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Saadh MJ, Hussain QM, Alazzawi TS, Fahdil AA, Athab ZH, Yarmukhamedov B, Al-Nuaimi AMA, Alsaikhan F, Farhood B. MicroRNA as Key Players in Hepatocellular Carcinoma: Insights into Their Role in Metastasis. Biochem Genet 2025; 63:1014-1062. [PMID: 39103713 DOI: 10.1007/s10528-024-10897-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
Liver cancer or hepatocellular carcinoma (HCC) remains the most common cancer in global epidemiology. Both the frequency and fatality of this malignancy have shown an upward trend over recent decades. Liver cancer is a significant concern due to its propensity for both intrahepatic and extrahepatic metastasis. Liver cancer metastasis is a multifaceted process characterized by cell detachment from the bulk tumor, modulation of cellular motility and invasiveness, enhanced proliferation, avoidance of the immune system, and spread either via lymphatic or blood vessels. MicroRNAs (miRNAs) are small non-coding ribonucleic acids (RNAs) playing a crucial function in the intricate mechanisms of tumor metastasis. A number of miRNAs can either increase or reduce metastasis via several mechanisms, such as control of motility, proliferation, attack by the immune system, cancer stem cell properties, altering the microenvironment, and the epithelial-mesenchymal transition (EMT). Besides, two other types of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can competitively bind to endogenous miRNAs. This competition results in the impaired ability of the miRNAs to inhibit the expression of the specific messenger RNAs (mRNAs) that are targeted. Increasing evidence has shown that the regulatory axis comprising circRNA/lncRNA-miRNA-mRNA is correlated with the regulation of HCC metastasis. This review seeks to present a thorough summary of recent research on miRNAs in HCC, and their roles in the cellular processes of EMT, invasion and migration, as well as the metastasis of malignant cells. Finally, we discuss the function of the lncRNA/circRNA-miRNA-mRNA network as a crucial modulator of carcinogenesis and the regulation of signaling pathways or genes that are relevant to the metastasis of HCC. These findings have the potential to offer valuable insight into the discovery of novel therapeutic approaches for management of liver cancer metastasis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | - Tuqa S Alazzawi
- College of Dentist, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | - Ali A Fahdil
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Bekhzod Yarmukhamedov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
| | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Alimoradi N, Ramezani A, Tahami M, Firouzabadi N. Metformin Exhibits Anti-Inflammatory Effects by Regulating microRNA-451/CXCL16 and B Cell Leukemia/Lymphoma 2 in Patients With Osteoarthritis. ACR Open Rheumatol 2025; 7:e11755. [PMID: 39435687 PMCID: PMC11694140 DOI: 10.1002/acr2.11755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 09/18/2024] [Accepted: 09/24/2024] [Indexed: 10/23/2024] Open
Abstract
OBJECTIVE Osteoarthritis (OA) is the most common cause of chronic disability in joints among older individuals. The primary goal of OA treatment is pain relief to improve the quality of life. Inflammation and aging are involved in the pathogenesis of pain in OA. In this study, we evaluated the ability of metformin to regulate microRNAs, such as miR-451 and miR-15b, and their target proteins, CXCL16 and B cell leukemia/lymphoma 2 (BCL-2), involved in inflammation and apoptosis. METHODS In this double-blind placebo-controlled clinical trial, patients were randomly divided into two groups: one receiving metformin and the other receiving a placebo for four months (starting at 0.5 g/day for the first week, increasing to 1 g/day for the second week, and increasing to 1.5 g/day for the remaining period). In addition to evaluating the clinical response using the Knee Injury and Osteoarthritis Outcome Score questionnaire, miR-451 and miR-15b expression levels were detected using real-time polymerase chain reaction. The serum levels of CXCL16 and BCL-2 were evaluated using enzyme-linked immunosorbent assay kits before (time zero) and after treatment (month four). RESULTS Metformin increased miR-451 expression levels simultaneously with pain reduction, whereas miR-15b expression did not change significantly after four months of treatment. Also, metformin decreased the serum levels of BCL-2 and CXCL16 in patients with OA. CONCLUSION The effects of metformin in reducing pain can be attributed to many factors, including its anti-inflammatory and antiaging effects. Our findings suggest that metformin may reduce pain and inflammation in patients with OA through the regulation of miR-451/CXCL16 and BCL-2.
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Shodry S, Hasan YTN, Ahdi IR, Ulhaq ZS. Gene targets with therapeutic potential in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4543-4547. [PMID: 39678796 PMCID: PMC11577361 DOI: 10.4251/wjgo.v16.i12.4543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 11/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Syifaus Shodry
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Yuliono Trika Nur Hasan
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Iwal Reza Ahdi
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Zulvikar Syambani Ulhaq
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency Republic of Indonesia, Cibinong 16911, Indonesia
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Sethi SC, Shrestha RL, Balachandra V, Durairaj G, Au WC, Nirula M, Karpova TS, Kaiser P, Basrai MA. β-TrCP-Mediated Proteolysis of Mis18β Prevents Mislocalization of CENP-A and Chromosomal Instability. Mol Cell Biol 2024; 44:429-442. [PMID: 39135477 PMCID: PMC11486186 DOI: 10.1080/10985549.2024.2382445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/08/2024] [Accepted: 07/12/2024] [Indexed: 10/15/2024] Open
Abstract
Restricting the localization of evolutionarily conserved histone H3 variant CENP-A to the centromere is essential to prevent chromosomal instability (CIN), an important hallmark of cancers. Overexpressed CENP-A mislocalizes to non-centromeric regions and contributes to CIN in yeast, flies, and human cells. Centromeric localization of CENP-A is facilitated by the interaction of Mis18β with CENP-A specific chaperone HJURP. Cellular levels of Mis18β are regulated by β-transducin repeat containing protein (β-TrCP), an F-box protein of SCF (Skp1, Cullin, F-box) E3-ubiquitin ligase complex. Here, we show that defects in β-TrCP-mediated proteolysis of Mis18β contributes to the mislocalization of endogenous CENP-A and CIN in a triple-negative breast cancer (TNBC) cell line, MDA-MB-231. CENP-A mislocalization in β-TrCP depleted cells is dependent on high levels of Mis18β as depletion of Mis18β suppresses mislocalization of CENP-A in these cells. Consistent with these results, endogenous CENP-A is mislocalized in cells overexpressing Mis18β alone. In summary, our results show that β-TrCP-mediated degradation of Mis18β prevents mislocalization of CENP-A and CIN. We propose that deregulated expression of Mis18β may be one of the key mechanisms that contributes to chromosome segregation defects in cancers.
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Affiliation(s)
- Subhash Chandra Sethi
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Roshan Lal Shrestha
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Vinutha Balachandra
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Geetha Durairaj
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA
| | - Wei-Chun Au
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Michael Nirula
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Tatiana S. Karpova
- Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Peter Kaiser
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA
| | - Munira A. Basrai
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Han T, Liu Y, Zhou J, Guo J, Xing Y, Xie J, Bai Y, Wu J, Hu D. Development of an invasion score based on metastasis-related pathway activity profiles for identifying invasive molecular subtypes of lung adenocarcinoma. Sci Rep 2024; 14:1692. [PMID: 38243040 PMCID: PMC10799059 DOI: 10.1038/s41598-024-51681-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 01/08/2024] [Indexed: 01/21/2024] Open
Abstract
The invasive capacity of lung adenocarcinoma (LUAD) is an important factor influencing patients' metastatic status and survival outcomes. However, there is still a lack of suitable biomarkers to evaluate tumor invasiveness. LUAD molecular subtypes were identified by unsupervised consistent clustering of LUAD. The differences in prognosis, tumor microenvironment (TME), and mutation were assessed among different subtypes. After that, the invasion-related gene score (IRGS) was constructed by genetic differential analysis, WGCNA analysis, and LASSO analysis, then we evaluated the relationship between IRGS and invasive characteristics, TME, and prognosis. The predictive ability of the IRGS was verified by in vitro experiments. Next, the "oncoPredict" R package and CMap were used to assess the potential value of IRGS in drug therapy. The results showed that LUAD was clustered into two molecular subtypes. And the C1 subtype exhibited a worse prognosis, higher stemness enrichment activity, less immune infiltration, and higher mutation frequency. Subsequently, IRGS developed based on molecular subtypes demonstrated a strong association with malignant characteristics such as invasive features, higher stemness scores, less immune infiltration, and worse survival. In vitro experiments showed that the higher IRGS LUAD cell had a stronger invasive capacity than the lower IRGS LUAD cell. Predictive analysis based on the "oncoPredict" R package showed that the high IRGS group was more sensitive to docetaxel, erlotinib, paclitaxel, and gefitinib. Among them, in vitro experiments verified the greater killing effect of paclitaxel on high IRGS cell lines. In addition, CMap showed that purvalanol-a, angiogenesis-inhibitor, and masitinib have potential therapeutic effects in the high IRGS group. In summary we identified and analyzed the molecular subtypes associated with the invasiveness of LUAD and developed IRGS that can efficiently predict the prognosis and invasive ability of the tumor. IRGS may be able to facilitate the precision treatment of LUAD to some extent.
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Affiliation(s)
- Tao Han
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China
| | - Yafeng Liu
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, 232001, China
- Affiliated Cancer Hospital, Anhui University of Science and Technology, Huainan, 232035, China
| | - Jiawei Zhou
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, 232001, China
| | - Jianqiang Guo
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, 232001, China
| | - Yingru Xing
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China
- Department of Clinical Laboratory, Anhui Zhongke Gengjiu Hospital, Hefei, China
| | - Jun Xie
- Affiliated Cancer Hospital, Anhui University of Science and Technology, Huainan, 232035, China
| | - Ying Bai
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China.
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, 232001, China.
| | - Jing Wu
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China.
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, 232001, China.
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, 232001, China.
| | - Dong Hu
- School of Medicine, Anhui University of Science and Technology, Chongren Building, No 168, Taifeng St, Huainan, 232001, China.
