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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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Feng Y, Xia S, Hui J, Xu Y. Circular RNA circBNC2 facilitates glycolysis and stemness of hepatocellular carcinoma through the miR-217/high mobility group AT-hook 2 (HMGA2) axis. Heliyon 2023; 9:e17120. [PMID: 37360090 PMCID: PMC10285170 DOI: 10.1016/j.heliyon.2023.e17120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/01/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Hepatocellular cancer (HCC) accounts for approximately 90% of primary liver carcinoma and is a significant health threat worldwide. Circular RNA basonuclin 2 (circBNC2) is implicated with the progression of several cancers. However, its roles in carcinogenesis and glycolysis are still unclear in HCC. In this study, the levels of circBNC2 and high mobility group AT-hook 2 (HMGA2) were highly expressed, while these of miR-217 were poorly expressed in HCC tissues and cells. Upregulation of circBNC2 was related to poor prognosis and tumor node metastasis (TNM) stage. Knockdown of circBNC2 inhibited the HCC progression. Moreover, knockdown of circBNC2 suppressed the levels of Ras, ERK1/2, PCNA, HK2, and OCT4. Notably, circBNC2 functioned as a molecular sponge of microRNA 217 (miR-217) to upregulate the HMGA2 expression. The inhibitory effects of the circBNC2 silence on the growth and stemness of HCC cells, and levels of PCNA, HK2 and OCT4 were aggravated by the miR-217 overexpression, but neutralized by the HMGA2 overexpression. Besides, silencing of circBNC2 blocked the tumor growth through upregulating the expression of miR-217 and downregulating the levels of HMGA2, PCNA2, HK2 and OCT4 in vivo. Thus, the current data confirmed that circBNC2 sponged miR-217 to upregulate the HMGA2 level, thereby contributing to the HCC glycolysis and progression. These findings might present novel insight into the pathogenesis and treatment of HCC.
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Affiliation(s)
- Yan Feng
- Department of Integrated, Chongqing University Cancer Hospital & Chongqing Cancer Hospital, Chongqing, 400030, China
| | - Shufeng Xia
- Department of Integrated, Chongqing University Cancer Hospital & Chongqing Cancer Hospital, Chongqing, 400030, China
| | - Junlan Hui
- Department of Radiology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing, 400030, China
| | - Yan Xu
- Department of Integrated, Chongqing University Cancer Hospital & Chongqing Cancer Hospital, Chongqing, 400030, China
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3
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Jia J, Guo P, Zhang L, Kong W, Wang F. LINC01614 Promotes Colorectal Cancer Cell Growth and Migration by Regulating miR-217-5p/HMGA1 Axis. Anal Cell Pathol (Amst) 2023; 2023:6833987. [PMID: 39282156 PMCID: PMC11401691 DOI: 10.1155/2023/6833987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 05/10/2023] [Accepted: 05/23/2023] [Indexed: 09/18/2024] Open
Abstract
Colorectal cancer (CRC) substantially contributes to cancer-related deaths worldwide. Recently, a long non-coding RNA (lncRNA), LINC01614, has emerged as a vital gene regulator in cancer progression. Yet, how LINC01614 affects CRC progression remains enigmatic. Here, we defined LINC01614 expression in CRC, investigated the performance of CRC cells lacking LINC01614, and elucidated the underpinning mechanism. We observed that LINC01614 was upregulated in both CRC tissues and cell lines. LINC01614 knockdown repressed the proliferation and metastasis capacity of CRC cell lines. Consistently, an in vivo LINC01614 deficiency model exhibited slow tumor growth rate. Moreover, luciferase reporter assay, RNA pull-down, and immunoprecipitation confirmed that LINC01614 targeted miR-217-5p. LINC01614 knockdown reduced the expression of HMGA1 and N-cadherin, while increasing that of E-cadherin, resulting in decreased viability, proliferation, migration, and invasion capacity of CRC cells. Our results demonstrate that LINC01614 regulates CRC progression by modulating the miR-217-5p/HMGA1 axis, thus holding great potential as a prognostic biomarker for CRC diagnosis and treatment.
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Affiliation(s)
- Jiwei Jia
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Pei Guo
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Li Zhang
- Department of Pathology, Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Wenqing Kong
- Central Ward Operating Room, Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong 264000, China
| | - Fangfang Wang
- Outpatient Operating Room, Yantai Yuhuangding Hospital, 20 Yuhuangding East Road, Yantai, Shandong 264000, China
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Expression analysis of circulating miR-22, miR-122, miR-217 and miR-367 as promising biomarkers of acute lymphoblastic leukemia. Mol Biol Rep 2023; 50:255-265. [PMID: 36327023 DOI: 10.1007/s11033-022-08016-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND The role of serum-based biomarkers such as microRNAs in cancer diagnosis has been extensively established. This study aimed to determine the expression levels of bioinformatically selected miRNAs and whether they can be used as biomarkers or a new therapeutic target in patients with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS The expression levels of serum miR-22, miR-122, miR-217, and miR-367 in 21 ALL patients and 21 healthy controls were measured using quantitative real-time PCR. The receiver operating characteristic (ROC) curve and the associated area under the curve (AUC) was used to assess candidate miRNAs' diagnostic value as a biomarker. RESULTS The results showed that miR-217 was markedly decreased in patients with ALL compared to controls. Moreover, miR-22, miR-122, and miR-367 were found to be upregulated. Furthermore, ROC analysis showed that serum miR-217 and miR-367 could differentiate ALL patients from healthy individuals, while miR-22 has approximate discriminatory power that requires further investigation. CONCLUSION These results provide promising preliminary evidence that circulating miR-217 and miR-367 could be considered potent diagnostic biomarkers and therapeutic goals in this disease.
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Abu-Shahba N, Hegazy E, Khan FM, Elhefnawi M. In Silico Analysis of MicroRNA Expression Data in Liver Cancer. Cancer Inform 2023; 22:11769351231171743. [PMID: 37200943 PMCID: PMC10185868 DOI: 10.1177/11769351231171743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/04/2023] [Indexed: 05/20/2023] Open
Abstract
Abnormal miRNA expression has been evidenced to be directly linked to HCC initiation and progression. This study was designed to detect possible prognostic, diagnostic, and/or therapeutic miRNAs for HCC using computational analysis of miRNAs expression. Methods: miRNA expression datasets meta-analysis was performed using the YM500v2 server to compare miRNA expression in normal and cancerous liver tissues. The most significant differentially regulated miRNAs in our study undergone target gene analysis using the mirWalk tool to obtain their validated and predicted targets. The combinatorial target prediction tool; miRror Suite was used to obtain the commonly regulated target genes. Functional enrichment analysis was performed on the resulting targets using the DAVID tool. A network was constructed based on interactions among microRNAs, their targets, and transcription factors. Hub nodes and gatekeepers were identified using network topological analysis. Further, we performed patient data survival analysis based on low and high expression of identified hubs and gatekeeper nodes, patients were stratified into low and high survival probability groups. Results: Using the meta-analysis option in the YM500v2 server, 34 miRNAs were found to be significantly differentially regulated (P-value ⩽ .05); 5 miRNAs were down-regulated while 29 were up-regulated. The validated and predicted target genes for each miRNA, as well as the combinatorially predicted targets, were obtained. DAVID enrichment analysis resulted in several important cellular functions that are directly related to the main cancer hallmarks. Among these functions are focal adhesion, cell cycle, PI3K-Akt signaling, insulin signaling, Ras and MAPK signaling pathways. Several hub genes and gatekeepers were found that could serve as potential drug targets for hepatocellular carcinoma. POU2F1 and PPARA showed a significant difference between low and high survival probabilities (P-value ⩽ .05) in HCC patients. Our study sheds light on important biomarker miRNAs for hepatocellular carcinoma along with their target genes and their regulated functions.
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Affiliation(s)
- Nourhan Abu-Shahba
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
- Stem Cell Research Group, Medical Research Center of Excellence, National Research Centre, Cairo, Egypt
| | - Elsayed Hegazy
- School of Information Technology and Computer Science, Nile University, Giza, Egypt
| | - Faiz M. Khan
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
| | - Mahmoud Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt
- Mahmoud Elhefnawi, Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, 33, elbohouth street, Cairo 11211, Egypt.
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Liu P, Wang Z, Ou X, Wu P, Zhang Y, Wu S, Xiao X, Li Y, Ye F, Tang H. The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition. Mol Cancer 2022; 21:198. [PMID: 36224562 PMCID: PMC9555172 DOI: 10.1186/s12943-022-01653-2] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/01/2022] [Indexed: 12/24/2022] Open
Abstract
Background Metastasis of breast cancer have caused the majority of cancer-related death worldwide. The circRNAs are associated with tumorigenesis and metastasis in breast cancer according to recent research. However, the biological mechanism of circRNAs in liver metastatic breast cancer remains ambiguous yet. Methods Microarray analysis of three pairs of primary BC tissues and matched hepatic metastatic specimens identified circEZH2. We used RT-qPCR and FISH assays to confirm circEZH2 existence, characteristics, and expression. Both in vivo and in vitro, circEZH2 played an oncogenic role which promoted metastasis as well. A range of bioinformatic analysis, Western blot, RNA pull-down, RIP, ChIP, and animal experiments were used to define the feedback loop involving FUS, circEZH2, miR-217-5p, KLF5, FUS, CXCR4 as well as epithelial and mesenchymal transition. Results In our research, circEZH2 was proved to be upregulated in liver metastases in BC and predicted the worse prognosis in breast cancer patients. Overexpression of circEZH2 notably accentuated the vitality and invasion of BC cells, whereas knockdown of circEZH2 elicited the literally opposite effects. Besides, overexpressed circEZH2 promoted tumorigenesis and liver metastasis in vivo. Moreover, circEZH2 could adsorb miR-217-5p to upregulate KLF5 thus leading to activate FUS transcription which would facilitate the back-splicing program of circEZH2. Meanwhile, KLF5 could upregulated CXCR4 transcriptionally to accelerate epithelial and mesenchymal transition of breast cancer. Conclusions Consequently, a novel feedback loop FUS/circEZH2/KLF5/CXCR4 was established while circEZH2 could be novel biomarker and potential target for BC patients’ therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01653-2.
