TCGA) and UCSC Xena databases were used to obtain mRNA expression and the corresponding clinical information, respectively. The differential expression and Arp2/3 subunits in HCC were analyzed using the “limma” package of R 4.0.4 software. The prognostic value of each subunit was evaluated using Kaplan–Meier survival analysis and Cox proportional hazards regression analyses. The results revealed that mRNA expression of Arp2/3 members (ACTR2, ACTR3, ARPC1A, APRC1B, ARPC2, ARPC3, ARPC4, ARPC5, and ARPC5L) was upregulated in HCC. Higher expression of Arp2/3 members was significantly correlated with worse overall survival (OS) and shorter progression-free survival (PFS) in HCC patients. Cox proportional hazards regression analyses demonstrated that ACTR3, ARPC2, and ARPC5 were independent prognostic biomarkers of survival in patients with HCC. The relation between tumor immunocyte infiltration and the prognostic subunits was determined using the TIMER 2.0 platform and the GEPIA database. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanisms of prognostic subunits in the carcinogenesis of HCC. The results revealed that ACTR3, ARPC2, and ARPC5 were significantly positively correlated with the infiltration of immune cells in HCC. The GSEA results indicated that ACTR3, ARPC2, and ARPC5 are involved in multiple cancer-related pathways that promote the development of HCC. In brief, various analyses indicated that Arp2/3 complex subunits were significantly upregulated and predicted worse survival in HCC, and they found that ACTR3, ARPC2, and ARPC5 could be used as independent predictors of survival and might be applied as promising molecular targets for diagnosis and therapy of HCC in the future.
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Affiliation(s)
- Shenglan Huang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Dan Li
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - LingLing Zhuang
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China.,Department of Gynaecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Liying Sun
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Jianbing Wu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
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13
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Kim HR, Park JS, Karabulut H, Yasmin F, Jun CD. Transgelin-2: A Double-Edged Sword in Immunity and Cancer Metastasis. Front Cell Dev Biol 2021; 9:606149. [PMID: 33898417 PMCID: PMC8060441 DOI: 10.3389/fcell.2021.606149] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
Transgelin-2, a small actin-binding protein, is the only transgelin family member expressed in immune cells. In T and B lymphocytes, transgelin-2 is constitutively expressed, but in antigen-presenting cells, it is significantly upregulated upon lipopolysaccharide stimulation. Transgelin-2 acts as a molecular staple to stabilize the actin cytoskeleton, and it competes with cofilin to bind filamentous (F)-actin. This action may enable immune synapse stabilization during T-cell interaction with cognate antigen-presenting cells. Furthermore, transgelin-2 blocks Arp2/3 complex-nucleated actin branching, which is presumably related to small filopodia formation, enhanced phagocytic function, and antigen presentation. Overall, transgelin-2 is an essential part of the molecular armament required for host defense against neoplasms and infectious diseases. However, transgelin-2 acts as a double-edged sword, as its expression is also essential for a wide range of tumor development, including drug resistance and metastasis. Thus, targeting transgelin-2 can also have a therapeutic advantage for cancer treatment; selectively suppressing transgelin-2 expression may prevent multidrug resistance in cancer chemotherapy. Here, we review newly discovered molecular characteristics of transgelin-2 and discuss clinical applications for cancer and immunotherapy.
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Affiliation(s)
- Hye-Ran Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea
| | - Jeong-Su Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea
| | - Hatice Karabulut
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea
| | - Fatima Yasmin
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea
| | - Chang-Duk Jun
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea
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14
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Li H, Sun Y, Chen R. Constructing and validating a diagnostic nomogram for multiple sclerosis via bioinformatic analysis. 3 Biotech 2021; 11:127. [PMID: 33680693 DOI: 10.1007/s13205-021-02675-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/01/2021] [Indexed: 12/11/2022] Open
Abstract
The purpose of this study was to identify biomarkers and construct a diagnostic prediction model for multiple sclerosis (MS). Microarray datasets in the Gene Expression Omnibus (GEO) were downloaded. Weighted gene coexpression analysis (WGCNA) was used to search for hub modules and biomarkers related to MS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to roughly define their biological functions and pathways. Least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis were used to identify the diagnostic biomarkers and construct a nomogram. The calibration curve and receiver operating characteristic (ROC) curve were used to judge the diagnostic predictive ability. In addition, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was used to calculate the proportion of 22 kinds of immune cells. GSE41850 was used as the training set, and GSE17048 was used as the test set. WGCNA revealed one hub module containing 165 hub genes. Most of their biological functions and pathways are related to cell metabolism and immune cell activation. The diagnostic nomogram contained ARPC5, ROD1, UBQLN2, ZNF281, ABCA1 and FAS. The ROC curve and the calibration curve of the training set and test set confirmed that the nomogram had great prediction ability. In addition, monocytes and M0 macrophages were significantly different between MS patients and healthy people. The expression of ARPC5, ZNF281 and ABCA1 is correlated with M0 macrophages. The nomogram provides new insights and contributes to the accurate diagnosis of MS. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s13205-021-02675-1.
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Affiliation(s)
- Hao Li
- Department of Pediatrics, Hejiang People's Hospital, Sichuan, China
| | - Yong Sun
- Department of Pediatrics, Hejiang People's Hospital, Sichuan, China
| | - Rong Chen
- Department of Pediatrics, Hejiang People's Hospital, Sichuan, China
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15
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Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype. Cell Death Dis 2021; 12:171. [PMID: 33568634 PMCID: PMC7876150 DOI: 10.1038/s41419-021-03436-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 01/10/2023]
Abstract
Global dysregulation of RNA splicing and imbalanced sphingolipid metabolism has emerged as promoters of cancer cell transformation. Here, we present specific signature of alternative splicing (AS) events of sphingolipid genes for each breast cancer subtype from the TCGA-BRCA dataset. We show that ceramide synthase 2 (CERS2) undergoes a unique cassette exon event specifically in Luminal B subtype tumors. We validated this exon 8 skipping event in Luminal B cancer cells compared to normal epithelial cells, and in patient-derived tumor tissues compared to matched normal tissues. Differential AS-based survival analysis shows that this AS event of CERS2 is a poor prognostic factor for Luminal B patients. As Exon 8 corresponds to catalytic Lag1p domain, overexpression of AS transcript of CERS2 in Luminal B cancer cells leads to a reduction in the level of very-long-chain ceramides compared to overexpression of protein-coding (PC) transcript of CERS2. We further demonstrate that this AS event-mediated decrease of very-long-chain ceramides leads to enhanced cancer cell proliferation and migration. Therefore, our results show subtype-specific AS of sphingolipid genes as a regulatory mechanism that deregulates sphingolipids like ceramides in breast tumors, and can be explored further as a suitable therapeutic target.
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16
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Liu W, Shi X, Wang B. microRNA-133a exerts tumor suppressive role in oral squamous cell carcinoma through the Notch signaling pathway via downregulation of CTBP2. Cancer Gene Ther 2021; 29:62-72. [PMID: 33531645 DOI: 10.1038/s41417-020-00289-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022]
Abstract
microRNAs (miRNAs) have been revealed to participate in some oral cancers and are proved to be effective. In the present study, we tried to explore the biological function of miR-133a in oral squamous cell carcinoma (OSCC) cells. The relationship that C-terminal-binding proteins 2 (CTBP2) was the putative target gene of miR-133a revealed from bioinformatics analysis was further was further validated by dual-luciferase reporter gene assay. In total, 40 patients with OSCC were enrolled for characterization of miR-133a, CTBP2, and Notch signaling pathway-related gene expression in clinical OSCC tissues. Low expression of miR-133a and high expression of CTBP2, Hes1, Notch-1, and Notch-3 were determined in OSCC tissues. OSCC cell lines were transfected with miR-133a inhibitor, miR-133a mimic, or shRNA targeting CTBP2, in response to which cell proliferation, migration, invasion, cell cycle, and apoptosis were evaluated. Transfection of miR-133a mimic induced apoptosis and inhibited OSCC cell proliferation, migration, and invasion and this was demonstrated to be attributable to decreased CTBP2 expression and suppression of the Notch signaling pathway. Taken together, we concluded that miR-133a acted as a tumor suppressor in OSCC through inhibition of the Notch signaling pathway via binding to CTBP2.
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Affiliation(s)
- Wei Liu
- Department of Stomatology, Linyi People's Hospital, 276000, Linyi, P. R. China
| | - Xiaoming Shi
- Department of Stomatology, Linyi People's Hospital, 276000, Linyi, P. R. China
| | - Baoliang Wang
- Department of Stomatology, Linyi People's Hospital, 276000, Linyi, P. R. China.