- Anhui Province Engineering Laboratory of Occupational Health and Safety, Anhui University of Science and Technology, Huainan, 232001, China.
- Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, 232001, China.
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Zhang X, Gu W, Lin A, Duan R, Lian L, Huang Y, Li T, Sun Q. The role of OIP5 in the carcinogenesis and progression of ovarian cancer. J Ovarian Res 2023; 16:185. [PMID: 37660035 PMCID: PMC10474646 DOI: 10.1186/s13048-023-01265-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 08/17/2023] [Indexed: 09/04/2023] Open
Abstract
BACKGROUND Opa interacting protein 5 (OIP5), which is a cancer/testis-specific gene, plays a cancer-promoting role in various types of human cancer. However, the role of OIP5 in the carcinogenesis and progression of ovarian cancer remains unknown. METHODS We first analyzed the expression of OIP5 in ovarian cancer and various human tumors with the Sangerbox online analysis tool. GSE12470, GSE14407 and GSE54388 were downloaded from the Gene Expression Omnibus (GEO) database, and GEO2R was used to screen differentially expressed genes in ovarian cancer tissues. Gene Ontology (GO) enrichment analysis was used to explore the related biological processes. Receiver operating characteristic (ROC) curve was generated to evaluate the predictive ability of OIP5 for ovarian cancer. Next, RT-PCR, immunohistochemistry and Western blotting were utilized to evaluate the expression of OIP5 in ovarian cancer. CCK8, EdU proliferation assays and colony formation assays were used to measure cell proliferation, cell cycle progression was examined by PI staining and flow cytometry, and cell apoptosis was examined by Caspase3/7 activity assays. The effect of OIP5 on the migration and invasion of ovarian cancer cells was analyzed with Transwell assays. RESULTS We found that OIP5 is highly expressed in ovarian cancer through bioinformatics analysis, and importantly, OIP5 may be an important biomarker for the prognosis and diagnosis of ovarian cancer. RT-PCR assays, immunohistochemistry and Western blotting were also used to confirm the high expression of OIP5 in ovarian cancer. Subsequently, we demonstrated that the proliferation and migration of the ovarian cancer cell line A2780 were significantly inhibited after OIP5 gene silencing, apoptosis was increased and cell cycle progression was arrested at the G1 phase. CONCLUSION This study indicated that OIP5 was highly expressed in ovarian cancer and that downregulation of OIP5 inhibited the proliferation, migration and invasion of ovarian cancer cells, induced cell cycle arrest and promoted cell apoptosis. Therefore, OIP5 may be an important biomarker for the early diagnosis and potential target for treatment of ovarian cancer.
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Affiliation(s)
- Xin Zhang
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Wenjie Gu
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Aiqin Lin
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Renjie Duan
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Likai Lian
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Yuanyuan Huang
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China
| | - Tiechen Li
- School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, P.R. China.
| | - Qing Sun
- Department of Gynecology and Obstetrics, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P.R. China.
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El-Aziz MKA, Dawoud A, Kiriacos CJ, Fahmy SA, Hamdy NM, Youness RA. Decoding hepatocarcinogenesis from a noncoding RNAs perspective. J Cell Physiol 2023; 238:1982-2009. [PMID: 37450612 DOI: 10.1002/jcp.31076] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/11/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Being a leading lethal malignancy worldwide, the pathophysiology of hepatocellular carcinoma (HCC) has gained a lot of interest. Yet, underlying mechanistic basis of the liver tumorigenesis is poorly understood. The role of some coding genes and their respective translated proteins, then later on, some noncoding RNAs (ncRNAs) such as microRNAs have been extensively studied in context of HCC pathophysiology; however, the implication of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in HCC is indeed less investigated. As a subclass of the ncRNAs which has been elusive for long time ago, lncRNAs was found to be involved in plentiful cellular functions such as DNA, RNA, and proteins regulation. Hence, it is undisputed that lncRNAs dysregulation profoundly contributes to HCC via diverse etiologies. Accordingly, lncRNAs represent a hot research topic that requires prime focus in HCC. In this review, the authors discuss breakthrough discoveries involving lncRNAs and circRNAs dysregulation that have contributed to the contemporary concepts of HCC pathophysiology and how these concepts could be leveraged as potential novel diagnostic and prognostic HCC biomarkers. Further, this review article sheds light on future trends, thereby discussing the pathological roles of lncRNAs and circRNAs in HCC proliferation, migration, and epithelial-to-mesenchymal transition. Along this line of reasoning, future recommendations of how these targets could be exploited to achieve effective HCC-related drug development is highlighted.
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Affiliation(s)
- Mostafa K Abd El-Aziz
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Alyaa Dawoud
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Caroline J Kiriacos
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Sherif Ashraf Fahmy
- Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Rana A Youness
- Molecular Genetics Research Team (MGRT), Biology and Biochemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo, Egypt
- Molecular Genetics Research Team (MGRT), Pharmaceutical Biology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Xu Y, Xu X, Ni X, Pan J, Chen M, Lin Y, Zhao Z, Zhang L, Ge N, Song G, Zhang J. Gene-based cancer-testis antigens as prognostic indicators in hepatocellular carcinoma. Heliyon 2023; 9:e13269. [PMID: 36950598 PMCID: PMC10025098 DOI: 10.1016/j.heliyon.2023.e13269] [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] [Received: 09/23/2022] [Revised: 01/11/2023] [Accepted: 01/24/2023] [Indexed: 03/08/2023] Open
Abstract
Cancer/testis antigens (CTAs) are reproductive tissue-restricted genes, frequently ectopic expressed in tumors. CTA genes associate with a poor prognosis in some solid tumors, due to their potential roles in the tumorigenesis and progression. However, whether CTAs relate with hepatocellular carcinoma (HCC) remains unclear. In this study, the prognostic signatures based on CTA genes were investigated and validated in three cohorts including Chinese HCC patients with hepatitis B virus infection (CHCC-HBV), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) cohorts. Univariate, LASSO, and multivariate Cox regression analyses were used to screen prognostic genes and develop the prognostic gene signature. A prognosis model was established with six CTA genes (SSX1, CTCFL, OIP5, CEP55, NOL4, and TPPP2) in CHCC-HBV cohort, and further validated in the ICGC and TCGA cohorts. The CTA signature was an essential prognostic predictor independent of other clinical pathological factors. High-risk group exhibited up-regulated cell cycle-related and tumor-related pathways and more M0 macrophage, activated mast cell, activated memory CD4+ T cell, and memory B cell infiltration. Furthermore, CTA signature correlated with the sensitivity to multiple chemotherapy drugs. Our results highlighted that the CTA gene profiling was a prognostic assessment tool for HCC patients.
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Affiliation(s)
- Yingyu Xu
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Xin Xu
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Xiaojian Ni
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jiaomeng Pan
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - MaoPei Chen
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Youpei Lin
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhiying Zhao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ningling Ge
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Guohe Song
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Juan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
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Cui MY, Yi X, Zhu DX, Wu J. Identification of Differentially Expressed Genes Related to the Lipid Metabolism of Esophageal Squamous Cell Carcinoma by Integrated Bioinformatics Analysis. Curr Oncol 2022; 30:1-18. [PMID: 36661650 PMCID: PMC9858068 DOI: 10.3390/curroncol30010001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose: In recent years, lipid metabolism has been reprogrammed to meet the energy and substrate needs of tumorigenesis and development and is a potential new target for cancer treatment. However, the regulatory mechanism of lipid metabolism in esophageal squamous cell carcinoma is not well understood. Methods: We first downloaded the esophageal squamous cell carcinoma (ESCC) gene dataset in the GEO and TCGA databases and analyzed the central differentially expressed genes (DEGs) of ESCC through bioinformatics. Afterwards, the GSEA method was used to analyze the lipid metabolism-related pathway of the central gene in the pathological process of ESCC, and it was determined that the central gene OIP5 was significantly related to the fatty acid metabolism pathway. Our heatmap also revealed that the enrichment of the ACSL family in ESCC tissues was more pronounced than in normal tissues. We hypothesized that OIP5 can regulate the fatty acid metabolism process in ESCC cells and affect the tumorigenic ability of ESCC. Further statistical analysis and experiment were conducted to determine the lipid metabolism-related gene, OIP5′s, expression pattern and clinical significance in ESCC, analyze the effect of OIP5 expression on fatty acid metabolism-related enzymes in ESCC, revealing the specific mechanism of OIP5 that promotes ESCC development. Conclusions: Our study established a correlation between OIP5 expression and clinicopathological factors (tumor size, T stage, N stage, and clinical grade) in esophageal squamous cell carcinoma (p < 0.05). We have also experimentally demonstrated that OIP5 regulates ESCC fatty acid metabolism by influencing the expression of the key enzyme ACSL1 in lipid metabolism.
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Affiliation(s)
| | | | - Dan-Xia Zhu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou 213003, China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian St, Changzhou 213003, China
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10
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Tanigawa K, Misono S, Mizuno K, Asai S, Suetsugu T, Uchida A, Kawano M, Inoue H, Seki N. MicroRNA signature of small-cell lung cancer after treatment failure: impact on oncogenic targets by miR-30a-3p control. Mol Oncol 2022; 17:328-343. [PMID: 36345848 PMCID: PMC9892828 DOI: 10.1002/1878-0261.13339] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 10/10/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022] Open
Abstract
Small-cell lung cancer (SCLC) is associated with a high mortality rate and limited treatment efficacy. We created a microRNA (miRNA) expression signature by RNA sequencing using specimens from patients with SCLC who had failed treatment. Forty-nine miRNAs were downregulated in SCLC tissues and were candidate tumor-suppressive miRNAs. In this signature, both guide and passenger strands were downregulated for five miRNAs (miR-30a, miR-34b, miR-34c, miR-223, and miR-4529). Recent studies have revealed that passenger strands of miRNAs are involved in the molecular pathogenesis of human cancer. Although miR-30a-5p (the guide strand) has been shown to be a tumor-suppressive miRNA in various types of cancers, miR-30a-3p (the passenger strand) function is not well characterized in SCLC cells. We investigated the functional significance of miR-30a-3p and oncogenic genes regulated by miR-30a-3p in SCLC cells. Ectopic expression assays showed that miR-30a-3p expression inhibited cell proliferation and induced cell cycle arrest and apoptosis in two SCLC cell lines. Furthermore, in silico database searches and gene expression assays identified 25 genes as putative targets of miR-30a-3p in SCLC cells. Luciferase reporter assays revealed that downstream neighbor of SON (DONSON) was directly regulated by miR-30a-3p in SCLC cells. Knockdown of DONSON induced cell cycle arrest in SCLC cells and DONSON overexpression were detected in SCLC clinical samples. Analyzing the regulatory networks of tumor-suppressive miRNAs may lead to the identification of therapeutic targets in SCLC.