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Affiliation(s)
- Peng Liu
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zehao Wang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xueqi Ou
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Peng Wu
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yue Zhang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Song Wu
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiangsheng Xiao
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yuehua Li
- Department of Medical Oncology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China.
| | - Feng Ye
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
| | - Hailin Tang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
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Dutta M, Das B, Mohapatra D, Behera P, Senapati S, Roychowdhury A. MicroRNA-217 modulates pancreatic cancer progression via targeting ATAD2. Life Sci 2022; 301:120592. [PMID: 35504332 DOI: 10.1016/j.lfs.2022.120592] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/18/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022]
Abstract
AIMS Pancreatic cancer is a fatal disease across the world with 5 years survival rate less than 10%. ATAD2, a valid cancer drug-target, is overexpressed in pancreatic malignancy with high oncogenic potential. However, the mechanism of the upregulated expression of ATAD2 in pancreatic cancer is unknown. Since microRNAs (miRNAs) could potentially control target mRNA expressions, and are involved in cancer as tumor-suppressors, oncomiR or both, we examine the possibility of miRNA-mediated regulation of ATAD2 in pancreatic cancer cells (PCCs). MAIN METHODS Our in-silico approach first identifies hsa-miR-217 as a candidate regulator for ATAD2 expression. For further validation, luciferase reporter assay is performed. We overexpress hsa-miRNA-217 and assess cellular viability, migration, apoptosis and cell cycle progression in three different PCCs (BxPC3, PANC1, and MiaPaCa2). KEY FINDINGS We find hsa-miRNA-217 has potential binding site at the 3'UTR of ATAD2. Luciferase assay confirms that ATAD2 is a direct target of hsa-miR-217. Overexpression of hsa-miR-217 drastically downregulates ATAD2 expression in PCCs, thus, corroborating binding studies. The elevated expression of hsa-miRNA-217 diminishes cell proliferation and migration as well as induces apoptosis and cell cycle arrest in PCCs. Finally, siRNA mediated ATAD2 knockdown or overexpression of hsa-miRNA-217 in PCCs showed inactivation of the AKT signaling pathway. Therefore, hsa-miR-217 abrogates pancreatic cancer progression through inactivation of the AKT signaling pathway and this might be partly due to miR-217 mediated suppression of ATAD2 expression. SIGNIFICANCE The application of hsa-miR-217 mimic could be a promising therapeutic strategy for the treatment of pancreatic cancer patients in near future.
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Affiliation(s)
- Madhuri Dutta
- Biochemistry and Cell Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India
| | - Biswajit Das
- Tumor Microenvironment and Animal Models Laboratory, Institute of Life Sciences, Bhubaneswar, Odisha 751023, India
| | - Debasish Mohapatra
- Tumor Microenvironment and Animal Models Laboratory, Institute of Life Sciences, Bhubaneswar, Odisha 751023, India
| | - Padmanava Behera
- Tumor Microenvironment and Animal Models Laboratory, Institute of Life Sciences, Bhubaneswar, Odisha 751023, India; Department of Microbiology, Shiksha 'O' Anusandhan (SOA) University, Bhubaneswar, Odisha 751003, India
| | - Shantibhusan Senapati
- Tumor Microenvironment and Animal Models Laboratory, Institute of Life Sciences, Bhubaneswar, Odisha 751023, India.
| | - Anasuya Roychowdhury
- Biochemistry and Cell Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India.
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Yang L, Liu S, Yang L, Xu B, Wang M, Kong X, Song Z. miR‑217‑5p suppresses epithelial‑mesenchymal transition and the NF‑κB signaling pathway in breast cancer via targeting of metadherin. Oncol Lett 2022; 23:162. [PMID: 35399330 PMCID: PMC8987938 DOI: 10.3892/ol.2022.13282] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/11/2022] [Indexed: 11/17/2022] Open
Abstract
MicroRNAs (miRNAs) have been associated with a number of human malignancies, including breast cancer (BC). However, the expression, biological function and fundamental underlying mechanism of miR-217-5p in BC remain unclear. Therefore, in the present study, the expression levels of miR-217-5p and metadherin (MTDH) were examined in BC tissues and BC cell lines using reverse transcription-quantitative PCR. Cell Counting Kit-8 assays, cell proliferation, wound healing assays, Transwell assays and western blotting were used to examine the effects of miR-217-5p on cell proliferation, migration, the epithelial-mesenchymal transition (EMT) and NF-κB signaling pathway expression. The direct relationship between miR-217-5p and MTDH was assessed using a dual-luciferase reporter assay. The results demonstrated that significantly reduced expression levels of miR-217-5p but significantly increased mRNA expression levels of MTDH were observed in BC tissues from 35 patients with BC compared with non-tumor breast tissues. Furthermore, BC cell lines SK-BR3 and BT549 expressed miR-217-5p at markedly lower levels and MTDH at markedly higher levels compared with the breast epithelial MCF10A cell line. miR-217-5p overexpression significantly inhibited cell proliferation, invasion and migration and suppressed the EMT in BC cells. miR-217-5p overexpression also inhibited the NF-κB signaling pathway by markedly decreasing p65 mRNA and protein expression levels but significantly increasing IκBα expression levels. Furthermore, miR-217-5p knockdown markedly increased MTDH mRNA and protein expression levels. The expression levels of miR-217-5p were negatively correlated with those of MTDH in BC tissues. These results suggested that restoration of MTDH expression levels could potentially attenuate the inhibitory effects of miR-217-5p overexpression on BC cell proliferation. Therefore, in conclusion miR-217-5p overexpression may inhibit cell migration, invasion, the EMT and NF-κB signaling pathway in BC via targeting of MTDH. miR-217-5p may serve as an important potential target in BC therapy.
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Affiliation(s)
- Lixian Yang
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Shuo Liu
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Liu Yang
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Bin Xu
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Meiqi Wang
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xiangshun Kong
- Department of Breast Surgery, Xingtai People's Hospital, Xingtai, Hebei 054000, P.R. China
| | - Zhenchuan Song
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Wang BR, Chu DX, Cheng MY, Jin Y, Luo HG, Li N. Progress of HOTAIR-microRNA in hepatocellular carcinoma. Hered Cancer Clin Pract 2022; 20:4. [PMID: 35093153 PMCID: PMC8800341 DOI: 10.1186/s13053-022-00210-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 01/13/2022] [Indexed: 01/02/2023] Open
Abstract
The Hox transcript antisense intergenic RNA (HOTAIR) has been identified as a tumor gene, and its expression in HCC is significantly increased. HOTAIR is associated with the proliferation, invasion, metastasis and poor prognosis of HCC. In addition, HOTAIR can also regulate the expression and function of microRNA by recruiting the polycomb repressive complex 2 (PRC2) and competitive adsorption, thus promoting the occurrence and development of HCC. In this review, we discussed the two mechanisms of HOTAIR regulating miRNA through direct binding miRNA and indirect regulation, and emphasized the role of HOTAIR in HCC through miRNA, explained the regulatory pathway of HOTAIR-miRNA-mRNA and introduced the role of this pathway in HCC proliferation, drug resistance, invasion and metastasis.
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Affiliation(s)
- Bing-Rong Wang
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Dong-Xia Chu
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Mei-Yu Cheng
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Yu Jin
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Hao-Ge Luo
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China
| | - Na Li
- Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, Jilin, 130012, People's Republic of China.
- The Basic Medical College, Jilin Medical University, Jilin, 132013, China.
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Wang Z, Yang L, Wu P, Li X, Tang Y, Ou X, Zhang Y, Xiao X, Wang J, Tang H. The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin. Mol Cancer 2022; 21:29. [PMID: 35073911 PMCID: PMC8785480 DOI: 10.1186/s12943-022-01498-9] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/03/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Metastasis causes the majority of cancer-related deaths worldwide. Increasing studies have revealed that circRNAs are associated with the carcinogenesis and metastasis of many cancers. Nevertheless, the biological mechanisms of circRNAs in breast cancer (BC) liver metastasis remain extremely ambiguous. METHODS In this study, we identified circROBO1 from three pairs of primary BC and metastatic liver sites by RNA sequencing. FISH assays and RT-qPCR were conducted to validate the existence and expression of circROBO1. The oncogenic role of circROBO1 was demonstrated both in vitro and in vivo. Western blot, ChIP, RIP, RNA pull-down, and dual-luciferase reporter assays were used to confirm the interaction of the feedback loop among circROBO1, miR-217-5p, KLF5, and FUS. Meanwhile, the regulation of selective autophagy was investigated by immunofluorescence, CoIP, and western blot. RESULTS In this study, upregulated expression of circROBO1 was found in BC-derived liver metastases and was correlated with poor prognosis. Knockdown of circROBO1 strikingly inhibited the proliferation, migration, and invasion of BC cells, whereas overexpression of circROBO1 showed the opposite effects. Moreover, overexpression of circROBO1 promoted tumor growth and liver metastasis in vivo. Further research revealed that circROBO1 could upregulate KLF5 by sponging miR-217-5p, allowing KLF5 to activate the transcription of FUS, which would promote the back splicing of circROBO1. Therefore, a positive feedback loop comprising circROBO1/KLF5/FUS was formed. More importantly, we found that circROBO1 inhibited selective autophagy of afadin by upregulating KLF5. CONCLUSIONS Our results demonstrated that circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1. Therefore, circROBO1 could be used not only as a potential prognostic marker but also as a therapeutic target in BC.
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Affiliation(s)
- Zehao Wang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Lu Yang
- Department of Radiotherapy, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Peng Wu
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Xing Li
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Yuhui Tang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Xueqi Ou
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Yue Zhang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Xiangsheng Xiao
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
| | - Jin Wang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
| | - Hailin Tang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
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Hamidi AA, Zangoue M, Kashani D, Zangouei AS, Rahimi HR, Abbaszadegan MR, Moghbeli M. MicroRNA-217: a therapeutic and diagnostic tumor marker. Expert Rev Mol Diagn 2021; 22:61-76. [PMID: 34883033 DOI: 10.1080/14737159.2022.2017284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Cancer as one of the most common causes of death has always been one of the major health challenges globally. Since, the identification of tumors in the early tumor stages can significantly reduce mortality rates; it is required to introduce novel early detection tumor markers. MicroRNAs (miRNAs) have pivotal roles in regulation of cell proliferation, migration, apoptosis, and tumor progression. Moreover, due to the higher stability of miRNAs than mRNAs in body fluids, they can be considered as non-invasive diagnostic or prognostic markers in cancer patients. AREAS COVERED In the present review we have summarized the role of miR-217 during tumor progressions. The miR-217 functions were categorized based on its target molecular mechanisms and signaling pathways. EXPERT OPINION It was observed that miR-217 mainly exerts its function by regulation of the transcription factors during tumor progressions. The WNT, MAPK, and PI3K/AKT signaling pathways were also important molecular targets of miR-217 in different cancers. The present review clarifies the molecular biology of miR-217 and paves the way of introducing miR-217 as a non-invasive diagnostic marker and therapeutic target in cancer therapy.