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17
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Hiraku Y, Watanabe J, Kaneko A, Ichinose T, Murata M. MicroRNA expression in lung tissues of asbestos-exposed mice: Upregulation of miR-21 and downregulation of tumor suppressor genes Pdcd4 and Reck. J Occup Health 2021; 63:e12282. [PMID: 34679210 PMCID: PMC8535435 DOI: 10.1002/1348-9585.12282] [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: 09/04/2020] [Revised: 08/18/2021] [Accepted: 09/04/2021] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Asbestos causes lung cancer and malignant mesothelioma in humans, but the precise mechanism has not been well understood. MicroRNA (miRNA) is a short non-coding RNA that suppresses gene expression and participates in human diseases including cancer. In this study, we examined the expression levels of miRNA and potential target genes in lung tissues of asbestos-exposed mice by microarray analysis. METHODS We intratracheally administered asbestos (chrysotile and crocidolite, 0.05 or 0.2 mg/instillation) to 6-week-old ICR male mice four times weekly. We extracted total RNA from lung tissues and performed microarray analysis for miRNA and gene expression. We also carried out real-time polymerase chain reaction (PCR), Western blotting, and immunohistochemistry to confirm the results of microarray analysis. RESULTS Microarray analysis revealed that the expression levels of 14 miRNAs were significantly changed by chrysotile and/or crocidolite (>2-fold, P < .05). Especially, miR-21, an oncogenic miRNA, was significantly upregulated by both chrysotile and crocidolite. In database analysis, miR-21 was predicted to target tumor suppressor genes programmed cell death 4 (Pdcd4) and reversion-inducing-cysteine-rich protein with kazal motifs (Reck). Although real-time PCR showed that Pdcd4 was not significantly downregulated by asbestos exposure, Western blotting and immunohistochemistry revealed that PDCD4 expression was reduced especially by chrysotile. Reck was significantly downregulated by chrysotile in real-time PCR and immunohistochemistry. CONCLUSIONS This is the first study demonstrating that miR-21 was upregulated and corresponding tumor suppressor genes were downregulated in lung tissues of asbestos-exposed animals. These molecular events are considered to be an early response to asbestos exposure and may contribute to pulmonary toxicity and carcinogenesis.
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Grants
- 23659328 Ministry of Education, Culture, Sports, Science and Technology, Japan
- 24390153 Ministry of Education, Culture, Sports, Science and Technology, Japan
- 15H04784 Ministry of Education, Culture, Sports, Science and Technology, Japan
- 18H03038 Ministry of Education, Culture, Sports, Science and Technology, Japan
- Grants-in-Aid for Scientific Research
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Affiliation(s)
- Yusuke Hiraku
- Department of Environmental HealthUniversity of Fukui School of Medical SciencesEiheijiFukuiJapan
- Department of Environmental and Molecular MedicineMie University Graduate School of MedicineTsuMieJapan
| | - Jun Watanabe
- Department of Environmental and Molecular MedicineMie University Graduate School of MedicineTsuMieJapan
| | - Akira Kaneko
- Department of Environmental and Molecular MedicineMie University Graduate School of MedicineTsuMieJapan
| | - Takamichi Ichinose
- Department of Health SciencesOita University of Nursing and Health SciencesOitaJapan
| | - Mariko Murata
- Department of Environmental and Molecular MedicineMie University Graduate School of MedicineTsuMieJapan
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18
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Huang S, Wei YK, Kaliamurthi S, Cao Y, Nangraj AS, Sui X, Chu D, Wang H, Wei DQ, Peslherbe GH, Selvaraj G, Shi J. Circulating miR-1246 Targeting UBE2C, TNNI3, TRAIP, UCHL1 Genes and Key Pathways as a Potential Biomarker for Lung Adenocarcinoma: Integrated Biological Network Analysis. J Pers Med 2020; 10:162. [PMID: 33050659 PMCID: PMC7712139 DOI: 10.3390/jpm10040162] [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: 08/20/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
Analysis of circulating miRNAs (cmiRNAs) before surgical operation (BSO) and after the surgical operation (ASO) has been informative for lung adenocarcinoma (LUAD) diagnosis, progression, and outcomes of treatment. Thus, we performed a biological network analysis to identify the potential target genes (PTGs) of the overexpressed cmiRNA signatures from LUAD samples that had undergone surgical therapy. Differential expression (DE) analysis of microarray datasets, including cmiRNAs (GSE137140) and cmRNAs (GSE69732), was conducted using the Limma package. cmiR-1246 was predicted as a significantly upregulated cmiRNA of LUAD samples BSO and ASO. Then, 9802 miR-1246 target genes (TGs) were predicted using 12 TG prediction platforms (MiRWalk, miRDB, and TargetScan). Briefly, 425 highly expressed overlapping miRNA-1246 TGs were observed between the prediction platform and the cmiRNA dataset. ClueGO predicted cell projection morphogenesis, chemosensory behavior, and glycosaminoglycan binding, and the PI3K-Akt signaling pathways were enriched metabolic interactions regulating miRNA-1245 overlapping TGs in LUAD. Using 425 overlapping miR-1246 TGs, a protein-protein interaction network was constructed. Then, 12 PTGs of three different Walktrap modules were identified; among them, ubiquitin-conjugating enzyme E2C (UBE2C), troponin T1(TNNT1), T-cell receptor alpha locus interacting protein (TRAIP), and ubiquitin c-terminal hydrolase L1(UCHL1) were positively correlated with miR-1246, and the high expression of these genes was associated with better overall survival of LUAD. We conclude that PTGs of cmiRNA-1246 and key pathways, namely, ubiquitin-mediated proteolysis, glycosaminoglycan binding, the DNA metabolic process, and the PI3K-Akt-mTOR signaling pathway, the neurotrophin and cardiomyopathy signaling pathway, and the MAPK signaling pathway provide new insights on a noninvasive prognostic biomarker for LUAD.
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Affiliation(s)
- Siyuan Huang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, China; (S.H.); (X.S.)
| | - Yong-Kai Wei
- College of Science, Henan University of Technology, Zhengzhou 450001, China;
| | - Satyavani Kaliamurthi
- Centre for Research in Molecular Modeling and Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada; (S.K.); (D.-Q.W.); (G.H.P.); (G.S.)
- Center of Interdisciplinary Science-Computational Life Sciences, College of Biological Engineering, Henan University of Technology, No.100, Lianhua Street, Hi-Tech Development Zone, Zhengzhou 450001, China
| | - Yanghui Cao
- Department of General Surgery, Henan Tumor Hospital, No.127 Dongming Road, Zhengzhou 450008, China;
| | - Asma Sindhoo Nangraj
- The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China;
| | - Xin Sui
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, China; (S.H.); (X.S.)
| | - Dan Chu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, China; (D.C.); (H.W.)
| | - Huan Wang
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, China; (D.C.); (H.W.)
| | - Dong-Qing Wei
- Centre for Research in Molecular Modeling and Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada; (S.K.); (D.-Q.W.); (G.H.P.); (G.S.)
- Center of Interdisciplinary Science-Computational Life Sciences, College of Biological Engineering, Henan University of Technology, No.100, Lianhua Street, Hi-Tech Development Zone, Zhengzhou 450001, China
- The State Key Laboratory of Microbial Metabolism, College of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China;
| | - Gilles H. Peslherbe
- Centre for Research in Molecular Modeling and Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada; (S.K.); (D.-Q.W.); (G.H.P.); (G.S.)
| | - Gurudeeban Selvaraj
- Centre for Research in Molecular Modeling and Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, QC H4B 1R6, Canada; (S.K.); (D.-Q.W.); (G.H.P.); (G.S.)
- Center of Interdisciplinary Science-Computational Life Sciences, College of Biological Engineering, Henan University of Technology, No.100, Lianhua Street, Hi-Tech Development Zone, Zhengzhou 450001, China
| | - Jiang Shi
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou 450052, China; (D.C.); (H.W.)
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19
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Ren P, Xing L, Hong X, Chang L, Zhang H. LncRNA PITPNA-AS1 boosts the proliferation and migration of lung squamous cell carcinoma cells by recruiting TAF15 to stabilize HMGB3 mRNA. Cancer Med 2020; 9:7706-7716. [PMID: 32871048 PMCID: PMC7571819 DOI: 10.1002/cam4.3268] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/25/2020] [Accepted: 06/02/2020] [Indexed: 12/21/2022] Open
Abstract
Plenty of reports have probed the involvement of abnormally expressed lncRNAs in multiple cancers, including lung squamous cell carcinoma (LUSC). Through online database GEPIA, lncRNA PITPNA antisense RNA 1 (PITPNA-AS1) was highly expressed in LUSC samples, and these tendency was further affirmed in LUSC cells. The aim of current study was to investigate the related mechanism of PITPNA-AS1 in LUSC. Functional experiments verified that depletion of PITPNA-AS1 hampered the proliferative and migratory abilities, but accelerated apoptosis of LUSC cells. Additionally, we observed the increased expression of HMGB3 and its positive correlation with PITPNA-AS1 in LUSC samples. Interestingly, PITPNA-AS1 mainly located in the cytosol of LUSC cells, and also affected mRNA stability of HMGB3. Furthermore, the repressed mRNA stability of HMGB3 by PITPNA-AS1 via TAF15 was exposed through mechanism experiments. The mediatory function of PITPNA-AS1 on HMGB3 was validated via rescue assays. All in all, PITPNA-AS1 promoted the proliferation and migration of LUSC cells via stabilizing HMGB3 by TAF15. In conclusion, our study displayed a novel mechanism underlying PITPNA-AS1 in LUSC cells.
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Affiliation(s)
- Ping Ren
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Lei Xing
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Xiaodong Hong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Liang Chang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Hong Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
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20
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Zhang J, Bing Z, Yan P, Tian J, Shi X, Wang Y, Yang K. Identification of 17 mRNAs and a miRNA as an integrated prognostic signature for lung squamous cell carcinoma. J Gene Med 2020; 21:e3105. [PMID: 31215090 DOI: 10.1002/jgm.3105] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/22/2019] [Accepted: 06/05/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Gene signatures for predicting the outcome of lung squamous cell carcinoma (LUSC) have been employed for many years. However, various signatures have been applied in clinical practice. Therefore, in the present study, we aimed to filter out an effective LUSC prognostic gene signature by simultaneously integrating mRNA and microRNA (miRNA). METHODS First, based on data from the Cancer Genome Atlas (TCGA) (https://www.cancer.gov/tcga), mRNAs and miRNAs that were related to overall survival of LUSC were obtained by the least absolute shrinkage and selection operator method. Subsequently, the predicting effect was tested by time-dependent receiver operating characteristic curve analysis and Kaplan-Meier survival analysis. Next, related clinical indices were added to evaluate the efficiency of the selected gene signatures. Finally, validation and comparison using three independent gene signatures were performed using data from the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo). RESULTS Our data showed that the prognostic index (PI) contained 17 mRNAs and one miRNA. According to the best normalized cut-off of PI (0.0247), the hazard ratio of the PI was 3.40 (95% confidence interval = 2.33-4.96). Moreover, when clinical factors were introduced, the PI was still the most significant index. In addition, only two Gene Ontology terms with p < 0.05 were reported. Furthermore, validation implied that, using our 18-gene signature, only hazard ratio = 1.36 (95% confidence interval = 1.01-1.83) was significant compared to the other three groups of gene biomarkers. CONCLUSIONS The 18-gene signature selected based on data from the TCGA database had an effective prognostic value for LUSC patients.