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Affiliation(s)
- Kengo Tanigawa
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Shunsuke Misono
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Shunichi Asai
- Department of Functional GenomicsChiba University Graduate School of MedicineJapan
| | - Takayuki Suetsugu
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Akifumi Uchida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Minami Kawano
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental SciencesKagoshima UniversityJapan
| | - Naohiko Seki
- Department of Functional GenomicsChiba University Graduate School of MedicineJapan
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11
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Khare S, Khare T, Ramanathan R, Ibdah JA. Hepatocellular Carcinoma: The Role of MicroRNAs. Biomolecules 2022; 12:biom12050645. [PMID: 35625573 PMCID: PMC9138333 DOI: 10.3390/biom12050645] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
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Affiliation(s)
- Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
| | - Raghu Ramanathan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA; (S.K.); (T.K.); (R.R.)
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: 1-573-882-7349; Fax: 1-573-884-4595
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12
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Heydarnezhad Asl M, Pasban Khelejani F, Bahojb Mahdavi SZ, Emrahi L, Jebelli A, Mokhtarzadeh A. The various regulatory functions of long noncoding RNAs in apoptosis, cell cycle, and cellular senescence. J Cell Biochem 2022; 123:995-1024. [PMID: 35106829 DOI: 10.1002/jcb.30221] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 12/28/2021] [Accepted: 01/11/2022] [Indexed: 12/12/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a group of noncoding cellular RNAs involved in significant biological phenomena such as differentiation, cell development, genomic imprinting, adjusting the enzymatic activity, regulating chromosome conformation, apoptosis, cell cycle, and cellular senescence. The misregulation of lncRNAs interrupting normal biological processes has been implicated in tumor formation and metastasis, resulting in cancer. Apoptosis and cell cycle, two main biological phenomena, are highly conserved and intimately coupled mechanisms. Hence, some cell cycle regulators can influence both programmed cell death and cell division. Apoptosis eliminates defective and unwanted cells, and the cell cycle enables cells to replicate themselves. The improper regulation of apoptosis and cell cycle contributes to numerous disorders such as neurodegenerative and autoimmune diseases, viral infection, anemia, and mainly cancer. Cellular senescence is a tumor-suppressing response initiated by environmental and internal stress factors. This phenomenon has recently attained more attention due to its therapeutic implications in the field of senotherapy. In this review, the regulatory roles of lncRNAs on apoptosis, cell cycle, and senescence will be discussed. First, the role of lncRNAs in mitochondrial dynamics and apoptosis is addressed. Next, the interaction between lncRNAs and caspases, pro/antiapoptotic proteins, and also EGFR/PI3K/PTEN/AKT/mTORC1 signaling pathway will be investigated. Furthermore, the effect of lncRNAs in the cell cycle is surveyed through interaction with cyclins, cdks, p21, and wnt/β-catenin/c-myc pathway. Finally, the function of essential lncRNAs in cellular senescence is mentioned.
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Affiliation(s)
| | - Faezeh Pasban Khelejani
- Department of Cell and Molecular Biology, Faculty of Basic Sciences, University of Maragheh, Maragheh, Iran
| | | | - Leila Emrahi
- Department of Medical Genetics, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran.,Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Prognostic and Therapeutic Potential of the OIP5 Network in Papillary Renal Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13174483. [PMID: 34503297 PMCID: PMC8431695 DOI: 10.3390/cancers13174483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 02/07/2023] Open
Abstract
Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC. The current understanding and management of pRCC remain poor. We report here OIP5 being a novel oncogenic factor and possessing robust prognostic values and therapeutic potential. OIP5 upregulation is observed in pRCC. The upregulation is associated with pRCC adverse features (T1P < T2P < CIMP, Stage1 + 2 < Stage 3 < Stage 4, and N0 < N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation; the latter is correlated with network alterations related to immune regulation, metabolism, and hypoxia. A set of differentially expressed genes (DEFs) was derived from ACHN OIP5 xenografts and primary pRCCs (n = 282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p < 2 × 10-16) and relapse (p < 2 × 10-16) possibilities. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5. PLK1 inhibitor BI2356 inhibits the growth of xenografts formed by ACHN OIP5 cells. Collectively, the OIP5 network can be explored for personalized therapies in management of pRCC patients.
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14
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lncRNA OIP5-AS1 Suppresses Cell Proliferation and Invasion of Endometrial Cancer by Regulating PTEN/AKT via Sponging miR-200c-3p. J Immunol Res 2021; 2021:4861749. [PMID: 34368370 PMCID: PMC8342140 DOI: 10.1155/2021/4861749] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/05/2021] [Indexed: 11/17/2022] Open
Abstract
Background Endometrial carcinoma (EC) is one of the major gynecologic malignancy cancers affecting females with dismal prognosis and high mortality around the world. Numerous studies have proven that an aberrant level of long noncoding RNAs is present in many endometrial cancer patients, while the underlying molecular mechanism remains unclear. Method The expression levels of lncRNA OIP5-AS1, miR200c-3p, and PTEN were measured by a quantitative real-time polymerase chain reaction in endometrial cancer tissue and endometrial cancer cells. CCK8 assay, wound-healing assay, and cell colony formation were applied to evaluate cell proliferation, cell migration, and cell colony formation ability. Cell cycle and cell apoptosis were detected by flow cytometry. The interactions between OIP5-AS1, miR200c-3p, and PTEN were explored by luciferase activity. Results In the present study, we demonstrated that long noncoding RNA OIP5-AS1 was significantly reduced in EC tissue compared with normal tissue. The lower expression level of OIP5-AS1 was also confirmed in four kinds of EC cell lines compared with the normal endometrial cell line. Gain- and loss-of-function of experiments indicated that upregulation of OIP5-AS1 could inhibit the proliferation, migration, and invasion of EC cells in vitro. Meanwhile, overexpression of OIP5-AS1 could also suppress the growth of tumor in the xenograft model. Moreover, further study revealed that miR-200c-3p could bind to OIP5-AS1, and the loss function of miR-200c-3p could reverse the elevated OIP5-AS1's inhibitory effect on the progression of EC. Furthermore, we found that downregulation of miR-200c-3p was inversely correlated with PTEN expression in EC cells. Reduced OIP5-AS1 could lead to the accumulation of miR-200c-3p, which could induce the upregulation of PTEN indirectly. Conclusion Our study demonstrated a novel molecular mechanism that lncRNA OIP5-AS1 could modulate the progression of EC by combining competitively with miR-200c-3p to control the PTEN/AKT pathway in EC cells, which might supply important information for developing novel therapeutic strategies for EC patients.
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15
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Shahrisa A, Tahmasebi-Birgani M, Ansari H, Mohammadi Z, Carloni V, Mohammadi Asl J. The pattern of gene copy number alteration (CNAs) in hepatocellular carcinoma: an in silico analysis. Mol Cytogenet 2021; 14:33. [PMID: 34215297 PMCID: PMC8254242 DOI: 10.1186/s13039-021-00553-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 05/19/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common type of liver cancer that occurs predominantly in patients with previous liver conditions. In the absence of an ideal screening modality, HCC is usually diagnosed at an advanced stage. Recent studies show that loss or gain of genomic materials can activate the oncogenes or inactivate the tumor suppressor genes to predispose cells toward carcinogenesis. Here, we evaluated both the copy number alteration (CNA) and RNA sequencing data of 361 HCC samples in order to locate the frequently altered chromosomal regions and identify the affected genes. RESULTS Our data show that the chr1q and chr8p are two hotspot regions for genomic amplifications and deletions respectively. Among the amplified genes, YY1AP1 (chr1q22) possessed the largest correlation between CNA and gene expression. Moreover, it showed a positive correlation between CNA and tumor grade. Regarding deleted genes, CHMP7 (chr8p21.3) possessed the largest correlation between CNA and gene expression. Protein products of both genes interact with other cellular proteins to carry out various functional roles. These include ASH1L, ZNF496, YY1, ZMYM4, CHMP4A, CHMP5, CHMP2A and CHMP3, some of which are well-known cancer-related genes. CONCLUSIONS Our in-silico analysis demonstrates the importance of copy number alterations in the pathology of HCC. These findings open a door for future studies that evaluate our results by performing additional experiments.