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Affiliation(s)
- Amir Abbas Hamidi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Zangoue
- Department of Anesthesiology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Daniel Kashani
- Department of Internal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Price RL, Bhan A, Mandal SS. HOTAIR beyond repression: In protein degradation, inflammation, DNA damage response, and cell signaling. DNA Repair (Amst) 2021; 105:103141. [PMID: 34183273 PMCID: PMC10426209 DOI: 10.1016/j.dnarep.2021.103141] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 05/13/2021] [Accepted: 05/21/2021] [Indexed: 01/17/2023]
Abstract
Long noncoding RNAs (lncRNAs) are pervasively transcribed from the mammalian genome as transcripts that are usually >200 nucleotides long. LncRNAs generally do not encode proteins but are involved in a variety of physiological processes, principally as epigenetic regulators. HOX transcript antisense intergenic RNA (HOTAIR) is a well-characterized lncRNA that has been implicated in several cancers and in various other diseases. HOTAIR is a repressor lncRNA and regulates various repressive chromatin modifications. However, recent studies have revealed additional functions of HOTAIR in regulation of protein degradation, microRNA (miRNA) sponging, NF-κB activation, inflammation, immune signaling, and DNA damage response. Herein, we have summarized the diverse functions and modes of action of HOTAIR in protein degradation, inflammation, DNA repair, and diseases, beyond its established functions in gene silencing.
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Affiliation(s)
- Rachel L Price
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, 76019, United States
| | - Arunoday Bhan
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, 76019, United States
| | - Subhrangsu S Mandal
- Gene Regulation and Epigenetics Research Laboratory, Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX, 76019, United States.
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13
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A 3D screening approach identifies the compound epitajixanthone hydrate as a new inhibitor of cancer cell growth and invasion. Anticancer Drugs 2021; 31:890-899. [PMID: 32960529 DOI: 10.1097/cad.0000000000000873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
With unique advantages, the small-molecule anticancer drugs have recently gained growing attention. Particular strategies, exemplified by high-throughput screening, fragment-based drug discovery, virtual screening and knowledge-based design, have been developed to identify active compounds. However, such screens generally rely on sophisticated and expensive instrumentations. Herein, we developed a simple spheroids 3D culture system to enable direct screening of small molecules with reliable results. Using this system, we screened 27 fungal natural products and three fungal crude extracts for their inhibitory effects on cancer cell growth, and invasion. We identified that the compound M23 (epitajixanthone hydrate, a derivative of prenylxanthone) and the crude extracts (MPT-191) from the fungi Taxus chinensis showed potential anticancer activity. The effect of epitajixanthone hydrate on cancer cell growth and invasion were further confirmed by the assays of cells viability, trans-well migration and invasion, colony formation and cells reattachment. Overall, Epitajixanthone hydrate was identified as an effective inhibitor of cancer cell growth and invasion by our simple and fast screening platform.
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Tang LB, Ma SX, Chen ZH, Huang QY, Wu LY, Wang Y, Zhao RC, Xiong LX. Exosomal microRNAs: Pleiotropic Impacts on Breast Cancer Metastasis and Their Clinical Perspectives. BIOLOGY 2021; 10:biology10040307. [PMID: 33917233 PMCID: PMC8067993 DOI: 10.3390/biology10040307] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/28/2021] [Accepted: 04/03/2021] [Indexed: 01/07/2023]
Abstract
As a major threat factor for female health, breast cancer (BC) has garnered a lot of attention for its malignancy and diverse molecules participating in its carcinogenesis process. Among these complex carcinogenesis processes, cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis are the major causes for the occurrence of metastasis and chemoresistance which account for cancer malignancy. MicroRNAs packaged and secreted in exosomes are termed "exosomal microRNAs (miRNAs)". Nowadays, more researches have uncovered the roles of exosomal miRNAs played in BC metastasis. In this review, we recapitulated the dual actions of exosomal miRNAs exerted in the aggressiveness of BC by influencing migration, invasion, and distant metastasis. Next, we presented how exosomal miRNAs modify angiogenesis and stemness maintenance. Clinically, several exosomal miRNAs can govern the transformation between drug sensitivity and chemoresistance. Since the balance of the number and type of exosomal miRNAs is disturbed in pathological conditions, they are able to serve as instructive biomarkers for BC diagnosis and prognosis. More efforts are needed to connect the theoretical studies and clinical traits together. This review provides an outline of the pleiotropic impacts of exosomal miRNAs on BC metastasis and their clinical implications, paving the way for future personalized drugs.
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Affiliation(s)
- Li-Bo Tang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Shu-Xin Ma
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Zhuo-Hui Chen
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Qi-Yuan Huang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China;
| | - Long-Yuan Wu
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Yi Wang
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
| | - Rui-Chen Zhao
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China;
| | - Li-Xia Xiong
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (L.-B.T.); (Q.-Y.H.); (L.-Y.W.); (Y.W.); (R.-C.Z.)
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang 330006, China
- Correspondence: ; Tel.: +86-791-8636-0556
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microRNA-217 suppressed epithelial-to-mesenchymal transition through targeting PTPN14 in gastric cancer. Biosci Rep 2021; 40:221385. [PMID: 31793993 PMCID: PMC6946620 DOI: 10.1042/bsr20193176] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/15/2019] [Accepted: 11/26/2019] [Indexed: 11/17/2022] Open
Abstract
Background: Gastric cancer (GC) is the one of most common malignancies and its mechanism of metastasis remains unclear. The study was designed to investigate the effects of microRNA-217 on epithelial-to-mesenchymal transition. Methods: The expression levels of miR-217 in GC were assayed by real-time qPCR. Metastasis and invasion of cancer cell were assayed by transwell chamber. Double luciferase reporter gene was used to verify the target regulatory relationship between microRNA-217 and tyrosine–protein phosphatase non-receptor type 14 (PTPN14) on gastric cell lines. Epithelial-to-mesenchymal transition (EMT) markers were assayed by Western blot. Results: We found that miR-217 had a low level expression in gastric tumor tissues of 40 patients with GC, and a lower expression in the gastric tumor tissues of the patients with GC metastasis. Moreover, miR-217 markedly suppressed the metastasis and invasion of gastric cancer cell line in vitro. Furthermore, miR-217 inhibited the expression of PTPN14 by directly targeting its 3′UTR. Moreover, the down-regulation of PTPN14 reduced the metastasis and invasion, whereas up-regulation of PTPN14 led to the enhanced metastases and invasion of gastric cells. miR-217 induced the down-regulation of PTPN14 and inhibited the EMT in gastric cancer cells. Conclusion: miR-217 inhibited the EMT through directly targeting to the 3′UTR of PTPN14.
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Liu J, Zhao G, Liu XL, Zhang G, Zhao SQ, Zhang SL, Luo LH, Yin DC, Zhang CY. Progress of non-coding RNAs in triple-negative breast cancer. Life Sci 2021; 272:119238. [PMID: 33600860 DOI: 10.1016/j.lfs.2021.119238] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023]
Abstract
Non-coding RNAs (ncRNAs) include miRNA, lncRNA, and circRNA. NcRNAs are involved in multiple biological processes, including chromatin remodeling, signal transduction, post-transcriptional modification, cell autophagy, carbohydrate metabolism, and cell cycle regulation. Triple negative breast cancer (TNBC) is notorious for high invasiveness and metastasis, poor prognosis, and high mortality, and it is the most malignant breast cancer, while the effective targets for TNBC treatment are still lacking. NcRNAs act as oncogenes or suppressor genes, as well as promote or inhibit the occurrence and development of TNBC. Here, we reviewed some important miRNAs, lncRNAs, circRNAs, their target(s) and molecular mechanisms in TNBC. It is benefited to understand the occurrence and development of TNBC, further some ncRNAs might be potential targets for TNBC treatment.
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Affiliation(s)
- Jie Liu
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Gang Zhao
- Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin Province 130021, PR China
| | - Xin-Li Liu
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Ge Zhang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Shi-Qi Zhao
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Shi-Long Zhang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Li-Heng Luo
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China
| | - Da-Chuan Yin
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China.
| | - Chen-Yan Zhang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, Shaanxi, PR China.
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17
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Zhu X, Liu C, Shi J, Zhou Z, Chen S, Jami SA. Circular RNA circANKIB1 promotes the progression of osteosarcoma by regulating miR-217/PAX3 axis. J Bone Oncol 2021; 27:100347. [PMID: 33552886 PMCID: PMC7844576 DOI: 10.1016/j.jbo.2021.100347] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/21/2020] [Accepted: 01/05/2021] [Indexed: 11/17/2022] Open
Abstract
Background Circular RNAs (circRNAs) have been discovered to exert essential roles in human cancers, including osteosarcoma (OS). The aim of this study was to investigate the exact roles and regulatory mechanism of circRNA ankyrin repeat and IBR domain containing 1 (circANKIB1) in OS. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of circANKIB1, microRNA-217 (miR-217) and paired box 3 (PAX3). Cell proliferation was assessed by colony formation assay. Cell cycle distribution and apoptosis rate were determined by flow cytometry analysis. Wound healing assay and transwell assay were employed to evaluate cell migration and invasion abilities. Western blot assay was used to analyze the protein levels of PAX3, E-cadherin and Vimentin. Targeting relationship between miR-217 and circANKIB1 or PAX3 was predicted by Circular RNA Interactome or TargetScan and demonstrated by dual-luciferase reporter assay. The mice xenograft model was established to confirm the role of circANKIB1 in vivo. Results CircANKIB1 and PAX3 were high-expressed, whereas miR-217 was low-expressed in OS tissues and cells. Knockdown of circANKIB1 inhibited the progression of OS by reducing cell proliferation, migration, invasion, and tumor growth (in vivo), and inducing apoptosis. MiR-217 was a direct target of circANKIB1, and its inhibition reversed the inhibitory effect of circANKIB1 knockdown on the progression of OS cells. Moreover, PAX3 was a direct target of miR-217, and miR-217 exerted the anti-tumor role in OS cells by targeting PAX3. Furthermore, circANKIB1 positively regulated PAX3 expression by sponging miR-217. Conclusion Knockdown of circANKIB1 suppressed OS progression by upregulating miR-217 and downregulating PAX3, which might provide a novel insight into the pathogenesis of OS.