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Affiliation(s)
- Jingyun Zhang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Zhitong Bing
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,Department of Computational Physics, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Peijing Yan
- Institution of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital, Lanzhou, China
| | - Jinhui Tian
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Xiue Shi
- Gansu Rehabilitation Center Hospital, Lanzhou, China.,Gansu Evidence-Based Rehabilitation Medicine Center, Lanzhou, China
| | - Yongfeng Wang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Kehu Yang
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.,Institution of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital, Lanzhou, China.,Gansu Evidence-Based Rehabilitation Medicine Center, Lanzhou, China
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21
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Zhang X, Wang L, Li H, Zhang L, Zheng X, Cheng W. Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression. Cell Death Dis 2020; 11:580. [PMID: 32709863 PMCID: PMC7381619 DOI: 10.1038/s41419-020-02772-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
Cancer progression including proliferation, metastasis, and chemoresistance has become a serious hindrance to cancer therapy. This phenomenon mainly derives from the innate insensitive or acquired resistance of cancer cells to apoptosis. Ferroptosis is a newly discovered mechanism of programmed cell death characterized by peroxidation of the lipid membrane induced by reactive oxygen species. Ferroptosis has been confirmed to eliminate cancer cells in an apoptosis-independent manner, however, the specific regulatory mechanism of ferroptosis is still unknown. The use of ferroptosis for overcoming cancer progression is limited. Noncoding RNAs have been found to play an important roles in cancer. They regulate gene expression to affect biological processes of cancer cells such as proliferation, cell cycle, and cell death. Thus far, the functions of ncRNAs in ferroptosis of cancer cells have been examined, and the specific mechanisms by which noncoding RNAs regulate ferroptosis have been partially discovered. However, there is no summary of ferroptosis associated noncoding RNAs and their functions in different cancer types. In this review, we discuss the roles of ferroptosis-associated noncoding RNAs in detail. Moreover, future work regarding the interaction between noncoding RNAs and ferroptosis is proposed, the possible obstacles are predicted and associated solutions are put forward. This review will deepen our understanding of the relationship between noncoding RNAs and ferroptosis, and provide new insights in targeting noncoding RNAs in ferroptosis associated therapeutic strategies.
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Affiliation(s)
- Xuefei Zhang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Lingling Wang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Haixia Li
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Lei Zhang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
| | - Xiulan Zheng
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
| | - Wen Cheng
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
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22
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Liu L, Li Y, Zhang R, Li C, Xiong J, Wei Y. MIR205HG acts as a ceRNA to expedite cell proliferation and progression in lung squamous cell carcinoma via targeting miR-299-3p/MAP3K2 axis. BMC Pulm Med 2020; 20:163. [PMID: 32513149 PMCID: PMC7278044 DOI: 10.1186/s12890-020-1174-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 04/29/2020] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Long noncoding RNAs (lncRNAs) have been associated with many types of cancers, but their molecular mechanisms in lung squamous cell carcinoma (LUSC) have not been fully studied. Therefore, the current study investigated the regulation role of microRNA-205 host gene (MIR205HG) in LUSC and recognized the target genes managed by this lncRNA. METHODS MIR205HG expression was assessed by the quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The effects of silenced MIR205HG on cell biological behaviors were detected by colony formation assay, transwell assay, flow cytometry analysis and western blot analysis. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were utilized to proof the binding relationship between miR-299-3p and MIR205HG/mitogen-activated protein kinase kinase kinase 2 (MAP 3 K2). RESULTS The expression levels of MIR205HG in LUSC tissues and cell lines were obviously up-regulated. Down-regulation of MIR205HG expression remarkably reduced cell proliferation, migration and epithelial-to-mesenchymal transition (EMT) progression, whereas promoted cell apoptosis. MIR205HG could bind with miR-299-3p and down-regulation of MIR205HG elevated miR-299-3p expression. MAP 3 K2 acted as the target gene of miR-299-3p and was up-regulated by MIR205HG overexpression. Overexpressing MAP 3 K2 could counteract the effects of down-regulating MIR205HG on LUSC progression to some degree. CONCLUSION MIR205HG acts as a competing endogenous RNA (ceRNA) to expedite cell proliferation and progression via targeting miR-299-3p in LUSC.
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Affiliation(s)
- Limin Liu
- Respiration Department, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, No.9, Tujialing, Wuchang District, Wuhan, 430064, Hubei, China
| | - Yulei Li
- Respiration Department, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, No.9, Tujialing, Wuchang District, Wuhan, 430064, Hubei, China
| | - Ruifang Zhang
- Respiration Department, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, No.9, Tujialing, Wuchang District, Wuhan, 430064, Hubei, China
| | - Chun Li
- Respiration Department, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, No.9, Tujialing, Wuchang District, Wuhan, 430064, Hubei, China
| | - Jing Xiong
- Respiration Department, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, No.9, Tujialing, Wuchang District, Wuhan, 430064, Hubei, China
| | - Yuan Wei
- Three Wards of Outpatient Service, Wuhan Jin Yin Tan Hospital, No.1 Yintan Road, Dongxihu District, Wuhan, 433013, Hubei, China.
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23
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Xu N, Chen SH, Lin TT, Cai H, Ke ZB, Dong RN, Huang P, Li XD, Chen YH, Zheng QS. Development and validation of hub genes for lymph node metastasis in patients with prostate cancer. J Cell Mol Med 2020; 24:4402-4414. [PMID: 32130760 PMCID: PMC7176841 DOI: 10.1111/jcmm.15098] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 12/24/2022] Open
Abstract
Lymph node metastasis is one of the most important independent risk factors that can negatively affect the prognosis of prostate cancer (PCa); however, the exact mechanisms have not been well studied. This study aims to better understand the underlying mechanism of lymph node metastasis in PCa by bioinformatics analysis. We analysed a total of 367 PCa cases from the cancer genome atlas database and performed weighted gene co-expression network analysis to explore some modules related to lymph node metastasis. Gene Ontology analysis and pathway enrichment analysis were conducted for functional annotation, and a protein-protein interaction network was built. Samples from the International Cancer Genomics Consortium database were used as a validation set. The turquoise module showed the most relevance with lymph node metastasis. Functional annotation showed that biological processes and pathways were mainly related to activation of the processes of cell cycle and mitosis. Four hub genes were selected: CKAP2L, CDCA8, ERCC6L and ARPC1A. Further validation showed that the four hub genes well-distinguished tumour and normal tissues, and they were good biomarkers for lymph node metastasis of PCa. In conclusion, the identified hub genes facilitate our knowledge of the underlying molecular mechanism for lymph node metastasis of PCa.
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Affiliation(s)
- Ning Xu
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Shao-Hao Chen
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ting-Ting Lin
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Hai Cai
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Zhi-Bin Ke
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ru-Nan Dong
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Peng Huang
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xiao-Dong Li
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ye-Hui Chen
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qing-Shui Zheng
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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24
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Chen YC, Sahoo S, Brien R, Jung S, Humphries B, Lee W, Cheng YH, Zhang Z, Luker KE, Wicha MS, Luker GD, Yoon E. Single-cell RNA-sequencing of migratory breast cancer cells: discovering genes associated with cancer metastasis. Analyst 2019; 144:7296-7309. [PMID: 31710321 PMCID: PMC8942075 DOI: 10.1039/c9an01358j] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
Considerable evidence suggests breast cancer metastasis arises from cells undergoing epithelial-to-mesenchymal-transition (EMT) and cancer stem-like cells (CSCs). Using a microfluidic device that enriches migratory breast cancer cells with enhanced capacity for tumor formation and metastasis, we identified genes differentially expressed in migratory cells by high-throughput single-cell RNA-sequencing. Migratory cells exhibited overall signatures of EMT and CSCs with variable expression of marker genes, and they retained expression profiles of EMT over time. With single-cell resolution, we discovered intermediate EMT states and distinct epithelial and mesenchymal sub-populations of migratory cells, indicating breast cancer cells can migrate rapidly while retaining an epithelial state. Migratory cells showed differential profiles for regulators of oxidative stress, mitochondrial morphology, and the proteasome, revealing potential vulnerabilities and unexpected consequences of drugs. We also identified novel genes correlated with cell migration and outcomes in breast cancer as potential prognostic biomarkers and therapeutic targets to block migratory cells in metastasis.