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Affiliation(s)
- Arman Shahrisa
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Tahmasebi-Birgani
- Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Hossein Ansari
- Department of Biotechnology, Islamic Azad University, Ahvaz Branch, Ahvaz, Iran
| | - Zahra Mohammadi
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vinicio Carloni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Javad Mohammadi Asl
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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16
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Zhang J, Zhang X, Yang S, Bao Y, Xu D, Liu L. FOXH1 promotes lung cancer progression by activating the Wnt/β-catenin signaling pathway. Cancer Cell Int 2021; 21:293. [PMID: 34090445 PMCID: PMC8180118 DOI: 10.1186/s12935-021-01995-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The expression of forkhead box protein H1 (FOXH1) is frequently upregulated in various cancers. However, the molecular mechanisms underlying the association between FOXH1 expression and lung cancer progression still remain poorly understood. Thus, the main objective of this study is to explore the role of FOXH1 in lung cancer. METHODS The Cancer Genome Atlas dataset was used to investigate FOXH1 expression in lung cancer tissues, and the Kaplan-Meier plotter dataset was used to determine the role of FOXH1 in patient prognosis. A549 and PC9 cells were transfected with short hairpin RNA targeting FOXH1 mRNA. The Cell Counting Kit-8, colony formation, soft agar, wound healing, transwell invasion and flow cytometry assays were performed to evaluate proliferation, migration and invasion of lung cancer cells. Tumorigenicity was examined in a BALB/c nude mice model. Western blot analysis was performed to assess the molecular mechanisms, and β-catenin activity was measured by a luciferase reporter system assay. RESULTS Higher expression level of FOXH1 was observed in tumor tissue than in normal tissue, and this was associated with poor overall survival. Knockdown of FOXH1 significantly inhibited lung cancer cell proliferation, migration, invasion, and cycle. In addition, the mouse xenograft model showed that knockdown of FOXH1 suppressed tumor growth in vivo. Further experiments revealed that FOXH1 depletion inhibited the epithelial-mesenchymal transition of lung cancer cells by downregulating the expression of mesenchymal markers (Snail, Slug, matrix metalloproteinase-2, N-cadherin, and Vimentin) and upregulating the expression of an epithelial marker (E-cadherin). Moreover, knockdown of FOXH1 significantly downregulated the activity of β-catenin and its downstream targets, p-GSK-3β and cyclin D1. CONCLUSION FOXH1 exerts oncogenic functions in lung cancer through regulation of the Wnt/β-catenin signaling pathway. FOXH1 might be a potential therapeutic target for patients with certain types of lung cancer.
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Affiliation(s)
- Jun Zhang
- Department of Morphological Experiment Center, Medical College of Yanbian University, Yanji, Jilin, 133000, China
- Department of Histology and Embryology, Jilin Medical University, Jilin, Jilin, 132013, China
| | - Xian Zhang
- Department of General Surgery, Affiliated Hospital of Yanbian University, Yanji, Jilin, 133000, China
| | - Shasha Yang
- Department of Morphological Experiment Center, Medical College of Yanbian University, Yanji, Jilin, 133000, China
| | - Yanqiu Bao
- Department of Pathology, Affiliated Hospital of Yanbian University, Yanji, Jilin, 133000, China
| | - Dongyuan Xu
- Department of Morphological Experiment Center, Medical College of Yanbian University, Yanji, Jilin, 133000, China.
| | - Lan Liu
- Department of Pathology, Affiliated Hospital of Yanbian University, Yanji, Jilin, 133000, China.
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17
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Zhu J, Xu X, Liang Y, Zhu R. Downregulation of microRNA-15b-5p Targeting the Akt3-Mediated GSK-3 β/ β-Catenin Signaling Pathway Inhibits Cell Apoptosis in Parkinson's Disease. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8814862. [PMID: 33506036 PMCID: PMC7806375 DOI: 10.1155/2021/8814862] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/07/2020] [Accepted: 12/18/2020] [Indexed: 12/13/2022]
Abstract
Parkinson's disease (PD) is an incurable progressive disorder resulting from neurodegeneration, and apoptosis is considered a dominant mechanism underlying the process of neurodegeneration. MicroRNAs (miRNAs), which are small and noncoding RNAs involved in many a biological process like apoptosis and regulation of gene expressions, have been found in postmortem brain samples of patients with PD, as well as in vitro and in vivo models of PD. To explore the impact of miR-15b-5p and Akt3 on apoptosis in the progression of PD, the method of quantitative reverse transcription polymerase chain reaction (qRT-PCR) was employed, and the analysis result showed upregulated expression of miR-15b-5p and downregulated expression of Akt3 in the serum of PD patients, MPP+-induced SH-SY5Y cells, and the brain tissues of MPTP-induced mice. Meanwhile, the dual-luciferase reporter assay was used to demonstrate the regulator-target interaction between miR-15b-5p and Akt3; flow cytometry and spectrophotometry revealed that transfection of miR-15b-5p mimic and si-Akt3 increased the rate of apoptosis and caspase-3 activity, whereas transfecting the miR-15b-5p inhibitor and Akt3-overexpression plasmid repressed the rate of apoptosis and caspase-3 activity in the MPP+-induced SH-SY5Y cell model and the MPTP-induced mouse model. Additionally, analysis of western blotting (WB) assays in vivo and in vitro revealed that proapoptosis proteins (Bax, caspase-3, GSK-3β, and β-catenin) showed markedly upregulated expression in the miR-15b-5p inhibitor and si-Akt3-overexpression groups, while the expression of an antiapoptosis gene (i.e., Bcl2) was downregulated. These analysis results indicate that downregulation of miR-15b-5p by targeting the Akt3-mediated GSK-3β/β-catenin signaling pathway would repress cell apoptosis in PD in vivo and in vitro. It is expected that the research findings would help find new therapeutic targets for treatment of PD.
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Affiliation(s)
- Jianzhong Zhu
- Department of Neurology, Longmen County People's Hospital, Huizhou 516800, China
| | - Xue Xu
- Department of Neurology, The First Affiliated Hospital of Sun Yatsen University, Guangzhou 510080, China
| | - Yingyin Liang
- Department of Neurology, The First Affiliated Hospital of Sun Yatsen University, Guangzhou 510080, China
| | - Ronglan Zhu
- Department of Neurology, The First Affiliated Hospital of Sun Yatsen University, Guangzhou 510080, China
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LncRNA miR503HG inhibits epithelial-mesenchymal transition and angiogenesis in hepatocellular carcinoma by enhancing PDCD4 via regulation of miR-15b. Dig Liver Dis 2021; 53:107-116. [PMID: 33046427 DOI: 10.1016/j.dld.2020.09.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To reveal the effect of lncRNA miR503HG on epithelial-mesenchymal transition (EMT) and angiogenesis in hepatocellular carcinoma (HCC). METHODS The expressions of miR503HG, miR-15b and PDCD4 in HCC tissues and cell lines were measured. After cell transfection, Transwell assay tested the migration and invasion ability of HCC cells. qRT-PCR and Western blot detected the expressions of EMT markers (E-cad, N-cad, Vim and Snail-1). Matrigel-based tube formation assay assessed the angiogenesis capacity of human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium of treated HCC cells. ELISA detected the level of VEGF in supernatant of HUVECs. RIP, RNA pulldown and dual-luciferase reporter assay were applied to verify the binding of miR-15b to miR503HG or PDCD4. pcDNA3.1-miR503HG-BEL-7404 cells or pcDNA3.1-BEL-7404 cells were implanted into nude mice for construction of HCC model in vivo. RESULTS miR503HG and PDCD4 were under-expressed and miR-15b was over-expressed in HCC cells and tissues. Up-regulation of miR503HG and PDCD4 or inhibition of miR-15b hindered migration, invasion and EMT of HCC cells and angiogenesis of HUVECs. Both miR503HG and PDCD4 could bind to miR-15b. Over-expression of miR503HG suppressed HCC growth and angiogenesis in nude mice. CONCLUSION LncRNA miR503HG suppresses EMT and angiogenesis in HCC via miR-15b/PDCD4 axis.
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Resaz R, Cangelosi D, Morini M, Segalerba D, Mastracci L, Grillo F, Bosco MC, Bottino C, Colombo I, Eva A. Circulating exosomal microRNAs as potential biomarkers of hepatic injury and inflammation in a murine model of glycogen storage disease type 1a. Dis Model Mech 2020; 13:dmm043364. [PMID: 32620541 PMCID: PMC7520457 DOI: 10.1242/dmm.043364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 06/23/2020] [Indexed: 12/17/2022] Open
Abstract
Most patients affected by glycogen storage disease type 1a (GSD1a), an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α), develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma. The purpose of this study was to identify potential biomarkers of the pathophysiology of the GSD1a-affected liver. To this end, we used the plasma exosomes of a murine model of GSD1a, the LS-G6pc-/- mouse, to uncover the modulation in microRNA expression associated with the disease. The microRNAs differentially expressed between LS-G6pc-/- and wild-type mice, LS-G6pc-/- mice with hepatocellular adenoma and LS-G6pc-/- mice without adenoma, and LS-G6pc-/- mice with amyloidosis and LS-G6pc-/- mice without amyloidosis were identified. Pathway analysis demonstrated that the target genes of the differentially expressed microRNA were significantly enriched for the insulin signaling pathway, glucose and lipid metabolism, Wnt/β-catenin, telomere maintenance and hepatocellular carcinoma, and chemokine and immune regulation signaling pathways. Although some microRNAs were common to the different pathologic conditions, others were unique to the cancerous or inflammatory status of the animals. Therefore, the altered expression of several microRNAs is correlated with various pathologic liver states and might help to distinguish them during the progression of the disease and the development of late GSD1a-associated complications.