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Affiliation(s)
- Xi Zhu
- Department of Spinal Surgery, General Hospital of Ningxia Medical University, Ningxia, China
| | - Changhao Liu
- Department of Spinal Surgery, Ningxia Medical University, Ningxia, China
| | - Jiandang Shi
- Department of Spinal Surgery, General Hospital of Ningxia Medical University, Ningxia, China
- Corresponding author at: Department of Spinal Surgery, General Hospital of Ningxia Medical University, No. 804 Shengli South Street, Yinchuan City, Ningxia Hui Autonomous Region 750004, China.
| | - Zhanwen Zhou
- Department of Spinal Surgery, General Hospital of Ningxia Medical University, Ningxia, China
| | - Suoli Chen
- Department of Spinal Surgery, General Hospital of Ningxia Medical University, Ningxia, China
| | - Sayed Abdulla Jami
- Department of Spinal Surgery, General Hospital of Ningxia Medical University, Ningxia, China
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Zhou S, Zhu C, Pang Q, Liu HC. MicroRNA-217: A regulator of human cancer. Biomed Pharmacother 2021; 133:110943. [PMID: 33254014 DOI: 10.1016/j.biopha.2020.110943] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 10/17/2020] [Accepted: 10/25/2020] [Indexed: 12/13/2022] Open
Abstract
As highly conserved non-coding RNAs of approximately 18-24 nucleotides, microRNAs (miRNAs) regulate the expression of target genes. Multiple studies have demonstrated that miRNAs participate in the regulation of human cancer. MircoRNA-217 (miR-217) participates in the regulation of various tumors by specifically binding target genes and post-transcriptional regulation. In recent years, there have been numerous reports about miR-217 in tumor progression. MiR-217 is known mainly as a tumor suppressor, although some studies have shown that it functions as an oncomiR. Here, we review the current research related to miR-217, including its role in tumor progression and the molecular mechanisms.
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Affiliation(s)
- Shuai Zhou
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui, 233000, China.
| | - Chao Zhu
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui, 233000, China.
| | - Qing Pang
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui, 233000, China.
| | - Hui Chun Liu
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of Bengbu Medical College, Anhui, 233000, China.
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Zhang L, Chu Q, Chang R, Xu T. Inducible MicroRNA-217 Inhibits NF-κB– and IRF3-Driven Immune Responses in Lower Vertebrates through Targeting TAK1. THE JOURNAL OF IMMUNOLOGY 2020; 205:1620-1632. [DOI: 10.4049/jimmunol.2000341] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/11/2020] [Indexed: 12/23/2022]
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Xu X, Song F, Jiang X, Hong H, Fei Q, Jin Z, Zhu X, Dai B, Yang J, Sui C, Xu M. Long Non-Coding RNA SNHG14 Contributes to the Development of Hepatocellular Carcinoma via Sponging miR-217. Onco Targets Ther 2020; 13:4865-4876. [PMID: 32581548 PMCID: PMC7269013 DOI: 10.2147/ott.s244530] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Thousands of long non-coding RNAs (lncRNAs) have been functionally verified as crucial regulators of physiological processes and disease progressions, yet their roles in hepatocellular carcinoma (HCC) have not been clearly illuminated. Methods We analyzed the expression of lncRNA-SNHG14 in TCGA data via bioinformatic analysis and detected its expression in HCC specimens by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). Loss-of-function experiments were used to study the biological function of SNHG14 in HCC cells. RT-qPCR, Western blotting and dual-luciferase reporter assay were carried out to investigate the molecular mechanism of SNHG14 in HCC. Results The upregulation of lncRNA-SNHG14 was observed in HCC tissues compared with normal tissues via RT-qPCR and bioinformatic analysis of TCGA data. Silencing of SNHG14 inhibited cell proliferation and induced cell apoptosis in HCC cells. microRNA-217 (miR-217), the tumor-suppressive miRNA in HCC, was predicted and confirmed as a miRNA sponged by SNHG14 in HCC cells. Via downregulation of miR-217, SNHG14 increased the expression of several miR-217-related oncogenes and subsequently activated oncogene-related signaling pathways in HCC cells. In addition, inhibition of miR-217 reversed SNHG14 silencing induced decrease of cell proliferation and increase of cell apoptosis. Their association was verified in the published microarray dataset and the collected HCC samples. Conclusion In summary, SNHG14 is involved in the development of HCC via sponging miR-217 and it may be a biomarker for patients with HCC.
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Affiliation(s)
- Xiaoyong Xu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
| | - Feihong Song
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People's Republic of China
| | - Xinwei Jiang
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
| | - Han Hong
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
| | - Qiang Fei
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
| | - Zhengkang Jin
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
| | - Xiang Zhu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
| | - Binghua Dai
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People's Republic of China
| | - Jiamei Yang
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People's Republic of China
| | - Chengjun Sui
- Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People's Republic of China
| | - Minhui Xu
- Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China
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MiR-217 Inhibits M2-Like Macrophage Polarization by Suppressing Secretion of Interleukin-6 in Ovarian Cancer. Inflammation 2020; 42:1517-1529. [PMID: 31049770 DOI: 10.1007/s10753-019-01004-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Ovarian cancer is one of the most deadly cancers with rapid proliferation and poor prognosis among patients. Therapies focusing on regulation of tumor immunity and microenvironments are developing. MiR-217 was dysregulated in cancer progress and plays important roles in tumorigenesis and metastasis. However, the role of miR-217 in regulation of macrophage polarization and its underlying molecular mechanism remain unclear. The expression of miR-217 in ovarian cancerous tissues and cell lines were assessed by qRT-PCR. And we detected the staining of CD86 and CD206 via flow-cytometry and the levels of Arg-1 and CCR2 by western-blot in order to evaluate M2 macrophage polarization. The targeting regulation of miR-217 on pro-inflammatory factor IL-6 was assessed by dual-luciferase reporter assay and western-blot. ELISA assay was used to evaluate the secretion of IL-6 and IL-10 of cells. MiR-217 was found to be downregulated in ovarian cancerous tissues and cell lines. This downregulation correlated with an increased expression of the IL-6, Arg-1, CCR2, and CD206 gene. The overexpression of miR-217 in SKOV3 cells can inhibit the polarization of macrophages towards an M2-like phenotype. We also found that IL-6 was validated to induce M2 macrophage polarization and its secretion in SKOV-3 cells was inhibited by miR-217 directly. Moreover, we revealed that miR-217 suppressed M2 macrophage polarization partly thought JAK/STAT3 signal pathway. Taken together, these findings indicate that miR-217 inhibits tumor-induced M2 macrophage polarization through targeting of IL-6 and regulation JAK3/STAT3 signaling pathway, which may provide a potential therapeutic target for treating ovarian cancer.
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Wang Q, Shi D, Geng Y, Huang Q, Xiang L. Baicalin augments the differentiation of osteoblasts via enhancement of microRNA-217. Mol Cell Biochem 2020; 463:91-100. [PMID: 31606864 DOI: 10.1007/s11010-019-03632-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 09/25/2019] [Indexed: 12/17/2022]
Abstract
Baicalin (BAI), a sort of flavonoid monomer, acquires from Scutellaria baicalensis Georgi, which was forcefully reported in diversified ailments due to the pleiotropic properties. But, the functions of BAI in osteoblast differentiation have not been addressed. The intentions of this study are to attest the influences of BAI in the differentiation of osteoblasts. MC3T3-E1 cells or rat primary osteoblasts were exposed to BAI, and then cell viability, ALP activity, mineralization process, and Runx2 and Ocn expression were appraised through implementing CCK-8, p-nitrophenyl phosphate (pNPP), Alizarin red staining, western blot, and RT-qPCR assays. The microRNA-217 (miR-217) expression was evaluated in MC3T3-E1 cells or rat primary osteoblasts after BAI disposition; meanwhile, the functions of miR-217 in BAI-administrated MC3T3-E1 cells were estimated after miR-217 inhibitor transfection. The impacts of BAI and miR-217 inhibition on Wnt/β-catenin and MEK/ERK pathways were probed to verify the involvements in BAI-regulated the differentiation of osteoblasts. BAI accelerated cell viability, osteoblast activity, and Runx2 and Ocn expression in MC3T3-E1 cells or rat primary osteoblasts, and the phenomena were mediated via activations of Wnt/β-catenin and MEK/ERK pathways. Elevation of miR-217 was observed in BAI-disposed MC3T3-E1 cells or rat primary osteoblasts, and miR-217 repression annulled the functions of BAI in MC3T3-E1 cell viability and differentiation. Additionally, the activations of Wnt/β-catenin and MEK/ERK pathways evoked by BAI were both restrained by repression of miR-217. These explorations uncovered that BAI augmented the differentiation of osteoblasts via activations of Wnt/β-catenin and MEK/ERK pathways by ascending miR-217 expression.
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Affiliation(s)
- Qi Wang
- Department of Orthopaedics, Heze Municipal Hospital, No. 2888 Caozhou Road, Heze, 274031, China
| | - Donglei Shi
- Department of Orthopaedics, Heze Municipal Hospital, No. 2888 Caozhou Road, Heze, 274031, China
| | - Yuanyuan Geng
- Department of Comprehensive Medical, Heze Infectious Disease Hospital, No. 298 Juyang Road, Heze, 274029, China
| | - Qishan Huang
- Department of Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan West Road, Wenzhou, 325000, China
| | - Longzhan Xiang
- Department of Orthopaedics, Heze Municipal Hospital, No. 2888 Caozhou Road, Heze, 274031, China.