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Affiliation(s)
- Yu-Chih Chen
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
- Forbes Institute for Cancer Discovery, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA
| | - Saswat Sahoo
- Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel, Blvd. Ann Arbor, MI 48109-2099, USA
| | - Riley Brien
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
| | - Seungwon Jung
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
| | - Brock Humphries
- Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
| | - Woncheol Lee
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
| | - Yu-Heng Cheng
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
| | - Zhixiong Zhang
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
| | - Kathryn E. Luker
- Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
| | - Max S. Wicha
- Forbes Institute for Cancer Discovery, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA
| | - Gary D. Luker
- Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel, Blvd. Ann Arbor, MI 48109-2099, USA
- Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
- Department of Microbiology and Immunology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
| | - Euisik Yoon
- Department of Electrical Engineering and Computer Science, University of Michigan, 1301 Beal Avenue, Ann Arbor, MI 48109-2122
- Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel, Blvd. Ann Arbor, MI 48109-2099, USA
- Center for Nanomedicine, Institute for Basic Science (IBS) and Graduate Program of Nano Biomedical Engineering (Nano BME), Yonsei University, Seoul 03722, Korea
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25
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Reale E, Taverna D, Cantini L, Martignetti L, Osella M, De Pittà C, Virga F, Orso F, Caselle M. Investigating the epi-miRNome: identification of epi-miRNAs using transfection experiments. Epigenomics 2019; 11:1581-1599. [PMID: 31693439 DOI: 10.2217/epi-2019-0050] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Aim: Growing evidence shows a strong interplay between post-transcriptional regulation, mediated by miRNAs (miRs) and epigenetic regulation. Nevertheless, the number of experimentally validated miRs (called epi-miRs) involved in these regulatory circuitries is still very small. Material & methods: We propose a pipeline to prioritize candidate epi-miRs and to identify potential epigenetic interactors of any given miR starting from miR transfection experiment datasets. Results & conclusion: We identified 34 candidate epi-miRs: 19 of them are known epi-miRs, while 15 are new. Moreover, using an in-house generated gene expression dataset, we experimentally proved that a component of the polycomb-repressive complex 2, the histone methyltransferase enhancer of zeste homolog 2 (EZH2), interacts with miR-214, a well-known prometastatic miR in melanoma and breast cancer, highlighting a miR-214-EZH2 regulatory axis potentially relevant in tumor progression.
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Affiliation(s)
- Elisa Reale
- Department of Physics & INFN, University of Torino, 10125, Torino, Italy
| | - Daniela Taverna
- Molecular Biotechnology Center (MBC), 10126, Torino, Italy.,Department of Molecular Biotechnology & Health Sciences, 10126, Torino, Italy.,Center for Complex Systems in Molecular Biology & Medicine, University of Torino, 10123, Torino, Italy
| | - Laura Cantini
- Institut Curie, PSL Research University, INSERM U900, Paris, France.,Computational Systems Biology Team, Institut de Biologie de l'Ecole Normale Supérieure, CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, Paris Sciences et Lettres Research University, 75005 Paris, France
| | | | - Matteo Osella
- Department of Physics & INFN, University of Torino, 10125, Torino, Italy
| | | | - Federico Virga
- Molecular Biotechnology Center (MBC), 10126, Torino, Italy.,Department of Molecular Biotechnology & Health Sciences, 10126, Torino, Italy
| | - Francesca Orso
- Molecular Biotechnology Center (MBC), 10126, Torino, Italy.,Department of Molecular Biotechnology & Health Sciences, 10126, Torino, Italy.,Center for Complex Systems in Molecular Biology & Medicine, University of Torino, 10123, Torino, Italy
| | - Michele Caselle
- Department of Physics & INFN, University of Torino, 10125, Torino, Italy
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26
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Yu M, Xu B, Yang H, Xue S, Zhang R, Zhang H, Ying X, Dai Z. MicroRNA-218 regulates the chemo-sensitivity of cervical cancer cells through targeting survivin. Cancer Manag Res 2019; 11:6511-6519. [PMID: 31372052 PMCID: PMC6636183 DOI: 10.2147/cmar.s199659] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 04/10/2019] [Indexed: 12/24/2022] Open
Abstract
Background: Cervical cancer is one of the most lethal malignancies among women in the world. Every year about 311,365 women die because of cervical cancer. Chemo-resistance is the main reason of the lethal malignancies, and the mechanism of chemo-resistance in cervical cancer still remains largely elusive. Purpose: Previous studies reported that microRNAs played important biological roles in the chemo-resistance in many types of cancers, in the present study we tried to investigate the biological roles of microRNA-218 in chemo-resistance in cervical cancer cells. Results: Real-time PCR results indicated microRNA-218 was downregulated in cisplatin-resistant HeLa/DDP and SiHa/DDP cells compared with the mock HeLa and SiHa cells. CCK-8 assay results showed upregulation of microRNA-218 enhanced the cisplatin sensitivity of cervical cancer cells; while downregulation of microRNA-218 decreased the cisplatin sensitivity of cervical cancer cells. Dual-luciferase assay indicated survivin was a direct target of microRNA-218. Western blotting and PCR results indicated the expression of survivin in HeLa/DDP and SiHa/DDP cells was significantly increased compared with HeLa and SiHa cells. Further study indicated induction of microRNA-218 decreased the expression of survivin while inhibition of microRNA-218 increased the expression of survivin in cervical cancer cells. Cell apoptosis results indicated induction of microRNA-218 induced the cell apoptosis in cervical cancer cells. Conclusion: Our data revealed microRNA-218 enhanced the cisplatin sensitivity in cervical cancer cells through regulation of cell growth and cell apoptosis, which could potentially benefit to the cervical cancer treatment in the future.
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Affiliation(s)
- Minmin Yu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, People's Republic of China.,Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, People's Republic of China
| | - Baozhen Xu
- Department of Obstetrics and Gynecology, Nanjing Lishui People's Hospital, Nanjing 211200, People's Republic of China
| | - Hui Yang
- Department of Obstetrics and Gynecology, Huaian Maternal and Child Health Care Hospital, Huaian 223002, People's Republic of China
| | - Songlin Xue
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, People's Republic of China
| | - Rong Zhang
- Department of Obstetrics and Gynecology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, People's Republic of China
| | - Hongmei Zhang
- Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, People's Republic of China
| | - Xiaoyan Ying
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, People's Republic of China
| | - Zhiqin Dai
- Department of Gynecologic Oncology, Jiangsu Cancer Hospital, Nanjing 210009, People's Republic of China
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27
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Xu N, Qu GY, Wu YP, Lin YZ, Chen DN, Li XD, Chen SH, Huang JB, Zheng QS, Xue XY, Wei Y. ARPC4 promotes bladder cancer cell invasion and is associated with lymph node metastasis. J Cell Biochem 2019; 121:231-243. [PMID: 31190401 DOI: 10.1002/jcb.29136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/08/2019] [Accepted: 05/10/2019] [Indexed: 12/30/2022]
Abstract
The significance of actin-related protein 2/3 complex subunit 4 (ARPC4) expression in bladder cancer, and its potential role in the invasion and migration of bladder cancer cells, has yet to be determined. This study was to identify the correlation between ARPC4 and lymph node metastasis, and to determine the role of ARPC4 in the invasive migration of T24 bladder cancer cells. One hundred and ninety-eight bladder cancer tissues and 40 normal bladder and lymph node tissues were examined. Tissue microarrays were constructed and subjected to immunohistochemical stating for ARPC4. Multiple logistic analysis was used to determine risk factors associated with bladder cancer metastasis. ARPC4 expression in T24 bladder cancer cells was suppressed using small interfering RNA and changes in protein levels were determined by Western blot analysis. The proliferation of bladder cancer cells after knocking down of ARPC4 was determined by cell counting kit-8. The effects of ARPC4 knockdown on T24 cell invasion and migration was determined using transwell and wound healing assays. Immunofluorescence analysis was performed to examine changes in pseudopodia formation and actin cytoskeleton structure. The expression of ARPC4 was elevated in bladder cancer tissues than normal tissues (84.3% vs 27.5%, P < 0.001). The multivariate logistic analysis demonstrated that the level of ARPC4, as a risk factor, was correlated with lymphatic metastasis (P < 0.05). ARPC4 knockdown attenuated proliferation, migration, invasion, and pseudopodia formation in T24 cells. ARPC4 expression, as a risk factor, is associated with lymphatic metastasis and is upregulated in bladder cancer tissues in comparison with normal tissues. Inhibition of ARPC4 expression significantly attenuates the proliferation, migration, and invasion of bladder cancer cell, possibly due to defects in pseudopodia formation.
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Affiliation(s)
- Ning Xu
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Gen-Yi Qu
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,Department of Urology, Zhuzhou Central Hospital, Zhuzhou, China
| | - Yu-Peng Wu
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yun-Zhi Lin
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Dong-Ning Chen
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xiao-Dong Li
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Shao-Hao Chen
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Jin-Bei Huang
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Qing-Shui Zheng
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xue-Yi Xue
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yong Wei
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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28
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Liu W, Cui Z, Zan X. Identifying cancer‐related microRNAs based on subpathways. IET Syst Biol 2018; 12:273-278. [DOI: 10.1049/iet-syb.2018.5025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Wenbin Liu
- Institute of Computational Science and Technology, Guangzhou UniversityGuangzhouPeople's Republic of China
| | - Zhendong Cui
- Institute of Computational Science and Technology, Guangzhou UniversityGuangzhouPeople's Republic of China
| | - Xiangzhen Zan
- Department of Information EngineeringWenzhou Vocational College of Science and TechnologyWenzhouPeople's Republic of China
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29
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Chen L, He X, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y. Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells. Sci Rep 2018; 8:15543. [PMID: 30341388 PMCID: PMC6195555 DOI: 10.1038/s41598-018-33913-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 10/08/2018] [Indexed: 12/11/2022] Open
Abstract
Dysregulation of microRNAs (miRNAs) contributes to epithelial-mesenchymal transition (EMT) of cancer, but the pathological roles of miRNAs in airway EMT of lung diseases remains largely unknown. We performed sequencing and real-time PCR analysis of the miRNA expression profile of human airway epithelial cells undergoing EMT, and revealed miR-133a to be one of the most common up-regulated miRNAs. MiR-133a was previously reported to be persistently up-regulated in airway epithelial cells of smokers. We found that mice exposed to cigarette smoke (CS) showed airway hyper-responsiveness, a typical symptom occurring in CS-related lung diseases, up-regulation of miR-133a and EMT marker protein N-cadherin in airway epithelium. Importantly, miR-133a overexpression induces airway epithelial cells to undergo spontaneous EMT via down-regulation of grainyhead-like 2 (GRHL2), an epithelial specific transcriptional factor. Loss of GRHL2 causes down-regulation of epithelial splicing regulatory protein 1 (ESRP1), a central coordinator of alternative splicing processes that are critical in the regulation of EMT. Down-regulation of ESRP1 induces isoform switching of adherens junction-associated protein p120-catenin, and leads to the loss of E-cadherin. Our study is the first to demonstrate that up-regulated miR-133a orchestrates airway EMT via alternative splicing processes, which points to novel therapeutic possibilities for the treatment of CS-related lung disease.