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Affiliation(s)
- Roberta Resaz
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Davide Cangelosi
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Martina Morini
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Daniela Segalerba
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Luca Mastracci
- Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, Università degli Studi di Genova, Viale Benedetto XV 6, 16132 Genova, Italy
- National Cancer Research Institute, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Federica Grillo
- Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, Università degli Studi di Genova, Viale Benedetto XV 6, 16132 Genova, Italy
- National Cancer Research Institute, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Cristina Bottino
- Department of Experimental Medicine, School of Medicine, Università degli Studi di Genova, Via L. B. Alberti 2, 16132 Genova, Italy
- Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
| | - Irma Colombo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via D. Trentacoste 2, 20134 Milano, Italy
| | - Alessandra Eva
- Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy
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Zhu K, Zhan H, Peng Y, Yang L, Gao Q, Jia H, Dai Z, Tang Z, Fan J, Zhou J. Plasma hsa_circ_0027089 is a diagnostic biomarker for hepatitis B virus-related hepatocellular carcinoma. Carcinogenesis 2020; 41:296-302. [PMID: 31535687 PMCID: PMC7221502 DOI: 10.1093/carcin/bgz154] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 08/10/2019] [Accepted: 09/12/2019] [Indexed: 12/11/2022] Open
Abstract
Circular RNAs (circRNAs) have recently been identified as a new member of endogenous noncoding RNAs. CircRNAs exhibit high stability and can thus can be used as valuable biomarkers for monitoring the occurrence and development of hepatocellular carcinoma (HCC). The present study sought to explore the diagnostic significance of plasma circRNAs in hepatitis B virus (HBV)-related HCC. Plasma circRNAs from 10 patients with hepatitis B (HBV)-related HCC and 5 patients with HBV-related liver cirrhosis were investigated by microarray to screen differentially expressed circRNAs, 157 upregulated and 161 downregulated circRNAs were found. Twenty-four circRNAs were further investigated via quantitative reverse-transcriptase–polymerase chain reaction assay in a training cohort (n = 48), hsa_circ_0027089 exhibited the highest significance and further distinguished 64 HCC patients from 40 cirrhosis patients and 72 healthy participants in a validation cohort. These results indicate that plasma hsa_circ_0027089 can serve as a new marker for the diagnosis of HBV-related HCC.
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Affiliation(s)
- Kai Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.,Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hao Zhan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Yuanfei Peng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Liuxiao Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Hao Jia
- Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhi Dai
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zhaoyou Tang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.,Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratorsy of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.,Key Laboratory of Medical Epigenetics and Metabolism, Institute of Biomedical Sciences, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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21
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Zou J, Qian J, Fu H, Yin F, Zhao W, Xu L. MicroRNA‑15b‑5p exerts its tumor repressive role via targeting GDI2: A novel insight into the pathogenesis of thyroid carcinoma. Mol Med Rep 2020; 22:2723-2732. [PMID: 32945458 PMCID: PMC7453593 DOI: 10.3892/mmr.2020.11343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 06/12/2020] [Indexed: 12/24/2022] Open
Abstract
Thyroid carcinoma (THCA) is a malignant tumor of the endocrine system. Previous studies have revealed the vital roles of microRNAs (miRNAs/miRs) in THCA procession. The present study aimed to explore the effects of miR-15b-5p on the progression of THCA and its targeting mechanism. The data of THCA and healthy samples were firstly collected from starbase2.0 and used to analyze the relationship of miR-15b-5p with THCA. Dual-luciferase assay was performed to detect the direct interaction between miR-15b-5p and the predicted target gene GDP dissociation inhibitor 2 (GDI2). The effects of miR-15b-5p and GDI2 on the overall survival of patients with THCA were analyzed using Kaplan-Meier analysis with log rank test. Cell Counting Kit-8 and Transwell assays were conducted to assess the impacts of miR-15b-5p and GDI2 on the proliferation and invasion of THCA cells. Reverse transcription-quantitative PCR and western blot analyses were performed to analyze the expression levels of the related miRNAs and proteins, respectively. miR-15b-5p was found to be downregulated both in THCA tissues and cells, and the low expression of miR-15b-5p was associated with the short overall survival time of patients. Moreover, the upregulation or downregulation of miR-15b-5p could inhibit or enhance the proliferation and invasion of THCA cells, respectively. miR-15b-5p reduced the protein expression levels of matrix metalloproteinase (MMP)2 and MMP9, which were related to cell invasion. Furthermore, GDI2, which was enhanced in THCA and related to the poor prognosis of patients with THCA, was identified as the target gene of miR-15b-5p and negatively regulated by miR-15b-5p. Additional experiments demonstrated that GDI2 overexpression could significantly reduce the antitumor effect of miR-15b-5p and its inhibitory action on the expression levels of MMP2 and MMP9. Thus, the results indicated a potential tumor suppressive role of miR-15b-5p in THCA, which was mainly exerted by targeting GDI2 and modulating MMP2 and MMP9. These findings will increase the understanding on the pathogenesis of THCA and provide novel candidates for THCA therapy.
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Affiliation(s)
- Jidong Zou
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Jiantong Qian
- Otolaryngology Department, Traditional Chinese Medicine Hospital of Juxian, Rizhao, Shandong 276599, P.R. China
| | - Haiyan Fu
- Pathology Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Fawen Yin
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Wanjun Zhao
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
| | - Liang Xu
- Thyroid Diseases Department, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250022, P.R. China
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22
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Zhang BH, Yang J, Jiang L, Lyu T, Kong LX, Tan YF, Li B, Zhu YF, Xi AY, Xu X, Yan LN, Yang JY. Development and validation of a 14-gene signature for prognosis prediction in hepatocellular carcinoma. Genomics 2020; 112:2763-2771. [PMID: 32198063 DOI: 10.1016/j.ygeno.2020.03.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 03/11/2020] [Accepted: 03/16/2020] [Indexed: 02/08/2023]
Abstract
Worldwide, hepatocellular carcinoma (HCC) remains a crucial medical problem. Precise and concise prognostic models are urgently needed because of the intricate gene variations among liver cancer cells. We conducted this study to identify a prognostic gene signature with biological significance. We applied two algorithms to generate differentially expressed genes (DEGs) between HCC and normal specimens in The Cancer Genome Atlas cohort (training set included) and performed enrichment analyses to expound on their biological significance. A protein-protein interactions network was established based on the STRING online tool. We then used Cytoscape to screen hub genes in crucial modules. A multigene signature was constructed by Cox regression analysis of hub genes to stratify the prognoses of HCC patients in the training set. The prognostic value of the multigene signature was externally validated in two other sets from Gene Expression Omnibus (GSE14520 and GSE76427), and its role in recurrence prediction was also investigated. A total of 2000 DEGs were obtained, including 1542 upregulated genes and 458 downregulated genes. Subsequently, we constructed a 14-gene signature on the basis of 56 hub genes, which was a good predictor of overall survival. The prognostic signature could be replicated in GSE14520 and GSE76427. Moreover, the 14-gene signature could be applied for recurrence prediction in the training set and GSE14520. In summary, the 14-gene signature extracted from hub genes was involved in some of the HCC-related signalling pathways; it not only served as a predictive signature for HCC outcome but could also be used to predict HCC recurrence.
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Affiliation(s)
- Bo-Han Zhang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Jian Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Li Jiang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Tao Lyu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Ling-Xiang Kong
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Yi-Fei Tan
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Bo Li
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Yun-Feng Zhu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Ao-Yao Xi
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Xi Xu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Lyu-Nan Yan
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China
| | - Jia-Yin Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, Sichuan, PR China.
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Wu B, Liu G, Jin Y, Yang T, Zhang D, Ding L, Zhou F, Pan Y, Wei Y. miR-15b-5p Promotes Growth and Metastasis in Breast Cancer by Targeting HPSE2. Front Oncol 2020; 10:108. [PMID: 32175269 PMCID: PMC7054484 DOI: 10.3389/fonc.2020.00108] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 01/21/2020] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) can participate in many behaviors of various tumors. Prior studies have reported that miR-15b-5p in different tumors can either promote or inhibit tumor progression. In breast cancer, the role of miR-15b-5p is unclear. The main objective of this paper is to explore miR-15b-5p effects and their mechanisms in breast cancer using both in vitro and in vivo experiments. This study showed that miR-15b-5p expression was upregulated in breast cancer compared with normal breast tissue and was positively correlated with poor overall survival in patients. Knockdown of miR-15b-5p in MCF-7 and MD-MBA-231 breast cancer cells restrained cell growth and invasiveness and induced apoptosis, whereas overexpression of miR-15b-5p achieved the opposite effects. We next revealed a negative correlation between miR-15b-5p and heparanase-2 (HPSE2) expression in breast cancer. Knockdown of miR-15b-5p significantly increased HPSE2 expression at both mRNA and protein levels in breast cancer cells in vitro. The underlying mechanisms of miR-15-5p in breast cancer were investigated using luciferase activity reporter assay and rescue experiments. In addition, miR-15b-5p knockdown significantly inhibited tumor growth in a xenograft model in mice. In summary, we showed that miR-15b-5p promotes breast cancer cell proliferation, migration, and invasion by directly targeting HPSE2. Accordingly, miR-15b-5p may serve both as a tool for prognosis and as a target for therapy of breast cancer patients.
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Affiliation(s)
- Balu Wu
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Guohong Liu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yanxia Jin
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Tian Yang
- Department of Clinical Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Dongdong Zhang
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Lu Ding
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yongchang Wei
- Hubei Key Laboratory of Tumor Biological Behaviors, Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
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24
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Wang L, Qu J, Liang Y, Zhao D, Rehman FU, Qin K, Zhang X. Identification and validation of key genes with prognostic value in non-small-cell lung cancer via integrated bioinformatics analysis. Thorac Cancer 2020; 11:851-866. [PMID: 32059076 PMCID: PMC7113067 DOI: 10.1111/1759-7714.13298] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 12/15/2022] Open
Abstract
Background Lung cancer is the most common cause of cancer‐related death among all human cancers and the five‐year survival rates are only 23%. The precise molecular mechanisms of non‐small cell lung cancer (NSCLC) are still unknown. The aim of this study was to identify and validate the key genes with prognostic value in lung tumorigenesis. Methods Four GEO datasets were obtained from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) were selected for Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology enrichment analysis. Protein‐protein interaction (PPI) networks were constructed using the STRING database and visualized by Cytoscape software and Molecular Complex Detection (MCODE) were utilized to PPI network to pick out meaningful DEGs. Hub genes, filtered from the CytoHubba, were validated using the Gene Expression Profiling Interactive Analysis database. The expressions and prognostic values of hub genes were carried out through Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan‐Meier plotter. Finally, quantitative PCR and the Oncomine database were used to verify the differences in the expression of hub genes in lung cancer cells and tissues. Results A total of 121 DEGs (49 upregulated and 72 downregulated) were identified from four datasets. The PPI network was established with 121 nodes and 588 protein pairs. Finally, AURKA, KIAA0101, CDC20, MKI67, CHEK1, HJURP, and OIP5 were selected by Cytohubba, and they all correlated with worse overall survival (OS) in NSCLC. Conclusion The results showed that AURKA, KIAA0101, CDC20, MKI67, CHEK1, HJURP, and OIP5 may be critical genes in the development and prognosis of NSCLC. Key points Our results indicated that AURKA, KIAA0101, CDC20, MKI67, CHEK1, HJURP, and OIP5 may be critical genes in the development and prognosis of NSCLC. Our methods showed a new way to explore the key genes in cancer development.