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Lin CJ, Lan YM, Ou MQ, Ji LQ, Lin SD. Expression of miR-217 and HIF-1α/VEGF pathway in patients with diabetic foot ulcer and its effect on angiogenesis of diabetic foot ulcer rats. J Endocrinol Invest 2019; 42:1307-1317. [PMID: 31079353 DOI: 10.1007/s40618-019-01053-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 04/30/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To investigate the expression of miR-217 and HIF-1α/VEGF pathway in patients with diabetic foot ulcer (DFU) and its effect on angiogenesis in DFU rats. METHODS The serum levels of miR-217, HIF-1α and VEGF were detected in DFU and simple diabetes mellitus (DM) patients, and healthy controls. DFU rat models were established and treated with miR-217 inhibitors and/or HIF-1α siRNA. The ulcer healing of DFU rats was observed. Besides, ELISA method was performed to detect the serum level of HIF-1α, VEGF and inflammatory factors, immunohistochemical (IHC) method to test the micro-vessel density (MVD), as well as qRT-PCR and Western blot to determine expressions of miR-217, HIF-1α, VEGF, VEGFR2, eNOS, MMP-2, and MMP-9 in tissues. RESULTS The serum levels of miR-217 were up-regulated while HIF-1α and VEGF were down-regulated in DFU patients and rats when compared with DM and healthy controls (all P < 0.05). Dual-luciferase reporter gene assay confirmed that HIF-1α was the direct target gene of miR-217. DFU rats treated with miR-217 inhibitors had decreased foot ulcer area and accelerated ulcer healing, with significantly reduced inflammatory factors (IL-1β, TNF-α and IL-6), as well as elevated HIF-1α and VEGF (all P < 0.05); meanwhile, they remarkably increased the MVD in foot dorsum wound tissues and the protein expressions of HIF-1α, VEGF, VEGFR2, eNOS, MMP-2, and MMP-9 (all P < 0.05). CONCLUSION Inhibiting miR-217 could up-regulate HIF-1α/VEGF pathway to promote angiogenesis and ameliorate inflammation of DFU rats, thereby effectively advancing the healing of ulcerated area.
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Affiliation(s)
- C-J Lin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, People's Republic of China.
| | - Y-M Lan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, People's Republic of China
| | - M-Q Ou
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, People's Republic of China
| | - L-Q Ji
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, People's Republic of China
| | - S-D Lin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Shantou University Medical College, No. 57, Changping Road, Shantou, 515041, Guangdong, People's Republic of China
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24
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Liu J, Li W, Zhang J, Ma Z, Wu X, Tang L. Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma. PeerJ 2019; 7:e8021. [PMID: 31695969 PMCID: PMC6827457 DOI: 10.7717/peerj.8021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 10/10/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although multiple efforts have been made to understand the development of HCC, morbidity, and mortality rates remain high. In this study, we aimed to discover the mRNAs and long non-coding RNAs (lncRNAs) that contribute to the progression of HCC. We constructed a lncRNA-related competitive endogenous RNA (ceRNA) network to elucidate the molecular regulatory mechanism underlying HCC. METHODS A microarray dataset (GSE54238) containing information about both mRNAs and lncRNAs was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and lncRNAs (DElncRNAs) in tumor tissues and non-cancerous tissues were identified using the limma package of the R software. The miRNAs that are targeted by DElncRNAs were predicted using miRcode, while the target mRNAs of miRNAs were retrieved from miRDB, miRTarBas, and TargetScan. Functional annotation and pathway enrichment of DEGs were performed using the EnrichNet website. We constructed a protein-protein interaction (PPI) network of DEGs using STRING, and identified the hub genes using Cytoscape. Survival analysis of the hub genes and DElncRNAs was performed using the gene expression profiling interactive analysis database. The expression of molecules with prognostic values was validated on the UALCAN database. The hepatic expression of hub genes was examined using the Human Protein Atlas. The hub genes and DElncRNAs with prognostic values as well as the predictive miRNAs were selected to construct the ceRNA networks. RESULTS We found that 10 hub genes (KPNA2, MCM7, CKS2, KIF23, HMGB2, ZWINT, E2F1, MCM4, H2AFX, and EZH2) and four lncRNAs (FAM182B, SNHG6, SNHG1, and SNHG3) with prognostic values were overexpressed in the hepatic tumor samples. We also constructed a network containing 10 lncRNA-miRNA-mRNA pathways, which might be responsible for regulating the biological mechanisms underlying HCC. CONCLUSION We found that the 10 significantly overexpressed hub genes and four lncRNAs were negatively correlated with the prognosis of HCC. Further, we suggest that lncRNA SNHG1 and the SNHG3-related ceRNAs can be potential research targets for exploring the molecular mechanisms of HCC.
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Affiliation(s)
- Jun Liu
- Department of Clinical Laboratory, Yue Bei People’s Hospital, Shaoguan, Guangdong, China
- Morning Star Academic Cooperation, Shanghai, China
| | - Wenli Li
- Reproductive Medicine Center, Yue Bei People’s Hospital, Shaoguan, Guangdong, China
| | - Jian Zhang
- Department of Clinical Laboratory, Yue Bei People’s Hospital, Shaoguan, Guangdong, China
| | - Zhanzhong Ma
- Department of Clinical Laboratory, Yue Bei People’s Hospital, Shaoguan, Guangdong, China
| | - Xiaoyan Wu
- Community Healthcare Center, Shanghai, Shanghai, China
| | - Lirui Tang
- Morning Star Academic Cooperation, Shanghai, China
- Shanghai JiaoTong University School of Medicine, Shanghai Ninth People’s Hospital, Shanghai, China
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25
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Zhu L, Yang S, Wang J. miR-217 inhibits the migration and invasion of HeLa cells through modulating MAPK1. Int J Mol Med 2019; 44:1824-1832. [PMID: 31485607 PMCID: PMC6777686 DOI: 10.3892/ijmm.2019.4328] [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: 01/24/2019] [Accepted: 07/10/2019] [Indexed: 02/07/2023] Open
Abstract
MicroRNA (miR)‑217 serves a pivotal role in the progression of colorectal cancer, renal cell carcinoma and glioma, however, the role of miR‑217 in cervical cancer (CC) remains unclear. In the present study, the mechanism of miR‑217 in cervical cancer was explored. The mRNA expression of miR‑217 and mitogen‑activated protein kinase 1 (MAPK1) were assessed using reverse transcription‑quantitative polymerase chain reaction analysis. Cell Counting‑Kit 8, wound‑healing and Transwell assays were performed to detect cell viability, migration and invasion, respectively. Apoptosis and cell cycle were determined by flow cytometry. TargetScan 7.2 and dual‑luciferase reporter assays were respectively used to determine miR‑217 target genes and their binding capacities. The protein expression levels of MAPK1, phosphorylated (p)‑extracellular signal‑regulated kinase 1/2 (ERK1/2)/ERK1/2, Bcl‑2, Bax and cleaved caspase‑3 were quantified by western blotting. It was found that miR‑217 was downregulated in patients with CC and in CC cells. The viability, migration and invasion of cells were suppressed by a miR‑217 mimic. It was also found that apoptosis was increased and cell cycle was inhibited by the miR‑217mimic, which was supported by changes in Bcl‑2, Bax and cleaved caspase‑3. MAPK1 was upregulated in patients with CC and was a target gene of miR‑217. MAPK1 reversed the inhibition of miR‑217 on cell viability, migration, invasion and apoptosis. The protein levels of MAPK1 and p‑ERK1/2, which were higher in the mimic MAPK1 group than those in the control or mimic groups, were ameliorated by PD98059. The results of the present study demonstrated that miR‑217 had an anti‑CC effect and may be effectively used in the treatment of CC.
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Affiliation(s)
- Lihong Zhu
- The Second Clinical Medical College, Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi 712046
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi 712000
| | - Shumei Yang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710038
| | - Jianfeng Wang
- Clinical Laboratory, People's Hospital of Tongchuan, Tongchuan, Shaanxi 727031, P.R. China
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26
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Tang D, Zhao L, Peng C, Ran K, Mu R, Ao Y. LncRNA CRNDE promotes hepatocellular carcinoma progression by upregulating SIX1 through modulating miR‐337‐3p. J Cell Biochem 2019; 120:16128-16142. [PMID: 31099050 DOI: 10.1002/jcb.28894] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 03/10/2019] [Accepted: 03/22/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Dan Tang
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Zunyi Medical College Zunyi Guizhou China
| | - Lijin Zhao
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Zunyi Medical College Zunyi Guizhou China
| | - Cijun Peng
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Zunyi Medical College Zunyi Guizhou China
| | - Kaiqiong Ran
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Zunyi Medical College Zunyi Guizhou China
| | - Rui Mu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Zunyi Medical College Zunyi Guizhou China
| | - Yu Ao
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hospital of Zunyi Medical College Zunyi Guizhou China
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27
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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28
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Wang LP, Wang JP, Wang XP. HOTAIR contributes to the growth of liver cancer via targeting miR-217. Oncol Lett 2018; 15:7963-7972. [PMID: 29849802 DOI: 10.3892/ol.2018.8341] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 02/23/2018] [Indexed: 01/17/2023] Open
Abstract
Non-coding RNAs are important in the progression of liver cancer. The present study aimed to investigate the effects of long non-coding RNA HOX transcript antisense RNA (HOTAIR) on the proliferation of liver cancer and the association between HOTAIR and microRNA (miR)-217. It was demonstrated that the expression of HOTAIR was upregulated in liver cancer tissues and 3 liver cancer cell lines (MHCC97H, HepG2 and Hep3B). Inhibition of HOTAIR with HOTAIR small interfering (si) RNA lentiviral vectors significantly suppressed the cell proliferation of HepG2 cells, and downregulated the protein expression levels of two proliferation markers, Ki67 and proliferating cell nuclear antigen (PCNA). Furthermore, inhibition of HOTAIR induced G0/G1 cycle arrest by increasing the expression of p27 and decreasing the expression of cyclin D1. It was then predicted and verified that miR-217 was the target of HOTAIR. Expression of miR-217 was downregulated in liver cancer tissues and the 3 liver cancer cell lines. Further results revealed that inhibition of HOTAIR markedly upregulated the expression of miR-217 in HepG2 cells, and miR-217 inhibitor-induced reduction of miR-217 was significantly suppressed by HOTAIR inhibition. Furthermore, the increased cell proliferation and growth, the upregulated expression of Ki67 and PCNA, and the reduced G0/G1 cycle arrest induced by miR-217 inhibitor were partly rescued by inhibition of HOTAIR. Finally, the in vivo experiment indicated that HOTAIR inhibition suppressed tumorigenesis, including the smaller tumor volume and the reduced levels of Ki67. Overall, HOTAIR contributes to the proliferation and growth of liver cancer via downregulation of miR-217.