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Affiliation(s)
- Linjie Chen
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Xiaobai He
- College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Yan Xie
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Yapei Huang
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Dennis W Wolff
- Kansas City University of Medicine and Biosciences-Joplin, Joplin, MO, USA
| | - Peter W Abel
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Yaping Tu
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA.
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Xia E, Kanematsu S, Suenaga Y, Elzawahry A, Kondo H, Otsuka N, Moriya Y, Iizasa T, Kato M, Yoshino I, Yokoi S. MicroRNA induction by copy number gain is associated with poor outcome in squamous cell carcinoma of the lung. Sci Rep 2018; 8:15363. [PMID: 30337605 PMCID: PMC6194131 DOI: 10.1038/s41598-018-33696-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 10/03/2018] [Indexed: 12/14/2022] Open
Abstract
Copy number gains in cancer genomes have been shown to induce oncogene expression and promote carcinogenesis; however, their role in regulating oncogenic microRNAs (onco-miRNAs) remains largely unknown. Our aim was to identify onco-miRNAs induced by copy number gains in human squamous cell carcinoma (Sq) of the lung. We performed a genome-wide screen of onco-miRNAs from 245 Sqs using data sets from RNA-sequencing, comparative genomic hybridization, and the corresponding clinical information from The Cancer Genome Atlas. Among 1001 miRNAs expressed in the samples, 231 were correlated with copy number alternations, with only 11 of these being highly expressed in Sq compared to adenocarcinoma and normal tissues. Notably, miR-296-5p, miR-324-3p, and miR-3928-3p expression was significantly associated with poor prognosis. Multivariate analysis using the Cox proportional hazards model showed that miRNA expression and smoking were independent prognostic factors and were associated with poor prognosis. Furthermore, the three onco-miRNAs inhibited FAM46C to induce MYC expression, promoting proliferation of Sq cells. We found that copy number gains in Sq of the lung induce onco-miRNA expression that is associated with poor prognosis.
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Affiliation(s)
- Endi Xia
- Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba, Japan.,Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sotaro Kanematsu
- Division of Genetic Diagnostics, Chiba Cancer Center, Chiba, Japan
| | - Yusuke Suenaga
- Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Asmaa Elzawahry
- Department of Bioinformatics, National Cancer Center, Tokyo, Japan
| | - Hitomi Kondo
- Division of Genetic Diagnostics, Chiba Cancer Center, Chiba, Japan
| | - Noriko Otsuka
- Division of Genetic Diagnostics, Chiba Cancer Center, Chiba, Japan
| | - Yasumitsu Moriya
- Division of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan
| | - Toshihiko Iizasa
- Division of Thoracic Diseases, Chiba Cancer Center, Chiba, Japan
| | - Mamoru Kato
- Department of Bioinformatics, National Cancer Center, Tokyo, Japan
| | - Ichiro Yoshino
- Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sana Yokoi
- Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba, Japan. .,Division of Genetic Diagnostics, Chiba Cancer Center, Chiba, Japan.
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31
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Lim JH, Kim SG, Choi JM, Yang HJ, Kim JS, Jung HC. Helicobacter pylori Is Associated with miR-133a Expression through Promoter Methylation in Gastric Carcinogenesis. Gut Liver 2018; 12:58-66. [PMID: 28950691 PMCID: PMC5753685 DOI: 10.5009/gnl17263] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 08/04/2017] [Accepted: 09/14/2017] [Indexed: 12/24/2022] Open
Abstract
Background/Aims To investigate whether Helicobacter pylori eradication can reverse epigenetic silencing of microRNAs (miRNAs) which are associated with H. pylori-induced gastric carcinogenesis. Methods We examined expression and promoter methylation of miR-34b/c, miR-133a, let-7a, and let-7i in gastric cancer cell line, before/after demethylation. Among them, epigenetically controlled miRNAs were identified. Their expression and promoter methylation was examined in human tissues of H. pylori-positive gastric cancer (T), H. pylori-positive gastritis (H), and H. pylori-negative controls (C). We also compared changes of miRNA expression and promoter methylation in H. pylori-positive patients who were endoscopically treated for early gastric cancer, between baseline and 1 year later according to eradication status. Results In gastric cancer cell line, miR-34b/c and miR-133a showed epigenetic silencing. In human tissues, miR-34b/c and miR-133a showed serial increase of promoter methylation in order of C, H, and T (all, p<0.01), and the miR-133a expression showed serial decrease (C vs H, p=0.02; H vs T, p=0.01; C vs T, p<0.01) while miR-34b and miR-34c expressions did not. H. pylori eradication induced decrease of methylation (p<0.01) and increase of miR-133a expression (p=0.03), compared with noneradication group. Conclusions This result suggests H. pylori eradication could reverse methylation-silencing of miR-133a which is involved in H. pylori-induced gastric carcinogenesis.
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Affiliation(s)
- Joo Hyun Lim
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Min Choi
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
| | - Hyo-Joon Yang
- Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Xiong T, Luo Z. The Expression of Actin-Related Protein 2/3 Complex Subunit 5 (ARPC5) Expression in Multiple Myeloma and its Prognostic Significance. Med Sci Monit 2018; 24:6340-6348. [PMID: 30201948 PMCID: PMC6144731 DOI: 10.12659/msm.908944] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Background The aim of this study was to analyze the prognostic value of ARPC5 in patients with multiple myeloma (MM). Material/Methods MM gene expression studies GSE6477, GSE31162, GSE24080, and GSE19784 were obtained and analyzed. The expression of ARPC5 was assessed in normal plasma cells, baseline MM cells, and relapsed MM cells. Univariate and multivariable analyses were used to determine the relationship between ARPC5 expression and clinical characteristics and survivals of MM patients. Quantitative PCR was used to detect the expression ARPC5 in bone marrow mononuclear cells of MM patients and normal controls. GSEA was conducted to identify associated mechanisms. Results ARPC5 expression was significantly increased in baseline MM cells compared to normal plasma cells (P=0.0414). Meanwhile, ARPC5 was significantly increased in relapsed MM cells compared to baseline MM cells (P<0.0001). ARPC5 expression was significantly associated with β2-microglobin (P=0.047), serum lactate dehydrogenase (P=0.007), and rates of aspirate plasma cells (P=0.007). Meanwhile, patients in the ARPC5 high expression group were associated with poor overall survival (P=0.0027) and event-free survival (P=0.0102) compared to those in the ARPC5 low expression group. Multivariable analysis indicated that ARPC5 was an independent prognostic factor for MM patients. Quantitative PCR demonstrated that ARPC5 was significantly increased in MM patients. GSEA results indicated that ARPC5 might affect cellular growth of myeloma cells through mammalian target of rapamycin (mTOR)C1 signaling pathway. Conclusions ARPC5 could be treated as an independent biomarker for patients with MM.
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Affiliation(s)
- Tao Xiong
- Department of Hematology, The Second Clinical Medical College, Yangtze University, Jingzhou Central Hospital, Jingzhou, Hubei, China (mainland)
| | - Zeyu Luo
- Department of Hematology, The First Affiliated Hospital Of University Of South China, Hengyang, Hunan, China (mainland)
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Sun Y, Peng W, He W, Luo M, Chang G, Shen J, Zhao X, Hu Y. Transgelin-2 is a novel target of KRAS-ERK signaling involved in the development of pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:166. [PMID: 30041673 PMCID: PMC6056937 DOI: 10.1186/s13046-018-0818-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 06/29/2018] [Indexed: 02/08/2023]
Abstract
Background The KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC). Downstream effectors of KRAS signal pathways are crucial to the development of PDAC. The purpose of this study was to investigate the relationship between KRAS mutation and transgelin-2. Transgelin-2 is highly expressed in PDAC tissues compared with adjacent normal tissues. The underlying mechanism for upregulating transgelin-2 is largely unknown. Methods Expression of transgelin-2 was analyzed by microarray data and qRT-PCR. The effect of KRAS signaling on transgelin-2 expression was examined in PDAC cells in the presence or absence of the ERK inhibitor. The interaction of transgelin-2 with ERK was confirmed by immunoprecipitation. ERK-mediated Phosphorylation of transglein-2 was detected by in vivo and in vitro kinase assays. The gain-of-function and loss-of-function approaches were used to examine the role of phosphorylation of transgelin-2 on cell proliferation. Phosphorylation of transgelin-2 was detected by immunohistochemistry in PDAC tissues. Results Here we found transgelin-2 expression was induced by KRAS mutation. In the case of KRAS mutation, ERK2 interacted with 29–31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC. In addition, S145 phosphorylation of transgelin-2 was associated with a poor prognosis in patients with PDAC. Conclusions This study indicated that KRAS-ERK-mediated transeglin-2 phosphorylation played an important role in the development of PDAC. Inhibition of transgelin-2 phosphorylation may be a potential therapeutic strategy for targeting PDAC with KRAS mutation.