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Affiliation(s)
- Li Wang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Jialin Qu
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Yu Liang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Deze Zhao
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Faisal Ul Rehman
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Kang Qin
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiaochun Zhang
- Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
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Identification of Potentially Therapeutic Target Genes of Hepatocellular Carcinoma. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17031053. [PMID: 32046048 PMCID: PMC7037431 DOI: 10.3390/ijerph17031053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major threat to public health. However, few effective therapeutic strategies exist. We aimed to identify potentially therapeutic target genes of HCC by analyzing three gene expression profiles. METHODS The gene expression profiles were analyzed with GEO2R, an interactive web tool for gene differential expression analysis, to identify common differentially expressed genes (DEGs). Functional enrichment analyses were then conducted followed by a protein-protein interaction (PPI) network construction with the common DEGs. The PPI network was employed to identify hub genes, and the expression level of the hub genes was validated via data mining the Oncomine database. Survival analysis was carried out to assess the prognosis of hub genes in HCC patients. RESULTS A total of 51 common up-regulated DEGs and 201 down-regulated DEGs were obtained after gene differential expression analysis of the profiles. Functional enrichment analyses indicated that these common DEGs are linked to a series of cancer events. We finally identified 10 hub genes, six of which (OIP5, ASPM, NUSAP1, UBE2C, CCNA2, and KIF20A) are reported as novel HCC hub genes. Data mining the Oncomine database validated that the hub genes have a significant high level of expression in HCC samples compared normal samples (t-test, p < 0.05). Survival analysis indicated that overexpression of the hub genes is associated with a significant reduction (p < 0.05) in survival time in HCC patients. CONCLUSIONS We identified six novel HCC hub genes that might be therapeutic targets for the development of drugs for some HCC patients.
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26
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Chen L, Wang R, Gao L, Shi W. Opa-Interacting Protein 5 Expression in Human Glioma Tissues Is Essential to the Biological Function of U251 Human Malignant Glioma Cells. Cancer Control 2020; 27:1073274820968914. [PMID: 33153318 PMCID: PMC7791457 DOI: 10.1177/1073274820968914] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Opa-interacting protein 5 (OIP5) is a member of the cancer-testis antigen (CTA) family that elicits a spontaneous antitumor immune response. The failure of current immunotherapies for glioma has prompted the search for novel biomarkers that may be utilized as therapeutic targets. This study aimed to investigate whether OIP5 serves as a target for malignant glioma immunotherapy. Glioma specimens from 53 adult patients were evaluated for OIP5 expression by immunohistochemical (IHC) staining, and the correlation of OIP5 expression with World Health Organization (WHO) tumor grade was analyzed. Endogenous expression of OIP5 in glioma cell lines was determined via real-time polymerase chain reaction (RT-PCR). Using lentiviral siOIP5, the effect of OIP5 gene knockdown on proliferation, cell cycle, and apoptosis in U251 glioma cells was studied. The results show that OIP5 is overexpressed in glioma tissues and is correlated with WHO tumor grade (P < 0.001). However, OIP5 protein expression is barely detectable in normal adult brain tissues. MTT assays and analysis using the Celigo Imaging Cytometry System reveal that the silencing of OIP5 inhibits U251 cell growth. Cell cycle assays and Annexin V staining show that OIP5 silencing disrupts the balance of the cell cycle and increases U251 cell death. These results indicate that OIP5 is upregulated in malignant glioma specimens but barely detected in normal brain tissues. OIP5 knockdown inhibits the biological function of glioma cells, reinforcing that OIP5 may serve as an immunotherapeutic target for malignant glioma.
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Affiliation(s)
- Libo Chen
- Neurosurgery Department, the Second Hospital of Weinan, Weinan,
Shaanxi, People’s Republic of China
| | - Ruizhi Wang
- Neurosurgery Department, the Second Affiliated Hospital of Xi’an
Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Ligui Gao
- Neurosurgery Department, the Second Affiliated Hospital of Xi’an
Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Wei Shi
- Neurosurgery Department, the Second Affiliated Hospital of Xi’an
Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
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27
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He J, Zhao Y, Zhao E, Wang X, Dong Z, Chen Y, Yang L, Cui H. Cancer-testis specific gene OIP5: a downstream gene of E2F1 that promotes tumorigenesis and metastasis in glioblastoma by stabilizing E2F1 signaling. Neuro Oncol 2019; 20:1173-1184. [PMID: 29547938 DOI: 10.1093/neuonc/noy037] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background The cancer-testis specific gene Opa interacting protein 5 (OIP5) is reactivated in many human cancers, but its functions in glioblastoma remain unclear. Here, we assessed the significance of OIP5 in the tumorigenesis and metastasis of glioblastoma for the first time. Methods An immunohistochemistry assay was performed to detect OIP5 expression changes in glioblastoma patients. Overall survival analysis was performed to evaluate the prognostic significance of OIP5. Growth curve, colony formation, and transwell assays were used to analyze cell proliferation and metastasis. Tumorigenicity potential was investigated in orthotopic tumor models, and immunoprecipitation, chromatin immunoprecipitation, and luciferase assays were employed to explore the mechanisms underlying the activation of OIP5 expression by E2F transcription factor 1 (E2F1) to stabilize and maintain E2F1 signaling. Results OIP5 was found to be upregulated in glioblastoma patients and to impair patient survival, and the increased expression of OIP5 was positively correlated with tumor stage. Compared with short hairpin green fluorescent protein cells, cells in which OIP5 was knocked down exhibited significantly reduced proliferation, metastasis, colony formation, and tumorigenicity abilities, whereas OIP5 recovery enhanced these abilities. OIP5 was highly correlated with cell cycle progression but had no obvious effects on apoptosis. Notably, we demonstrated a feedback loop in which E2F1 activates the expression of OIP5 to stabilize and maintain E2F1 signaling and promote the E2F1-regulated gene expression that is required for aggressive tumor biology. Conclusions Collectively, our findings demonstrate that OIP5 promotes glioblastoma progression and metastasis, suggesting that OIP5 is a potential target for anticancer therapy.
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Affiliation(s)
- Jiang He
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Yuzu Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Erhu Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Xianxing Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Yibiao Chen
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
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Lu L, Li Y, Wen H, Feng C. Overexpression of miR-15b Promotes Resistance to Sunitinib in Renal Cell Carcinoma. J Cancer 2019; 10:3389-3396. [PMID: 31293642 PMCID: PMC6603409 DOI: 10.7150/jca.31676] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 04/25/2019] [Indexed: 01/08/2023] Open
Abstract
Aim: Sunitinib remains the frontline treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Drug resistance is inevitable and related mechanism warrant insightful elaboration. Methods: In silico data mining of GEO and TCGA datasets was performed to identify potential target micro-RNA. In vitro and in vivo studies were performed to validate findings. Results: Reproduction of GEO datasets revealed miR-15b significantly upregulated in sunitinib- resistant ccRCC. Five out of seven ccRCC cell lines demonstrated significantly overexpressed miR-15b after sunitinib treatment. Vector-mediated overexpression of miR-15b significantly induced resistance to sunitinib in ccRCC cells. Overexpression of miR-15b significantly induced less population in G1 phase of cell cycle and less apoptosis in cells treated sunitinib. Expression of genes negatively correlated with miR-15b in TCGA ccRCC (KIRC) dataset were cross-referenced with predicted targets of miR-15b and CCNC was selected as potential target for resistance mediation. Overexpression of miR-15b suppressed CCNC expression and protein (Cyclin C) levels. Cyclin C-associated proteins CDK19 and CDK8 were also suppressed following miR-15b overexpression. Silencing of CCNC mimicked overexpression of miR-25 inducing cell cycle progression passing G1 phase and less apoptosis in ccRCC cells treated by sunitinib. Overexpression of miR-15b also counteracted suppression of migration and colony formation by sunitinib in ccRCC cell lines. In vivo mouse xenograft models showed recovered tumor growth with miR-15b expression in mice treated with sunitinib. Conclusion: We here show miR-15b as a possible culprit for sunitinib resistance in ccRCC. Targeting miR-15b could potentially overcome drug resistance and related mechanism warrants further investigation.
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Affiliation(s)
- Lu Lu
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Yanmin Li
- Department of Urology and Institute of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Hui Wen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Chenchen Feng
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China
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29
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Li Y, Xiao F, Li W, Hu P, Xu R, Li J, Li G, Zhu C. Overexpression of Opa interacting protein 5 increases the progression of liver cancer via BMPR2/JUN/CHEK1/RAC1 dysregulation. Oncol Rep 2019; 41:2075-2088. [PMID: 30816485 PMCID: PMC6412147 DOI: 10.3892/or.2019.7006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 01/30/2019] [Indexed: 12/24/2022] Open
Abstract
Opa interacting protein 5 (OIP5) overexpression is associated with human carcinoma. However, its biological function, underlying mechanism and clinical significance in liver cancer remain unknown. In the present study, the effects of OIP5 expression on liver cancer, and the mechanisms regulating these effects, were investigated. OIP5 expression was measured in human hepatocellular carcinoma (HCC) tissues and liver cancer cell lines. The effect of OIP5 knockdown on tumorigenesis was also detected in nude mice, and differentially‑expressed genes (DEGs) were identified and their biological functions were identified. The results indicated that OIP5 expression was significantly upregulated in HCC tissues and four liver cancer cell lines (P<0.01). Increased OIP5 protein expression significantly predicted reduced survival rate of patients with HCC (P<0.01). OIP5 knockdown resulted in the suppression of proliferation and colony forming abilities, cell cycle arrest at the G0/G1 or G2/M phases, and promotion of cell apoptosis. A total of 628 DEGs, including 87 upregulated and 541 downregulated genes, were identified following OIP5 knockdown. Functional enrichment analysis indicated that DEGs were involved in 'RNA Post‑Transcriptional Modification, Cancer and Organismal Injury and Abnormalities'. Finally, OIP5 knockdown in Huh7 cells dysregulated bone morphogenetic protein receptor type 2/JUN/checkpoint kinase 1/Rac family small GTPase 1 expression. In conclusion, the overall results demonstrated the involvement of OIP5 in the progression of liver cancer and its mechanism of action.