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Affiliation(s)
- Li-Ping Wang
- Department of Medicine, Xi'an Honghui Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Jun-Ping Wang
- Department of Medicine, The Friendship Hospital of Shaanxi, Xi'an, Shaanxi 710000, P.R. China
| | - Xin-Ping Wang
- Department of General Surgery, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China
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Yang G, Zeng X, Wang M, Wu A. The TET2/E-cadherin/β-catenin regulatory loop confers growth and invasion in hepatocellular carcinoma cells. Exp Cell Res 2018; 363:218-226. [PMID: 29331390 DOI: 10.1016/j.yexcr.2018.01.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/05/2018] [Accepted: 01/09/2018] [Indexed: 12/30/2022]
Abstract
The poor outcome of hepatocellular carcinoma (HCC) is mainly due to the development of fast growth, invasion and metastasis. The role of TET2 has been implicated in some cancer types, but its role and mechanisms in HCC remains elusive. In this study, our findings indicated that TET2 expression frequently increased in HCC and that TET2 expressional upregulation correlated with HCC progression. TET2 knockdown inhibited HCC cells proliferation in vitro and growth in vivo, and inhibited the invasion potential of HCC cells. Mechanically, TET2 knockdown upregulated E-cadherin expression and then attenuated β-catenin transactivation in HCC cells. TET2 repressed E-cadherin expression via recruited HDAC1 to E-cadherin promoter to reduce the H3K9Ac and H4K16Ac levels. Moreover, β-catenin signaling transcriptionally regulated TET2 expression to form a positive feedback in HCC cells. These findings indicate that the dysregulation of TET2/E-cadherin/β-catenin regulatory loop is a critical oncogenic event in HCC progression.
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Affiliation(s)
- Guohua Yang
- Department of General Surgery, Zhujiang Hospital of Southern Medical University, NO. 253 Guangzhou Industrial Avenue, Guangzhou 510282, Guangdong Province, China; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, NO. 78 Hengzhigang Road, Guangzhou 510095, Guangdong, China
| | - Xiang Zeng
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, NO. 78 Hengzhigang Road, Guangzhou 510095, Guangdong, China
| | - Mengchuan Wang
- Department of General Surgery, Zhujiang Hospital of Southern Medical University, NO. 253 Guangzhou Industrial Avenue, Guangzhou 510282, Guangdong Province, China
| | - Aiguo Wu
- Department of General Surgery, Zhujiang Hospital of Southern Medical University, NO. 253 Guangzhou Industrial Avenue, Guangzhou 510282, Guangdong Province, China.
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30
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Ren FH, Yang H, He RQ, Lu JN, Lin XG, Liang HW, Dang YW, Feng ZB, Chen G, Luo DZ. Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma. BMC Cancer 2018; 18:12. [PMID: 29298665 PMCID: PMC5753510 DOI: 10.1186/s12885-017-3941-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 12/19/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Currently, some studies have demonstrated that miR-34a could serve as a suppressor of several cancers including hepatocellular carcinoma (HCC). Previously, we discovered that miR-34a was downregulated in HCC and involved in the tumorigenesis and progression of HCC; however, the mechanism remains unclear. The purpose of this study was to estimate the expression of miR-34a in HCC by applying the microarray profiles and analyzing the predicted targets of miR-34a and their related biological pathways of HCC. METHODS Gene expression omnibus (GEO) datasets were conducted to identify the difference of miR-34a expression between HCC and corresponding normal tissues and to explore its relationship with HCC clinicopathologic features. The natural language processing (NLP), gene ontology (GO), pathway and network analyses were performed to analyze the genes associated with the carcinogenesis and progression of HCC and the targets of miR-34a predicted in silico. In addition, the integrative analysis was performed to explore the targets of miR-34a which were also relevant to HCC. RESULTS The analysis of GEO datasets demonstrated that miR-34a was downregulated in HCC tissues, and no heterogeneity was observed (Std. Mean Difference(SMD) = 0.63, 95% confidence intervals(95%CI):[0.38, 0.88], P < 0.00001; Pheterogeneity = 0.08 I2 = 41%). However, no association was found between the expression value of miR-34a and any clinicopathologic characteristics. In the NLP analysis of HCC, we obtained 25 significant HCC-associated signaling pathways. Besides, we explored 1000 miR-34a-related genes and 5 significant signaling pathways in which CCND1 and Bcl-2 served as necessary hub genes. In the integrative analysis, we found 61 hub genes and 5 significant pathways, including cell cycle, cytokine-cytokine receptor interaction, notching pathway, p53 pathway and focal adhesion, which proposed the relevant functions of miR-34a in HCC. CONCLUSION Our results may lead researchers to understand the molecular mechanism of miR-34a in the diagnosis, prognosis and therapy of HCC. Therefore, the interaction between miR-34a and its targets may promise better prediction and treatment for HCC. And the experiments in vivo and vitro will be conducted by our group to identify the specific mechanism of miR-34a in the progress and deterioration of HCC.
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Affiliation(s)
- Fang-Hui Ren
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Hong Yang
- Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Rong-Quan He
- Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Jing-Ning Lu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Xing-Gu Lin
- Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Hai-Wei Liang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Yi-Wu Dang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Zhen-Bo Feng
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
| | - Dian-Zhong Luo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People's Republic of China.
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Li X, Li X, Ren Y, Yin Z, Quan X, Xue X, Zhou B. Polymorphisms of rs1347093 and rs1397529 are associated with lung cancer risk in northeast Chinese population. Oncotarget 2017; 8:94862-94871. [PMID: 29212272 PMCID: PMC5706918 DOI: 10.18632/oncotarget.22030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 09/23/2017] [Indexed: 11/25/2022] Open
Abstract
Lung cancer is one of the malignant tumors with the highest morbidity and mortality all over the world. Here we researched the association between two SNPs (rs1347093 in MIR217HG and rs1397529 in Gab1) and the risk of lung cancer in northeast Chinese population, including 825 cases and 766 controls. We carried out χ2 test, unconditional logistic regression analysis and crossover analysis to estimate the relationship between SNPs and lung cancer risk and the interaction between SNPs and smoking on susceptibility to lung cancer. The results indicated that rs1347093, rs1397529 polymorphisms were associated with lung cancer risk, especially with adenocarcinoma risk. Dominant genetic model of the rs1347093 was associated with reduced risk of lung cancer compared to CC genotype (AC+AA vs. CC: adjusted OR = 0.599, 95%CI = 0.418-0.858, P=0.005). For rs1347093, the similar result was found. Dominant genetic model of the rs1397529 was associated with reduced risk of lung cancer compared to AA genotype (AC+CC vs. AA: adjusted OR = 0.664, 95%CI = 0.491-0.897, P=0.008). There is no significant interaction between rs1347093, rs1397529 polymorphism and smoking on susceptibility to lung cancer. Our study might demonstrate that rs1347093 in MIR217HG and rs1397529 in Gab1 could be meaningful as the novel biomarker for lung cancer risk.
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Affiliation(s)
- Xiaoying Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Department of Education, Liaoning, China
| | - XueLian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Department of Education, Liaoning, China
| | - Yangwu Ren
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Department of Education, Liaoning, China
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Department of Education, Liaoning, China
| | - Xiaowei Quan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Department of Education, Liaoning, China
| | - Xiaoxia Xue
- The Third Center of Laboratory Technology and Experimental Medicine, China Medical University, Shenyang, China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Department of Education, Liaoning, China
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32
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Jiang C, Yu M, Xie X, Huang G, Peng Y, Ren D, Lin M, Liu B, Liu M, Wang W, Kuang M. miR-217 targeting DKK1 promotes cancer stem cell properties via activation of the Wnt signaling pathway in hepatocellular carcinoma. Oncol Rep 2017; 38:2351-2359. [PMID: 28849121 DOI: 10.3892/or.2017.5924] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 05/24/2017] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies and exhibits heterogeneity in terms of clinical outcomes and biological activities. Emerging evidence has demonstrated that cancer stem cells (CSCs) play important roles in the tumorigenesis and progression of HCC. However, the molecular mechanisms underlying the stemness maintenance of CSCs remain largely unknown. In the present study, through real-time PCR, western blotting, luciferase assays, RNA immunoprecipitation, and in vitro and in vivo assays, we demonstrated that miR-217 expression was markedly increased in HCC tissues and cells. Overexpression of miR-217 promoted, while silencing miR-217 suppressed, the fraction of the side population and the expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further demonstrated that miR-217 promoted the CSC-like phenotype via dickkopf-1 (DKK1) targeting, resulting in constitutive activation of Wnt signaling. Moreover, the stimulatory effects of miR-217 on stem cell properties and Wnt signaling were antagonized by the upregulation of DKK1 in miR-217-overexpressing cells. Conversely, the inhibitory effects of silencing miR-217 on stem cell properties and Wnt signaling were reversed by the downregulation of DKK1 in miR-217-downregulated cells. Therefore, our results indicate that miR-217 plays a vital role in the CSC-like phenotypes of HCC cells and may be used as a potential therapeutic target against HCC.
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Affiliation(s)
- Chunlin Jiang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Miao Yu
- Center for Private Medical Service and Healthcare, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaoyan Xie
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Guangliang Huang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yao Peng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Dong Ren
- Department of Orthopaedic Surgery/Orthopaedic Research Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Manxia Lin
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Baoxian Liu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ming Liu
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wei Wang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ming Kuang
- Division of Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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Yerukala Sathipati S, Ho SY. Identifying the miRNA signature associated with survival time in patients with lung adenocarcinoma using miRNA expression profiles. Sci Rep 2017; 7:7507. [PMID: 28790336 PMCID: PMC5548864 DOI: 10.1038/s41598-017-07739-y] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 07/04/2017] [Indexed: 12/19/2022] Open
Abstract
Lung adenocarcinoma is a multifactorial disease. MicroRNA (miRNA) expression profiles are extensively used for discovering potential theranostic biomarkers of lung cancer. This work proposes an optimized support vector regression (SVR) method called SVR-LUAD to simultaneously identify a set of miRNAs referred to the miRNA signature for estimating the survival time of lung adenocarcinoma patients using their miRNA expression profiles. SVR-LUAD uses an inheritable bi-objective combinatorial genetic algorithm to identify a small set of informative miRNAs cooperating with SVR by maximizing estimation accuracy. SVR-LUAD identified 18 out of 332 miRNAs using 10-fold cross-validation and achieved a correlation coefficient of 0.88 ± 0.01 and mean absolute error of 0.56 ± 0.03 year between real and estimated survival time. SVR-LUAD performs well compared to some well-recognized regression methods. The miRNA signature consists of the 18 miRNAs which strongly correlates with lung adenocarcinoma: hsa-let-7f-1, hsa-miR-16-1, hsa-miR-152, hsa-miR-217, hsa-miR-18a, hsa-miR-193b, hsa-miR-3136, hsa-let-7g, hsa-miR-155, hsa-miR-3199-1, hsa-miR-219-2, hsa-miR-1254, hsa-miR-1291, hsa-miR-192, hsa-miR-3653, hsa-miR-3934, hsa-miR-342, and hsa-miR-141. Gene ontology annotation and pathway analysis of the miRNA signature revealed its biological significance in cancer and cellular pathways. This miRNA signature could aid in the development of novel therapeutic approaches to the treatment of lung adenocarcinoma.