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Affiliation(s)
- Yan Sun
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenfang Peng
- Department of Endocrinology, Shanghai Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200336, China
| | - Weiwei He
- Department of Thoracic Surgery, Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China
| | - Man Luo
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Guilin Chang
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jiping Shen
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaoping Zhao
- Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Yu Hu
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Jo S, Kim HR, Mun Y, Jun CD. Transgelin-2 in immunity: Its implication in cell therapy. J Leukoc Biol 2018; 104:903-910. [PMID: 29749649 DOI: 10.1002/jlb.mr1117-470r] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 12/31/2022] Open
Abstract
Transgelin-2 is a small 22-kDa actin-binding protein implicated in actin dynamics, which stabilizes actin structures and participates in actin-associated signaling pathways. Much curiosity regarding transgelin-2 has centered around its dysregulation in tumor development and associated diseases. However, recent studies have shed new light on the functions of transgelin-2, the only transgelin family member present in leukocytes, in the context of various immune responses. In this review, we outlined the biochemical properties of transgelin-2 and its physiological functions in T cells, B cells, and macrophages. Transgelin-2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse. Transgelin-2 in B cells also participates in the stabilization of T cell-B cell conjugates. While transgelin-2 is expressed at trace levels in macrophages, its expression is highly upregulated upon lipopolysaccharide stimulation and plays an essential role in macrophage phagocytosis. Since transgelin-2 increases T cell adhesion to target cells via boosting the "inside-out" costimulatory activation of leukocyte function-associated antigen 1, transgelin-2 could be a suitable candidate to potentiate the antitumor response of cytotoxic T cells by compensating for the lack of costimulation in tumor microenvironment. We discussed the feasibility of using native or engineered transgelin-2 as a synergistic molecule in cell-based immunotherapies, without inducing off-target disturbance in actin dynamics in other cells.
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Affiliation(s)
- Suin Jo
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Hye-Ran Kim
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - YeVin Mun
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Chang-Duk Jun
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.,Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology, Gwangju, Korea
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Gufford BT, Robarge JD, Eadon MT, Gao H, Lin H, Liu Y, Desta Z, Skaar TC. Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes. Pharmacol Res Perspect 2018; 6:e00386. [PMID: 29610665 PMCID: PMC5869567 DOI: 10.1002/prp2.386] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 01/12/2018] [Indexed: 01/06/2023] Open
Abstract
Rifampin is a pleiotropic inducer of multiple drug metabolizing enzymes and transporters. This work utilized a global approach to evaluate rifampin effects on conjugating enzyme gene expression with relevance to human xeno‐ and endo‐biotic metabolism. Primary human hepatocytes from 7 subjects were treated with rifampin (10 μmol/L, 24 hours). Standard methods for RNA‐seq library construction, EZBead preparation, and NextGen sequencing were used to measure UDP‐glucuronosyl transferase UGT, sulfonyltransferase SULT, N acetyltransferase NAT, and glutathione‐S‐transferase GST mRNA expression compared to vehicle control (0.01% MeOH). Rifampin‐induced (>1.25‐fold) mRNA expression of 13 clinically important phase II drug metabolizing genes and repressed (>1.25‐fold) the expression of 3 genes (P < .05). Rifampin‐induced miRNA expression changes correlated with mRNA changes and miRNAs were identified that may modulate conjugating enzyme expression. NAT2 gene expression was most strongly repressed (1.3‐fold) by rifampin while UGT1A4 and UGT1A1 genes were most strongly induced (7.9‐ and 4.8‐fold, respectively). Physiologically based pharmacokinetic modeling (PBPK) was used to simulate the clinical consequences of rifampin induction of CYP3A4‐ and UGT1A4‐mediated midazolam metabolism. Simulations evaluating isolated UGT1A4 induction predicted increased midazolam N‐glucuronide exposure (~4‐fold) with minimal reductions in parent midazolam exposure (~10%). Simulations accounting for simultaneous induction of both CYP3A4 and UGT1A4 predicted a ~10‐fold decrease in parent midazolam exposure with only a ~2‐fold decrease in midazolam N‐glucuronide metabolite exposure. These data reveal differential effects of rifampin on the human conjugating enzyme transcriptome and potential associations with miRNAs that form the basis for future mechanistic studies to elucidate the interplay of conjugating enzyme regulatory elements.
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Affiliation(s)
- Brandon T Gufford
- Department of Medicine Division of Clinical Pharmacology Indiana University School of Medicine Indianapolis IN
| | - Jason D Robarge
- Department of Medicine Division of Clinical Pharmacology Indiana University School of Medicine Indianapolis IN
| | - Michael T Eadon
- Department of Medicine Division of Clinical Pharmacology Indiana University School of Medicine Indianapolis IN
| | - Hongyu Gao
- Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN
| | - Hai Lin
- Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN
| | - Yunlong Liu
- Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN
| | - Zeruesenay Desta
- Department of Medicine Division of Clinical Pharmacology Indiana University School of Medicine Indianapolis IN
| | - Todd C Skaar
- Department of Medicine Division of Clinical Pharmacology Indiana University School of Medicine Indianapolis IN
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Jasinski-Bergner S, Reches A, Stoehr C, Massa C, Gonschorek E, Huettelmaier S, Braun J, Wach S, Wullich B, Spath V, Wang E, Marincola FM, Mandelboim O, Hartmann A, Seliger B. Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma. Oncotarget 2018; 7:26866-78. [PMID: 27057628 PMCID: PMC5042021 DOI: 10.18632/oncotarget.8567] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 03/11/2016] [Indexed: 12/18/2022] Open
Abstract
The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression.By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3' untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets.
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Affiliation(s)
- Simon Jasinski-Bergner
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Adi Reches
- Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel
| | - Christine Stoehr
- Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Chiara Massa
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Evamaria Gonschorek
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Stefan Huettelmaier
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Juliane Braun
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Sven Wach
- Clinic of Urology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Bernd Wullich
- Clinic of Urology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Verena Spath
- Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel
| | - Ena Wang
- Sidra Medical and Research Center, Qatar Foundation, Doha, Qatar
| | | | - Ofer Mandelboim
- Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel
| | - Arndt Hartmann
- Institute of Pathology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
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Human brown adipose tissue-function and therapeutic potential in metabolic disease. Curr Opin Pharmacol 2017; 37:1-9. [PMID: 28800407 DOI: 10.1016/j.coph.2017.07.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 07/20/2017] [Indexed: 12/22/2022]
Abstract
There has been a resurgence of interest in brown adipose tissue (BAT) over the last decade. Key to this has been our ability to accurately image it, which has improved significantly. The role of BAT in regulating energy expenditure is important, and its pharmacological manipulation may hold therapeutic potential in metabolic disease. There is ample evidence of BAT activation by cold exposure, and pharmacological utilisation of similar pathways, using B3 receptor agonists holds promise since the development of selective agonists with limited cross-reactivity has rekindled interest. Endogenous agents like irisin, FGF21 and certain gut hormones may hold value as BAT activators. Other agents such as steroid hormones may also hold therapeutic potential, although short-term worsening of metabolic profile remains problematic. Clearly, pharmacological manipulation of BAT is important, and thanks to recent advances we may one day be able to add such agents to our anti-obesity arsenal.
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Abstract
Actin-binding proteins are proteins that could bind to actin or actin fibers. As a member of actin-binding proteins, Transgelin-2 is expressed in smooth muscle cells and non-smooth muscle cells, and its gene, TAGLN2, is differently expressed in all cells and tissues. The deregulation of Transgelin-2 is considered to be correlated with progression of many kinds of diseases, especially the development of malignant tumors, such as invasion, metastasis, and resistance, yet the function and mechanism of action of Transgelin-2 remain elusive. Therefore, we reviewed the basic characteristics and function of Transgelin-2 and its biological role in various types of diseases in order to provide the theoretical basis for further research and new perspectives on cancer development.
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Affiliation(s)
- Ti Meng
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Leichao Liu
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Ruifang Hao
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Siying Chen
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Yalin Dong
- Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
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Mi Y, He M, Liu B. [MiR-133b Affect the Proliferation and Drug Sensitivity in A549 Lung Cancer Stem Cells by Targeting PKM2]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017. [PMID: 28641694 PMCID: PMC5973364 DOI: 10.3779/j.issn.1009-3419.2017.06.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND It has been proven that miR-133b could inhibit cancer cell growth, the expression level of miR-133b was significant reduction in lung cancer tissue and serum of patients, and increase the radiation sensitivity of squamous cell carcinoma by targeting PKM2, but the exist mechanisms is not clear. The aim of this study is to explore the effect of miR-133b on proliferation in A549 lung cancer stem cells and drug sensitivity in DDP, and to explore the relationship between miR-133b and PKM2 gene, as well as the effect of cancer stem cells. METHODS Using miRBase and miRNAMap database to sequence comparison miR-133b and PKM2 gene. Using immune magnetic separation method to select the CD133+/CD34+ lung cancer stem cells from A549 cells, and using flow cytometry to detect the purity. The expression of miR-133b mRNA was detected by real-time fluorescence quantitative PCR (qRT-PCR). Cell proliferation was detected by CCK8 assay. 15 μg/mL DDP was treated to cells which was transfected with miR-133b, and apoptosis was detected by flow Cytometry at 0 h, 12 h, 24 h, 72 h. The expression of PKM2 protein was detected by Western blot. RESULTS Gene binding site report that PKM2 gene may be the target gene of miR-133b; the results of flow cytometry showed that the purity of CD133+/CD34+ stem cells was (92.15±4.27)%. qRT-PCR results showed that compared with the control group, after overexpression of miR-133b, miR-133b was up-regulated and miR-133b was down regulated after miR-133b inhibition (P<0.05). Compared with the control group, cell proliferation of miR-133b mimics group was significantly decreased (P<0.05), PKM2 protein levels were significantly lower (P<0.05); and cell proliferation of the miR-133b inhibitor group and PKM2 level was increased (P<0.05). The apoptosis of miR-133b mimics group was significantly higher than that of control group (P<0.05) after DDP treatment with 12 h. The expression of PKM2 protein in miR-133b mimics+DDP group was significantly lower than that in control group (P<0.05). CONCLUSIONS Overexpression of miR-133b can inhibit the growth and proliferation of lung cancer stem cells by down regulating PKM2, and can enhance the sensitivity of lung cancer stem cells to DDP.