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MESH Headings
- Adult
- Animals
- Bone Morphogenetic Protein Receptors, Type II/metabolism
- Carcinogenesis/genetics
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Cell Cycle Proteins
- Cell Line, Tumor
- Checkpoint Kinase 1/metabolism
- Chromosomal Proteins, Non-Histone/genetics
- Chromosomal Proteins, Non-Histone/metabolism
- Disease Progression
- Down-Regulation
- Female
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- JNK Mitogen-Activated Protein Kinases/metabolism
- Kaplan-Meier Estimate
- Liver/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Male
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- RNA, Small Interfering/metabolism
- Up-Regulation
- Xenograft Model Antitumor Assays
- rac1 GTP-Binding Protein/metabolism
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Affiliation(s)
- Yuwen Li
- Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Fei Xiao
- Department of Infectious Diseases, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, P.R. China
| | - Wenting Li
- Third Liver Unit, Department of Infectious Disease, The First Affiliated Hospital of Science and Technology of China, Hefei, Anhui 230001, P.R. China
| | - Pingping Hu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Ruirui Xu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jun Li
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Guimei Li
- Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
- Correspondence to: Dr Guimei Li, Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, 9677 Jingshi Road, Jinan, Shandong 250021, P.R. China, E-mail:
| | - Chuanlong Zhu
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
- Dr Chuanlong Zhu, Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, P.R. China, E-mail:
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Wang X, Song P, Huang C, Yuan N, Zhao X, Xu C. Weighted gene co‑expression network analysis for identifying hub genes in association with prognosis in Wilms tumor. Mol Med Rep 2019; 19:2041-2050. [PMID: 30664180 PMCID: PMC6390024 DOI: 10.3892/mmr.2019.9881] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 10/22/2018] [Indexed: 12/21/2022] Open
Abstract
Wilms tumor (WT) is the most common type of renal malignancy in children. Survival rates are low and high-risk WT generally still carries a poor prognosis. To better elucidate the pathogenesis and tumorigenic pathways of high-risk WT, the present study presents an integrated analysis of RNA expression profiles of high-risk WT to identify predictive molecular biomarkers, for the improvement of therapeutic decision-making. mRNA sequence data from high-risk WT and adjacent normal samples were downloaded from The Cancer Genome Atlas to screen for differentially expressed genes (DEGs) using R software. From 132 Wilms tumor samples and six normal samples, 2,089 downregulated and 941 upregulated DEGs were identified. In order to identify hub DEGs that regulate target genes, weighted gene co-expression network analysis (WGCNA) was used to identify 11 free-scale gene co-expressed clusters. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were annotated using KEGG Orthology Based Annotation System annotation of different module genes. The Search Tool for the Retrieval of Interacting Genes was used to construct a protein-protein interaction network for the identified DEGs, and the hub genes of WGCNA modules were identified using the Cytohubb plugin with Cytoscape software. Survival analysis was subsequently performed to highlight hub genes with a clinical signature. The present results suggest that epidermal growth factor, cyclin dependent kinase 1, endothelin receptor type A, nerve growth factor receptor, opa-interacting protein 5, NDC80 kinetochore complex component and cell division cycle associated 8 are essential to high-risk WT pathogenesis, and they are closely associated with clinical prognosis.
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Affiliation(s)
- Xiaofu Wang
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Pan Song
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Chuiguo Huang
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Naijun Yuan
- College of Traditional Chinese Medicine, Institute of Integrated Traditional Chinese and Western Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xinghua Zhao
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Changbao Xu
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
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Wang D, Chen Z, Lin F, Wang Z, Gao Q, Xie H, Xiao H, Zhou Y, Zhang F, Ma Y, Mei H, Cai Z, Liu Y, Huang W. OIP5 Promotes Growth, Metastasis and Chemoresistance to Cisplatin in Bladder Cancer Cells. J Cancer 2018; 9:4684-4695. [PMID: 30588253 PMCID: PMC6299379 DOI: 10.7150/jca.27381] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 08/12/2018] [Indexed: 12/14/2022] Open
Abstract
Opa interacting protein 5 (OIP5) has previously been identified as a tumorigenesis gene. The purpose of this study is to explore the role of OIP5 in the progression of bladder cancer (BC). The OIP5 expression and clinical behaviors in bladder cancer were collected from lager database. Our study showed that OIP5 was highly expressed in bladder cancer tissues and cells. Overexpression of OIP5 in tumor patients predicted worse overall survival (OS) and higher histological grade. Vitro and vivo experiments demonstrated that knockdown of OIP5 significantly inhibited cell growth of BC. Scratch assay and transwell assay suggested that migration capacity of BC cells was decreased after knockdown of OIP5. Cisplatin sensitivity assay indicated that depletion of OIP5 increased the sensitivity of BC cells to cisplatin. Finally, we identified 38 overlapping differentially expressed genes (DEGs) between RNA-seq and TCGA analyses which were closely linked to OIP5. Bioinformatics analysis showed that these DEGs enriched in oocyte meiosis, fanconi anemia pathway, cell cycle, and microRNAs regulation. TOP2A, SPAG5, SKA1, EXO1, TK1 were confirmed to associated with bladder cancer development. Our study suggests that OIP5 may be a potential biomarker for growth, metastasis and drug-resistance in bladder cancer.
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Affiliation(s)
- Dailian Wang
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China
| | - Zhicong Chen
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China
| | - Fan Lin
- College of pharmacy, Guangdong Pharmaceutical University, Guangdong, China
| | - Ziqiang Wang
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
| | - Qunjun Gao
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
| | - Haibiao Xie
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
| | - Huizhong Xiao
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
| | - Yifan Zhou
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
| | - Fuyou Zhang
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
| | - Yingfei Ma
- Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Hongbin Mei
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China
| | - Zhiming Cai
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
- Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China
| | - Yuchen Liu
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China
| | - Weiren Huang
- Department of Urology, Shenzhen Second People's Hospital, Guangzhou Medical University, Guangdong, China
- Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen, China
- Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, China
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miR-103/miR-195/miR-15b Regulate SALL4 and Inhibit Proliferation and Migration in Glioma. Molecules 2018; 23:molecules23112938. [PMID: 30423818 PMCID: PMC6278493 DOI: 10.3390/molecules23112938] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 11/01/2018] [Accepted: 11/07/2018] [Indexed: 01/13/2023] Open
Abstract
Glioma is the common highly malignant primary brain tumor. However, the molecular pathways that result in the pathogenesis of glioma remain elusive. In this study, we found that microRNA-103 (miR-103), microRNA-195 (miR-195), or microRNA-15b (miR-15b), which all have the same 5' "seed" miRNA portion and share common binding sites in the SALL4 3'-untranslated region (UTR), were downregulated in glioma tissues and cell lines. These miRNAs suppressed glioma cell proliferation, migration, and invasion, induced cell apoptosis, and decreased the level of the SALL4 protein, but not that of SALL4 mRNA, which was identified as a direct target of all three miRNAs. The caspase-3/7 activity expression in U251 cells overexpressing these miRNAs was rescued during SALL4 upregulation. An obvious inverse correlation was observed between SALL4 and miR-103 or miR-195 expression levels in clinical glioma samples. Moreover, enforced expression of SALL4 stimulated cell proliferation, migration, and invasion. In conclusion, these data suggest that miR-103, miR-195, and miR-15b post-transcriptionally downregulated the expression of SALL4 and suppressed glioma cell growth, migration, and invasion, and increased cell apoptosis. These results provide a potential therapeutic target that may downregulate SALL4 in glioma.
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Vasuri F, Visani M, Acquaviva G, Brand T, Fiorentino M, Pession A, Tallini G, D’Errico A, de Biase D. Role of microRNAs in the main molecular pathways of hepatocellular carcinoma. World J Gastroenterol 2018; 24:2647-2660. [PMID: 29991871 PMCID: PMC6034147 DOI: 10.3748/wjg.v24.i25.2647] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/18/2018] [Accepted: 06/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignant neoplasia. HCC is characterized by a poor prognosis. The need to find new molecular markers for its diagnosis and prognosis has led to a progressive increase in the number of scientific studies on this topic. MicroRNAs (miRNAs) are small non-coding RNA that play a role in almost all main cellular pathways. miRNAs are involved in the regulation of expression of the major tumor-related genes in carcinogenesis, acting as oncogenes or tumor suppressor genes. The aim of this review was to identify papers published in 2017 investigating the role of miRNAs in HCC tumorigenesis. miRNAs were classified according to their role in the main molecular pathways involved in HCC tumorigenesis: (1) mTOR; (2) Wnt; (3) JAK/STAT; (4) apoptosis; and (5) MAPK. The role of miRNAs in prognosis/response prediction was taken into consideration. Bearing in mind that the analysis of miRNAs in serum and other body fluids would be crucial for clinical management, the role of circulating miRNAs in HCC patients was also investigated. The most represented miRNA-regulated pathway in HCC is mTOR, but apoptosis, Wnt, JAK/STAT or MAPK pathways are also influenced by miRNA expression levels. These miRNAs could thus be used in clinical practice as diagnostic, prognostic or therapeutic targets for HCC treatment.