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Affiliation(s)
| | - Shinn-Ying Ho
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan. .,Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
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Zhang J, Wang C, Xu H. miR-217 suppresses proliferation and promotes apoptosis in cardiac myxoma by targeting Interleukin-6. Biochem Biophys Res Commun 2017. [DOI: 10.1016/j.bbrc.2017.06.106] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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35
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Song X, Xie Y, Liu Y, Shao M, Yang W. MicroRNA-492 overexpression exerts suppressive effects on the progression of osteosarcoma by targeting PAK7. Int J Mol Med 2017; 40:891-897. [DOI: 10.3892/ijmm.2017.3046] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 05/24/2017] [Indexed: 11/06/2022] Open
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36
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Shivakumar M, Lee Y, Bang L, Garg T, Sohn KA, Kim D. Identification of epigenetic interactions between miRNA and DNA methylation associated with gene expression as potential prognostic markers in bladder cancer. BMC Med Genomics 2017; 10:30. [PMID: 28589857 PMCID: PMC5461531 DOI: 10.1186/s12920-017-0269-y] [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] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background One of the fundamental challenges in cancer is to detect the regulators of gene expression changes during cancer progression. Through transcriptional silencing of critical cancer-related genes, epigenetic change such as DNA methylation plays a crucial role in cancer. In addition, miRNA, another major component of epigenome, is also a regulator at the post-transcriptional levels that modulate transcriptome changes. However, a mechanistic role of synergistic interactions between DNA methylation and miRNA as epigenetic regulators on transcriptomic changes and its association with clinical outcomes such as survival have remained largely unexplored in cancer. Methods In this study, we propose an integrative framework to identify epigenetic interactions between methylation and miRNA associated with transcriptomic changes. To test the utility of the proposed framework, the bladder cancer data set, including DNA methylation, miRNA expression, and gene expression data, from The Cancer Genome Atlas (TCGA) was analyzed for this study. Results First, we found 120 genes associated with interactions between the two epigenomic components. Then, 11 significant epigenetic interactions between miRNA and methylation, which target E2F3, CCND1, UTP6, CDADC1, SLC35E3, METRNL, TPCN2, NACC2, VGLL4, and PTEN, were found to be associated with survival. To this end, exploration of TCGA bladder cancer data identified epigenetic interactions that are associated with survival as potential prognostic markers in bladder cancer. Conclusions Given the importance and prevalence of these interactions of epigenetic events in bladder cancer it is timely to understand further how different epigenetic components interact and influence each other. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0269-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Manu Shivakumar
- Biomedical & Translational Informatics Institute, Geisinger Health System, Danville, PA, USA
| | - Younghee Lee
- Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Lisa Bang
- Biomedical & Translational Informatics Institute, Geisinger Health System, Danville, PA, USA
| | - Tullika Garg
- Mowad Urology Department, Geisinger Health System, Danville, PA, USA
| | - Kyung-Ah Sohn
- Department of Software and Computer Engineering, Ajou University, Suwon, South Korea.
| | - Dokyoon Kim
- Biomedical & Translational Informatics Institute, Geisinger Health System, Danville, PA, USA. .,The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA.
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Xiao Y, Deng T, Su C, Shang Z. MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS. Oncol Lett 2017; 13:4986-4994. [PMID: 28599501 DOI: 10.3892/ol.2017.6076] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 01/19/2017] [Indexed: 01/21/2023] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignant disorder derived from the myeloid hematopoietic cells that accounts for ~80% of all adult acute leukemia. Numerous studies have shown that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to identify the mechanisms behind chemoresistance and seek therapeutic strategies to enhance efficacy in AML chemotherapy. MicroRNA (miR)-217 has been recognized as a tumor suppressor that is downregulated in various types of cancer, however the mechanisms behind the expression and function of miR-217 in AML have not yet been recognized. The expression of miR-217 was determined by quantitative polymerase chain reaction (qPCR). Following transfection with miR-217 mimics, an MTT assay, chemosensitivity assay, cell apoptosis assay and western blot analysis were performed in AML cell lines. Functional assays were also performed to explore the effects of endogenous Kirsten rat sarcoma viral oncogene homolog (KRAS) in AML. The results revealed that miR-217 was downregulated in patients with AML. Overexpression of miR-217 inhibited cellular proliferation and enhanced cell chemosensitivity to doxorubicin by the cell apoptosis pathway in AML cells. A dual-luciferase reporter assay demonstrated that KRAS was a direct target gene of miR-217 in vitro. qPCR and western blot analysis revealed that miR-217 negatively regulated KRAS protein expression, but had no impact on KRAS mRNA expression. Knockdown of KRAS expression markedly suppressed AML cellular proliferation, and enhanced cell chemosensitivity to doxorubicin via the cell apoptosis pathway. These findings indicate that miR-217 functions as a tumor suppressor in AML by directly targeting KRAS. Therefore, miR-217-based therapeutic strategies may provide a novel strategy for the enhancement of efficacy in the treatment of AML.
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Affiliation(s)
- Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Taoran Deng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Changliang Su
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhen Shang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
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Zhou W, Song F, Wu Q, Liu R, Wang L, Liu C, Peng Y, Mao S, Feng J, Chen C. miR-217 inhibits triple-negative breast cancer cell growth, migration, and invasion through targeting KLF5. PLoS One 2017; 12:e0176395. [PMID: 28437471 PMCID: PMC5402967 DOI: 10.1371/journal.pone.0176395] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/10/2017] [Indexed: 12/31/2022] Open
Abstract
Triple negative breast cancer (TNBC) is one of the most aggressive breast cancers without effective targeted therapies. Numerous studies have implied that KLF5 plays an important roles in TNBC. How is KLF5 regulated by microRNAs has not been well studied. Here, we demonstrated that miR-217 down-regulates the expression of KLF5 and KLF5's downstream target gene FGF-BP and Cyclin D1 in TNBC cell lines HCC1806 and HCC1937. Consequently, miR-217 suppresses TNBC cell growth, migration, and invasion. MiR-217 suppresses TNBC, at least partially, through down-regulating the KLF5 expression. These results suggest that the miR-217-KLF5 axis might serve as a potential target for treatment of TNBC.
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Affiliation(s)
- Wenhui Zhou
- Third Clinical College, Southern Medical University, Guangdong Province, Guangzhou, China
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan Province, Kunming, China
| | - Fangfang Song
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan Province, Kunming, China
- Department of Laboratory Medicine & Central Laboratory, Jinzhou Medical University Affiliated Fengxian Hospital, Shanghai, China
| | - Qiuju Wu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan Province, Kunming, China
- Department of Laboratory Medicine & Central Laboratory, Jinzhou Medical University Affiliated Fengxian Hospital, Shanghai, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan Province, Kunming, China
| | - Lulu Wang
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai, China
| | - Cuicui Liu
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai, China
| | - You Peng
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai, China
| | - Shuqin Mao
- Hubei University of Medicine Affiliated Taihe Hospital, Hubei Province, Shiyan, China
| | - Jing Feng
- Third Clinical College, Southern Medical University, Guangdong Province, Guangzhou, China
- Department of Laboratory Medicine & Central Laboratory, Southern Medical University Affiliated Fengxian Hospital, Shanghai, China
- * E-mail: (CC);
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan Province, Kunming, China
- * E-mail: (CC);
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Gao Y, Feng B, Lu L, Han S, Chu X, Chen L, Wang R. MiRNAs and E2F3: a complex network of reciprocal regulations in human cancers. Oncotarget 2017; 8:60624-60639. [PMID: 28947999 PMCID: PMC5601167 DOI: 10.18632/oncotarget.17364] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 04/03/2017] [Indexed: 12/14/2022] Open
Abstract
E2F transcription factor 3 (E2F3) is oncogenic in tumorigenesis. Alterations in E2F3 functions correspond with poor prognosis in various cancers, underscoring their status for the clinical cancer phenotype. Latest reports discovered intricate networks between microRNAs (miRNAs) and E2F3 in regulating the balance of these events, including proliferation, apoptosis, metastasis, as well as drug resistance. miRNAs are non-coding small RNAs which negatively regulate gene expressions post-transcriptionally mainly through 3′-UTR binding of target mRNAs. Increasing evidence shows that E2F3 can be activated/inhibited by numerous miRNAs whose dysregulation has been implicated in malignancy. In turn, miRNAs themselves can be transcriptionally regulated by E2F3, thus forming a negative feedback loop. These findings add a new challenging layer of complexity to E2F3 network. Current understanding of the reciprocal link between E2F3 and miRNAs in human cancers were summarized, which could help to develop potential therapeutic strategies.
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Affiliation(s)
- Yanping Gao
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Lu Lu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Siqi Han
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, PR China
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Dai J, Li Q, Bing Z, Zhang Y, Niu L, Yin H, Yuan G, Pan Y. Comprehensive analysis of a microRNA expression profile in pediatric medulloblastoma. Mol Med Rep 2017; 15:4109-4115. [PMID: 28440450 PMCID: PMC5436210 DOI: 10.3892/mmr.2017.6490] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 02/23/2017] [Indexed: 12/25/2022] Open
Abstract
Medulloblastoma is the most common malignant brain tumor of the central nervous system among children. Medulloblastoma is an embryonal tumor, of which little is known about the pathogenesis. Several efforts have been made to understand the molecular aspects of its tumorigenic pathways; however, these are poorly understood. microRNA (miRNA), a type of non-coding short RNA, has been proven to be associated with a number of physiological processes and pathological processes of serious diseases, including brain tumors. Differentially expressed miRNAs serve an important role in numerous types of malignancy. The present study aims to define a differentially expressed set of miRNAs in medulloblastoma tumor tissue, compared with normal samples, to improve the understanding of the tumorigenesis. It was identified that 22 miRNAs were upregulated and 26 miRNAs were downregulated in the tumor tissue compared with the normal group. However, when the medulloblastoma tissue was compared with normal cerebellum tissue, 9 miRNAs were identified to be up or downregulated in the tumor samples. The differentially expressed miRNAs in the tumor tissue were identified in order to clarify the networks and pathways of tumorigenesis using Ingenuity Pathway Analysis. Subsequently, key regulatory genes associated with the development of medulloblastoma were identified, including tumor protein p53, insulin like growth factor 1 receptor, argonaute 2, mitogen-activated protein kinases 1 and 3, sirtuin 1 and Y box binding protein 1.