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Affiliation(s)
- Yonghua Mi
- Department of Laboratory, Yongchuan Affiliated Hospital Chongqing Medical University, Chongqing 402160, China
| | - Miao He
- Respiratory Medicine, Xindu District People's Hospital of Chengdu, Chengdu 610500, China
| | - Beizhong Liu
- Department of Laboratory, Yongchuan Affiliated Hospital Chongqing Medical University, Chongqing 402160, China
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He B, Lin X, Tian F, Yu W, Qiao B. MiR-133a-3p Inhibits Oral Squamous Cell Carcinoma (OSCC) Proliferation and Invasion by Suppressing COL1A1. J Cell Biochem 2017; 119:338-346. [PMID: 28569392 DOI: 10.1002/jcb.26182] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 05/31/2017] [Indexed: 01/08/2023]
Abstract
The aim of our study was to investigate the effects of miR-133a-3p on human oral squamous cell carcinoma (OSCC) cells by regulating gene COL1A1. OSCC tissues, adjacent tongue epithelial tissues, the immortalized oral epithelial cell line HIOEC, and OSCC cell lines (CAL-27, TCA-8113, SCC-4, SCC-9, and SCC-15) were used in this research. Quantitative real-time PCR (RT-qPCR) was employed to determine the expression of miR-133a-3p and COL1A1. Dual luciferase reporter gene assay and Western blot were applied to verify the binding relationship between miR-133a-3p and COL1A1. Functional assays were also conducted in this study, including CCK-8 assay, colony formation assay, flow cytometry analysis as well as Transwell assay. MiR-133a-3p was found low-expressed both in OSCC tissues and cells lines compared with normal tissues and cell line, respectively, whereas COL1A1 was just the opposite. The over-expression of miR-133a-3p or the down-regulation of COL1A1 suppressed the proliferation, invasion, and mitosis of OSCC cells, whereas simultaneous down-regulation of miR-133a-3p and up-regulation of COL1A1 led to no significant alteration of cell activities. MiR-133a-3p could inhibit the proliferation and migration of OSCC cells through directly targeting COL1A1 and reducing its expression. J. Cell. Biochem. 119: 338-346, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Baoxia He
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450003, Henan, China
| | - Xiaozhen Lin
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450003, Henan, China
| | - Fengqi Tian
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450003, Henan, China
| | - Weijiang Yu
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450003, Henan, China
| | - Bin Qiao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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Wang Q, Liu S, Zhao X, Wang Y, Tian D, Jiang W. MiR-372-3p promotes cell growth and metastasis by targeting FGF9 in lung squamous cell carcinoma. Cancer Med 2017; 6:1323-1330. [PMID: 28440022 PMCID: PMC5463061 DOI: 10.1002/cam4.1026] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 12/26/2016] [Accepted: 01/06/2017] [Indexed: 01/04/2023] Open
Abstract
The aim of this study was to study the role of miR‐372‐3p in lung squamous cell carcinoma (LSCC) cell proliferation and invasion by suppressing FGF9. RT‐PCR was used to determine miR‐372‐3p and FGF9 mRNA expression in tissues and cells. Western blot was used to determine FGF9 expression in tissues and NCI‐H520 cell line. Dual luciferase reporter gene assay was conducted to confirm that FGF9 can be directly targeted by miR‐372‐3p. MTT, colony formation assays were conducted to investigate the effects of ectopic miR‐372‐3p and FGF9 expression on NCI‐H520 cell growth. Flow cytometry was used to analyze the influence of miR‐372‐3p and FGF9 expression on cell cycle distribution and apoptosis. Transwell assay was also conducted to see the effects of miR‐372‐3p and FGF9 expression on NCI‐H520 cell invasiveness. MiR‐372‐3p was found significantly overexpressed in both LSCC tissues and cell lines, whereas FGF9 mRNA was found underexpressed in LSCC tissues. MiR‐372‐3p directly bound to wild‐type FGF9 mRNA 3′UTR, therefore led to the reduction in FGF9 expression. The upregulation of FGF9 or the downregulation of miR‐372‐3p substantially retarded LSCC cell growth, mitosis, and invasion. MiR‐372‐3p enhanced LSCC cell proliferation and invasion through inhibiting FGF9.
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Affiliation(s)
- Qing Wang
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110032, China
| | - Siyang Liu
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110032, China
| | - Xitong Zhao
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110032, China
| | - Yuan Wang
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110032, China
| | - Dali Tian
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110032, China
| | - Wenjun Jiang
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110032, China
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Mizuno K, Mataki H, Arai T, Okato A, Kamikawaji K, Kumamoto T, Hiraki T, Hatanaka K, Inoue H, Seki N. The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes. J Hum Genet 2017; 62:671-678. [DOI: 10.1038/jhg.2017.27] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 02/02/2017] [Accepted: 02/07/2017] [Indexed: 12/12/2022]
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Xue D, Yang Y, Liu Y, Wang P, Dai Y, Liu Q, Chen L, Shen J, Ju H, Li Y, Tan Z. MicroRNA-206 attenuates the growth and angiogenesis in non-small cell lung cancer cells by blocking the 14-3-3ζ/STAT3/HIF-1α/VEGF signaling. Oncotarget 2016; 7:79805-79813. [PMID: 27806334 PMCID: PMC5346752 DOI: 10.18632/oncotarget.12972] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/14/2016] [Indexed: 01/09/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Angiogenesis is the major hallmark in NSCLC. So, further elucidation of molecular mechanisms underlying the angiogenesis of NSCLC is urgently needed. Here, we found that microRNA-206 (miR-206) decreased the angiogenic ability in NSCLC via inhibiting the 14-3-3ζ/STAT3/HIF-1α/VEGF pathway. Briefly, 14-3-3ζ bond with phosphorylated-STAT3, and in turn, elevated the expression of HIF-1α. Then, by enhancing the recruitment of HIF-1α to VEGF promoter, 14-3-3ζ increased the angiogenesis. However, miR-206 decreased the angiogenesis by targeting 14-3-3ζ, and inhibiting the STAT3/HIF-1α/VEGF pathway. In NSCLC cell xenograft model, either overexpression of miR-206 or inhibition of 14-3-3ζ inhibited the STAT3/HIF-1α/VEGF pathway and decreased the tumor growth and angiogenesis. Furthermore, there was a negative correlation between miR-206 and 14-3-3ζ in NSCLC specimens. NSCLC patients with low expressions of miR-206 but high expressions of 14-3-3ζ had the worst survival. Collectively, our findings provided the underlying mechanisms of miR-206/14-3-3ζ in tumor growth and angiogenesis, and implicated miR-206 and 14-3-3ζ as potential therapeutic targets for NSCLC.
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Affiliation(s)
- Dong Xue
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Ye Yang
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yawei Liu
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Peiwen Wang
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yi Dai
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Qinqiang Liu
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Lijun Chen
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jian Shen
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Huanyu Ju
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Yuan Li
- Department of Nutrition And Food Hygiene, School Of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Zhenguo Tan
- Department of Surgery, The Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China
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Wang Y, Li J, Chen H, Mo Y, Ye H, Luo Y, Guo K, Mai Z, Zhang Y, Chen B, Zhou Y, Yang Z. Down-regulation of miR-133a as a poor prognosticator in non-small cell lung cancer. Gene 2016; 591:333-7. [PMID: 27282282 DOI: 10.1016/j.gene.2016.06.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 05/20/2016] [Accepted: 06/01/2016] [Indexed: 02/07/2023]
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Pashaei E, Guzel E, Ozgurses ME, Demirel G, Aydin N, Ozen M. A Meta-Analysis: Identification of Common Mir-145 Target Genes that have Similar Behavior in Different GEO Datasets. PLoS One 2016; 11:e0161491. [PMID: 27655328 PMCID: PMC5031439 DOI: 10.1371/journal.pone.0161491] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Accepted: 08/05/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND MicroRNAs, which are small regulatory RNAs, post-transcriptionally regulate gene expression by binding 3'-UTR of their mRNA targets. Their deregulation has been shown to cause increased proliferation, migration, invasion, and apoptosis. miR-145, an important tumor supressor microRNA, has shown to be downregulated in many cancer types and has crucial roles in tumor initiation, progression, metastasis, invasion, recurrence, and chemo-radioresistance. Our aim is to investigate potential common target genes of miR-145, and to help understanding the underlying molecular pathways of tumor pathogenesis in association with those common target genes. METHODS Eight published microarray datasets, where targets of mir-145 were investigated in cell lines upon mir-145 over expression, were included into this study for meta-analysis. Inter group variabilities were assessed by box-plot analysis. Microarray datasets were analyzed using GEOquery package in Bioconducter 3.2 with R version 3.2.2 and two-way Hierarchical Clustering was used for gene expression data analysis. RESULTS Meta-analysis of different GEO datasets showed that UNG, FUCA2, DERA, GMFB, TF, and SNX2 were commonly downregulated genes, whereas MYL9 and TAGLN were found to be commonly upregulated upon mir-145 over expression in prostate, breast, esophageal, bladder cancer, and head and neck squamous cell carcinoma. Biological process, molecular function, and pathway analysis of these potential targets of mir-145 through functional enrichments in PPI network demonstrated that those genes are significantly involved in telomere maintenance, DNA binding and repair mechanisms. CONCLUSION As a conclusion, our results indicated that mir-145, through targeting its common potential targets, may significantly contribute to tumor pathogenesis in distinct cancer types and might serve as an important target for cancer therapy.