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Affiliation(s)
- Francesco Vasuri
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Michela Visani
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Thomas Brand
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), University of Bologna, Bologna 40127, Italy
| | - Michelangelo Fiorentino
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Annalisa Pession
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna - School of Medicine, Bologna 40138, Italy
| | - Antonia D’Errico
- Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S.Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie), Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna 40138, Italy
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Zou Y, Yao S, Chen X, Liu D, Wang J, Yuan X, Rao J, Xiong H, Yu S, Yuan X, Zhu F, Hu G, Wang Y, Xiong H. LncRNA OIP5-AS1 regulates radioresistance by targeting DYRK1A through miR-369-3p in colorectal cancer cells. Eur J Cell Biol 2018; 97:369-378. [PMID: 29773344 DOI: 10.1016/j.ejcb.2018.04.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 03/30/2018] [Accepted: 04/10/2018] [Indexed: 01/12/2023] Open
Abstract
OBJECT This study aimed to investigate the role of lncRNA OIP5-AS1 in regulating radioresistance of colorectal cancer (CRC) cells. METHODS Microarray analysis was used to screen out lncRNAs differentially expressed in radio-resistant CRC cell lines. Expression levels of OIP5-AS1, miR-369-3p and DYRK1A in CRC cell lines were measured by qRT-PCR. Protein expression of DYRK1A was determined by western blot. The target relationships among OIP5-AS1, miR-369-3p and DYRK1A were validated by dual luciferase reporter assay. Impacts of OIP5-AS1 or DYRK1A on CRC cellular activity and apoptosis were investigated by MTT assay, clonogenic survival assay and flow cytometry to analyze OIP5-AS1 or DYRK1A's effect on radioresistance of CRC cells. RESULTS LncRNA OIP5-AS1 and DYRK1A were down-regulated in radio-resistant CRC cell lines. OIP5-AS1 suppressed the expression of miR-369-3p, thus up-regulating DYRK1A, the downstream gene of miR-369-3p. OIP5-AS1 and DYRK1A impaired cell clonogenic survival and promoted cell apoptosis after irradiation, improving radiosensitivity of CRC cells. CONCLUSION LncRNA OIP5-AS1 suppressed cell viability, promoted radio-induced apoptosis, and enhanced the radiosensitivity of CRC cells by regulating DYRK1A expression through miR-369-3p.
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Affiliation(s)
- Yanmei Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shuo Yao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xiuqiong Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Dian Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jianhua Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jie Rao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Huihua Xiong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shiying Yu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xianglin Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Feng Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Guohong Hu
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological, Shanghai, 200031, China
| | - Yihua Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO171BJ, UK
| | - Hua Xiong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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Expression of microRNA Genes MIR221, MIR222, and MIR181B1 Increases during Induction of Inflammation in the Endothelial Barrier Model. Bull Exp Biol Med 2018; 164:749-752. [PMID: 29666964 DOI: 10.1007/s10517-018-4072-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Indexed: 12/11/2022]
Abstract
We studied expression profile of microRNA and their target genes in human umbilical vein endothelial cells (HUVEC) during proinflammatory activation with TNFα. TNFα-induced activation of HUVEC was accompanied by a decrease in the expression of CDKN1B, HIST1H3D, and OIP5 genes that are the common target genes for mature microRNA encoded by MIR221, MIR222, and MIR181B1 genes, whose expression increases in activated cells. Proteins encoded by HIST1H3D and OIP5 genes are associated with chromatin compaction and cell cycle. Our results suggest that fetal endothelial microRNA can appear in the maternal blood during various pathological states, e.g., under conditions of preeclampsia.
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Sun G, Wang Y, Zhang J, Lin N, You Y. MiR‐15b/HOTAIR/p53 form a regulatory loop that affects the growth of glioma cells. J Cell Biochem 2018; 119:4540-4547. [DOI: 10.1002/jcb.26591] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Accepted: 12/04/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Guan Sun
- Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Department of Neurosurgery, The First People's Hospital of YanchengThe Forth Affiliated Hospital of Nantong UniversityYanchengChina
| | - Yingyi Wang
- Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Junxia Zhang
- Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ning Lin
- Department of NeurosurgeryThe First People's Hospital of ChuzhouChuzhouChina
| | - Yongping You
- Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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Lv Z, Tao Y, Cai X, Zhou X, Li Y. Cluster of specified microRNAs in tissues and serum as biomarkers for early diagnosis of hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:990-997. [PMID: 31938193 PMCID: PMC6958011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 01/08/2018] [Indexed: 06/10/2023]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is a global public health concern that lacks efficient methods for early diagnosis. Accumulated evidence has revealed great potential using microRNAs (miRNAs) as noninvasive biomarkers in HCC detection. METHODS Serum miRNAs (miR21, miR122, miR-214, miR15b, and let-7f) were detected in 75 patients with HCC and 80 healthy controls (HC). In addition, 75 HCC tissues and paired normal adjacent tissues were also analyzed for comparison. Quantified by real-time quantitative RT-PCR was used to evaluate the expression of miRNAs. RESULTS We discovered significant up-regulation of miR-21 (P < 0.001) and miR-15b (P < 0.001) as well as a down-regulation of miR-122 (P = 0.01) in HCC tissues compared to adjacent non-tumor tissues. Additionally, miR-21 (P < 0.001) and miR-15b (P < 0.001) levels were upregulated in serum and miR-214 (P = 0.01) was decreased in HCC patients compared to that in healthy controls. Multivariate logistic regression analysis showed that serum miR-21 (OR = 1.68, P = 0.012) and miR-15b (OR = 1.736, P = 0.012) were independently associated with HCC whereas miR-214 (OR = 0.631, P = 0.006) was associated with a decreased risk of HCC. When we employed miR-(21 + 122 + 15b) classifier as biomarkers, we could discriminate HCC tissues from adjacent non-tumor tissues with an AUC of 0.885 (specificity: 89.7%; sensitivity: 73.1%). In serum, the cluster of miR-(21 + 214 + 15b) classifier (AUC = 0.887) had a sensitivity of 80.3% and a specificity of 87.0% for HCC diagnosis. CONCLUSION Our results suggest that these serum miRNAs may be useful markers for discriminating HCC patients from healthy controls. Combined determination of circulating miR-21, miR-122, miR-214, and miR-15b has great potential to serve as an accurate and noninvasive biomarker for the early HCC preliminary screening.
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Affiliation(s)
- Zhihua Lv
- Department of Clinical Laboratory, Rennin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
| | - Yu Tao
- Department of Nephrology, Renmin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
| | - Xuan Cai
- Department of Clinical Laboratory, Rennin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
| | - Xin Zhou
- Department of Clinical Laboratory Medicine and Center for Gene Diagnosis, Zhongnan Hospital of Wuhan UniversityWuhan 430071, Hubei, China
| | - Yan Li
- Department of Clinical Laboratory, Rennin Hospital of Wuhan UniversityWuhan 430060, Hubei, China
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Tuo H, Wang Y, Wang L, Yao B, Li Q, Wang C, Liu Z, Han S, Yin G, Tu K, Liu Q. MiR-324-3p promotes tumor growth through targeting DACT1 and activation of Wnt/β-catenin pathway in hepatocellular carcinoma. Oncotarget 2017; 8:65687-65698. [PMID: 29029464 PMCID: PMC5630364 DOI: 10.18632/oncotarget.20058] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 07/26/2017] [Indexed: 12/31/2022] Open
Abstract
Recently, it has been reported that miR-324-3p participates in regulation of the carcinogenesis and tumor progression in various cancers. However, the expression and function of miR-324-3p in hepatocellular carcinoma (HCC) remain unclear. In the current study, miR-324-3p expression was significantly up-regulated in HCC tissues and cell lines. HCC patients with high miR-324-3p level showed poor prognostic features and shorter overall survival and disease-free survival. And in vitro and in vivo experiments revealed that miR-324-3p promoted cell viability, colony formation, proliferation and cell cycle progression of HCC cells. Further studies demonstrated that miR-324-3p could directly target DACT1 (dishevelled binding antagonist of beta catenin 1) and negatively regulated its expression in HCC cells. And rescue experiments revealed that DACT1 could reverse the effects of miR-324-3p on HCC cells. Furthermore, the accumulation of both cytoplasmic and nuclear β-catenin as well as its downstream targets including c-Myc and cyclin D1 could be positively regulated by miR-324-3p. The regulatory effects of miR-324-3p on β-catenin, c-Myc and cyclin D1 levels could be reversed by DACT1. Overall, we concluded that miR-324-3p could promote tumor growth through targeting DACT1 and activation of Wnt/β-catenin pathway in HCC. MiR-324-3p may be a ponderable and promising therapeutic target for HCC.
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Affiliation(s)
- Hang Tuo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Yufeng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Liang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Bowen Yao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Qing Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Cong Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Zhikui Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Shaoshan Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Guozhi Yin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China
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Wang R, Li Y, Zhu G, Tian B, Zeng W, Yang Y, Li Z. Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway. Neuropsychiatr Dis Treat 2017; 13:1805-1813. [PMID: 28744130 PMCID: PMC5513825 DOI: 10.2147/ndt.s137171] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2) is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. METHODS This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. RESULTS By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251) compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan-Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt/β-catenin signaling pathway. CONCLUSION This study suggested that CASC2 may potentially serve as a valuable diagnostic and prognostic biomarker and a therapeutic target for glioma patients.
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Affiliation(s)
- Ronglin Wang
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University
| | - Yuqian Li
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University
| | - Gang Zhu
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University
| | - Bo Tian
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University
| | - Wen Zeng
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University
| | - Yang Yang
- Department of Neurosurgery, The 451th hospital of PLA, Xi'an, Shaanxi, People's Republic of China
| | - Zhihong Li
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University
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