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Affiliation(s)
- Elnaz Pashaei
- Department of Computer Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Esra Guzel
- Biruni University, Department of Molecular Biology and Genetics, Topkapi, Istanbul, Turkey
- Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey
| | - Mete Emir Ozgurses
- Biruni University, Department of Molecular Biology and Genetics, Topkapi, Istanbul, Turkey
| | - Goksun Demirel
- Biruni University, Department of Molecular Biology and Genetics, Topkapi, Istanbul, Turkey
| | - Nizamettin Aydin
- Department of Computer Engineering, Yildiz Technical University, Istanbul, Turkey
| | - Mustafa Ozen
- Biruni University, Department of Molecular Biology and Genetics, Topkapi, Istanbul, Turkey
- Department of Medical Genetics, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey
- Department of Pathology & Immunology Baylor College of Medicine, Houston, Texas, 77030, United States of America
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Kumamoto T, Seki N, Mataki H, Mizuno K, Kamikawaji K, Samukawa T, Koshizuka K, Goto Y, Inoue H. Regulation of TPD52 by antitumor microRNA-218 suppresses cancer cell migration and invasion in lung squamous cell carcinoma. Int J Oncol 2016; 49:1870-1880. [PMID: 27633630 PMCID: PMC5063422 DOI: 10.3892/ijo.2016.3690] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/19/2016] [Indexed: 12/15/2022] Open
Abstract
The development of targeted molecular therapies has greatly benefited patients with lung adenocarcinomas. In contrast, these treatments have had little benefit in the management of lung squamous cell carcinoma (lung SCC). Therefore, new treatment options based on current genomic approaches are needed for lung SCC. Aberrant microRNA (miRNA) expression has been shown to promote lung cancer development and aggressiveness. Downregulation of microRNA-218 (miR-218) was frequently observed in our miRNA expression signatures of cancers, and previous studies have shown an antitumor function of miR-218 in several types of cancers. However, the impact of miR-218 on lung SCC is still ambiguous. The present study investigated the antitumor roles of miR-218 in lung SCC to identify the target genes regulated by this miRNA. Ectopic expression of miR-218 greatly inhibited cancer cell migration and invasion in the lung SCC cell lines EBC-1 and SK-MES-1. Through a combination of in silico analysis and gene expression data searching, tumor protein D52 (TPD52) was selected as a putative target of miR-218 regulation. Moreover, direct binding of miR-218 to the 3'-UTR of TPD52 was observed by dual luciferase reporter assay. Overexpression of TPD52 was observed in lung SCC clinical specimens, and knockdown of TPD52 significantly suppressed cancer cell migration and invasion in lung SCC cell lines. Furthermore, the downstream pathways mediated by TPD52 involved critical regulators of genomic stability and mitotic checkpoint genes. Taken together, our data showed that downregulation of miR-218 enhances overexpression of TPD52 in lung SCC cells, promoting cancer cell aggressiveness. Identification of tumor-suppressive miRNA-mediated RNA networks of lung SCC will provide new insights into the potential mechanisms of the molecular pathogenesis of the disease.
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Affiliation(s)
- Tomohiro Kumamoto
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Naohiko Seki
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Hiroko Mataki
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Kazuto Kamikawaji
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Takuya Samukawa
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Keiichi Koshizuka
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Yusuke Goto
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
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MicroRNAs as key mediators of hepatic detoxification. Toxicology 2016; 368-369:80-90. [PMID: 27501766 DOI: 10.1016/j.tox.2016.08.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 08/01/2016] [Accepted: 08/04/2016] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) are a class of short noncoding RNAs that modulate gene expression at both transcriptional and post-transcriptional levels. Many studies have extensively revealed the significance of miRNAs in mediating liver development and diseases. However, their role in hepatic detoxification processes has been explored only recently. In this review, we summarized the up-to-date knowledge about miRNA dependent regulation of enzymes involved in all three phases of the drugs and xenobiotics detoxification process. We also discussed the role of miRNA in regulating some upstream nuclear receptors involving gene expression of enzymes for detoxification process in liver. The toxicological significance of miRNAs in liver diseases and future research perspectives are finally presented.
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MicroRNAs in non-small cell lung cancer and idiopathic pulmonary fibrosis. J Hum Genet 2016; 62:57-65. [PMID: 27488441 DOI: 10.1038/jhg.2016.98] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/25/2016] [Accepted: 06/27/2016] [Indexed: 12/21/2022]
Abstract
In spite of advances in the diagnosis and current molecular target therapies of lung cancer, this disease remains the most common cause of cancer-related death worldwide. Approximately 80% of lung cancers is non-small cell lung cancer (NSCLC), and 5-year survival rate of the disease is ~20%. On the other hand, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. IPF is refractory to treatment and has a very low survival rate. Moreover, IPF is frequently associated with lung cancer. However, the common mechanisms shared by these two diseases remain poorly understood. In the post-genome sequence era, the discovery of noncoding RNAs, particularly microRNAs (miRNAs), has had a major impact on most biomedical fields, and these small molecules have been shown to contribute to the pathogenesis of NSCLC and IPF. Investigation of novel RNA networks mediated by miRNAs has improved our understanding of the molecular mechanisms of these diseases. This review summarizes our current knowledge on aberrantly expressed miRNAs regulating NSCLC and IPF based on miRNA expression signatures.
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Wegner MS, Schiffmann S, Parnham MJ, Geisslinger G, Grösch S. The enigma of ceramide synthase regulation in mammalian cells. Prog Lipid Res 2016; 63:93-119. [PMID: 27180613 DOI: 10.1016/j.plipres.2016.03.006] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 03/17/2016] [Accepted: 03/27/2016] [Indexed: 12/20/2022]
Abstract
Ceramide synthases (CerS) are key enzymes in the lipid metabolism of eukaryotic cells. Their products, ceramides (Cer), are components of cellular membranes but also mediate signaling functions in physiological processes such as proliferation, skin barrier function and cerebellar development. In pathophysiological processes such as multiple sclerosis and tumor progression, ceramide levels are altered, which can be ascribed, partly, to dysregulation of CerS gene transcription. Most publications deal with the effects of altered ceramide levels on physiological and pathophysiological processes, but the regulation of the appropriate CerS is frequently not investigated. This is insufficient for the clarification of the role of ceramides, because most ceramide species are generated by at least two CerS. The mechanisms of CerS regulation are manifold and it seems that each CerS isoform is regulated individually. For this reason, we discuss the different CerS separately in this review. From transcriptional regulation to alteration of protein activity, the possibilities to influence CerS are diverse. Furthermore, CerS are influenced by a variety of molecules including hormones and lipids. Without claiming completeness, we provide a résumé of the regulatory mechanisms for each CerS in mammalian cells and how dysregulation of these mechanisms during physiological processes may lead to pathophysiological processes.
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Affiliation(s)
- Marthe-Susanna Wegner
- pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann- Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| | - Susanne Schiffmann
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany
| | - Michael John Parnham
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany
| | - Gerd Geisslinger
- pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann- Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Sabine Grösch
- pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann- Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
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Wang X, Zhu W, Zhao X, Wang P. miR-133a enhances the sensitivity of Hep-2 cells and vincristine-resistant Hep-2v cells to cisplatin by downregulating ATP7B expression. Int J Mol Med 2016; 37:1636-42. [PMID: 27121102 DOI: 10.3892/ijmm.2016.2569] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 03/09/2016] [Indexed: 11/06/2022] Open
Abstract
The expression levels of the copper transporter P-type adenosine triphosphatase (ATP7B) are known correlate with tumor cell sensitivity to cisplatin. However, the mechanisms underlying cisplatin resistance remained poorly understood. Therefore, in the present study, we treated Hep-2 cells and in-house-developed vincristine-resistant Hep-2v cells with 50, 100, or 200 µM cisplatin and assessed cell viability after 24 or 48 h. Hep-2v cells were shown to be resistant to 50-200 µM cisplatin. Furthermore, using immunofluorescence staining and western blot analysis, we noted that ATP7B, but not copper-transporting ATPase 1 (ATP7A), expression was significantly increased in Hep-2v cells, and this increase was maintained at a higher level compared with Hep-2 cells. As ATP7B is a target of microRNA 133a (miR‑133a), the ability of miR‑133a to influence cisplatin sensitivity in Hep-2v cells was then assessed by CCK-8 assay. We noted that miR‑133a expression was lower in both Hep-2 and Hep-2v cells compared with epithelial NP69 cells. Following treatment with 50 µM cisplatin, in Hep-2v cells expressing exogenous miR‑133a we noted reduced ATP7B expression, and these cells had a significantly lower survival rate compared with the control. The present study demonstrates that miR‑133a enhances the sensitivity of multidrug-resistant Hep-2v cells to cisplatin by downregulating ATP7B expression.
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Affiliation(s)
- Xurui Wang
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Zhu
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xiaodong Zhao
- Department of Otorhinolaryngology, Jilin Province Cancer Hospital, Changchun, Jilin 130012, P.R. China
| | - Ping Wang
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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