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Affiliation(s)
- Junqiang Dai
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Qiao Li
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Zhitong Bing
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China
| | - Yinian Zhang
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Liang Niu
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Hang Yin
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Guoqiang Yuan
- Institute of Neurology, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Yawen Pan
- Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
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41
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Zhang M, Li M, Li N, Zhang Z, Liu N, Han X, Liu Q, Liao C. miR-217 suppresses proliferation, migration, and invasion promoting apoptosis via targeting MTDH in hepatocellular carcinoma. Oncol Rep 2017; 37:1772-1778. [PMID: 28184926 DOI: 10.3892/or.2017.5401] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 12/27/2016] [Indexed: 01/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has frequent incidence and the third highest mortality rate among cancers in the world. This study aimed to clarify the roles of miR-217 and metadherin (MTDH) in HCC. First, we identified that miR-217 expression was downregulated and MTDH expression was upregulated in the HCC tissues. Functional studies revealed that miR-217 negatively regulated MTDH expression via binding to the 3'-untranslated region of MTDH mRNA in the HCC cells. In our further studies, the miR-217 overexpression resulted in downregulation of MTDH expression in HCC cells. The miR-217 overexpression in HCC cells suppressed proliferation, migration, and invasion inducing apoptosis. Taken together, our study provides the initial evidence that the increase of MTDH expression is associated with the decrease of miR-217 expression in HCC. This study also suggests that miR-217 inhibits malignant progression of HCC in vitro and may be used for miRNA-based therapy, possibly via directly targeting MTDH.
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Affiliation(s)
- Mao Zhang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Min Li
- Department of General Surgery, Shilong People's Hospital, Southern Medical University, Dongguan, Guangdong 523326, P.R. China
| | - Na Li
- Department of Obstetrics and Gynecology, Baotou City Central Hospital, Baotou, Inner Mongolia 014040, P.R. China
| | - Zilang Zhang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Ning Liu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiaoyu Han
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qincheng Liu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Caixian Liao
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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Zhang S, Liu X, Liu J, Guo H, Xu H, Zhang G. PGC-1 alpha interacts with microRNA-217 to functionally regulate breast cancer cell proliferation. Biomed Pharmacother 2017; 85:541-548. [DOI: 10.1016/j.biopha.2016.11.062] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 11/14/2016] [Accepted: 11/14/2016] [Indexed: 12/21/2022] Open
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43
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Wu L, Bai X, Xie Y, Yang Z, Yang X, Lin J, Zhu C, Wang A, Zhang H, Miao R, Wu Y, Robson SC, Zhao Y, Sang X, Zhao H. MetastamiRs: A promising choice for antihepatocellular carcinoma nucleic acid drug development. Hepatol Res 2017; 47:80-94. [PMID: 27138942 DOI: 10.1111/hepr.12737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 04/18/2016] [Accepted: 04/29/2016] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.
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Affiliation(s)
- Liangcai Wu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xue Bai
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Xie
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Yang
- Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianzhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chengpei Zhu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anqiang Wang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haohai Zhang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ruoyu Miao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yan Wu
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Simon C Robson
- Liver Center and The Transplant Institute, Departments of Medicine and Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Brookline, Massachusetts, USA
| | - Yi Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Center of Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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miR-217 and CAGE form feedback loop and regulates the response to anti-cancer drugs through EGFR and HER2. Oncotarget 2016; 7:10297-321. [PMID: 26863629 PMCID: PMC4891121 DOI: 10.18632/oncotarget.7185] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 01/23/2016] [Indexed: 02/07/2023] Open
Abstract
MicroRNA array analysis revealed that miR-217 expression was decreased in anti-cancer drug-resistant Malme3MR cancer cells. CAGE, a cancer/testis antigen, was predicted as a target of miR-217. Luciferase activity and ChIP assays revealed a negative feedback relationship between CAGE and miR-217. miR-217 and CAGE oppositely regulated the response to anti-cancer drugs such as taxol, gefitinib and trastuzumab, an inhibitor of HER2. miR-217 negatively regulated the tumorigenic, metastatic, angiogenic, migration and invasion potential of cancer cells. The xenograft of Malme3MR cells showed an increased expression of pEGFRY845. CAGE and miR-217 inhibitor regulated the expression of pEGFRY845. CAGE showed interactions with EGFR and HER2 and regulated the in vivo sensitivity to trastuzumab. The down-regulation of EGFR or HER2 enhanced the sensitivity to anti-cancer drugs. CAGE showed direct regulation of HER2 and was necessary for the interaction between EGFR and HER2 in Malme3MR cells. miR-217 inhibitor induced interactions of CAGE with EGFR and HER2 in Malme3M cells. The inhibition of EGFR by CAGE-binding GTGKT peptide enhanced the sensitivity to gefitinib and trastuzumab and prevented interactions of EGFR with CAGE and HER2. Our results show that miR-217-CAGE feedback loop serves as a target for overcoming resistance to various anti-cancer drugs, including EGFR and HER2 inhibitors.
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Siegismund CS, Rohde M, Kühl U, Escher F, Schultheiss HP, Lassner D. Absent MicroRNAs in Different Tissues of Patients with Acquired Cardiomyopathy. GENOMICS PROTEOMICS & BIOINFORMATICS 2016; 14:224-34. [PMID: 27475403 PMCID: PMC4996855 DOI: 10.1016/j.gpb.2016.04.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/29/2016] [Accepted: 04/18/2016] [Indexed: 01/22/2023]
Abstract
MicroRNAs (miRNAs) can be found in a wide range of tissues and body fluids, and their specific signatures can be used to determine diseases or predict clinical courses. The miRNA profiles in biological samples (tissue, serum, peripheral blood mononuclear cells or other body fluids) differ significantly even in the same patient and therefore have their own specificity for the presented condition. Complex profiles of deregulated miRNAs are of high interest, whereas the importance of non-expressed miRNAs was ignored. Since miRNAs regulate gene expression rather negatively, absent miRNAs could indicate genes with unaltered expression that therefore are normally expressed in specific compartments or under specific disease situations. For the first time, non-detectable miRNAs in different tissues and body fluids from patients with different diseases (cardiomyopathies, Alzheimer’s disease, bladder cancer, and ocular cancer) were analyzed and compared in this study. miRNA expression data were generated by microarray or TaqMan PCR-based platforms. Lists of absent miRNAs of primarily cardiac patients (myocardium, blood cells, and serum) were clustered and analyzed for potentially involved pathways using two prediction platforms, i.e., miRNA enrichment analysis and annotation tool (miEAA) and DIANA miRPath. Extensive search in biomedical publication databases for the relevance of non-expressed miRNAs in predicted pathways revealed no evidence for their involvement in heart-related pathways as indicated by software tools, confirming proposed approach.
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Affiliation(s)
| | - Maria Rohde
- Institute for Cardiac Diagnostics and Therapy (IKDT), 12203 Berlin, Germany
| | - Uwe Kühl
- Institute for Cardiac Diagnostics and Therapy (IKDT), 12203 Berlin, Germany; Department of Cardiology, Campus Virchow, Charité - University Hospital Berlin, 13353 Berlin, Germany
| | - Felicitas Escher
- Institute for Cardiac Diagnostics and Therapy (IKDT), 12203 Berlin, Germany; Department of Cardiology, Campus Virchow, Charité - University Hospital Berlin, 13353 Berlin, Germany
| | | | - Dirk Lassner
- Institute for Cardiac Diagnostics and Therapy (IKDT), 12203 Berlin, Germany.
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Zhang Y, Zhang Z, Li Z, Gong D, Zhan B, Man X, Kong C. MicroRNA-497 inhibits the proliferation, migration and invasion of human bladder transitional cell carcinoma cells by targeting E2F3. Oncol Rep 2016; 36:1293-300. [DOI: 10.3892/or.2016.4923] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 02/14/2016] [Indexed: 11/05/2022] Open
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Epigenetic mechanisms regulating the development of hepatocellular carcinoma and their promise for therapeutics. Hepatol Int 2016; 11:45-53. [PMID: 27271356 DOI: 10.1007/s12072-016-9743-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/17/2016] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers around the globe and third most fatal malignancy. Chronic liver disorders such as chronic hepatitis and liver cirrhosis often lead to the development of HCC. Accumulation of genetic and epigenetic alterations are involved in the development of HCC. Genetic research sparked by recent developments in next generation sequencing has identified the frequency of genetic alterations that occur in HCC and has led to the identification of genetic hotspots. Emerging evidence suggests that epigenetic aberrations are strongly associated with the initiation and development of HCC. Various important genes encoding tumor suppressors including P16, RASSF1A, DLC-1, RUNX3 and SOCS-1 are targets of epigenetic dysregulation during the development of HCC. The present review discusses the importance of epigenetic regulations including DNA methylation, histone modification and microRNA mediated regulation of gene expression during tumorigenesis and their use as disease biomarkers. Furthermore, these epigenetic alterations have been discussed in relationship with promising therapeutic perspectives for HCC and related cancers.
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Managing Pancreatic Adenocarcinoma: A Special Focus in MicroRNA Gene Therapy. Int J Mol Sci 2016; 17:ijms17050718. [PMID: 27187371 PMCID: PMC4881540 DOI: 10.3390/ijms17050718] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/06/2016] [Accepted: 05/06/2016] [Indexed: 01/17/2023] Open
Abstract
Pancreatic cancer is an aggressive disease and the fourth most lethal cancer in developed countries. Despite all progress in medicine and in understanding the molecular mechanisms of carcinogenesis, pancreatic cancer still has a poor prognosis, the median survival after diagnosis being around 3 to 6 months and the survival rate of 5 years being less than 4%. For pancreatic ductal adenocarcinoma (PDAC), which represents more than 90% of new pancreatic cancer cases, the prognosis is worse than for the other cancers with a patient mortality of approximately 99%. Therefore, there is a pressing need for developing new and efficient therapeutic strategies for pancreatic cancer. In this regard, microRNAs not only have been seen as potential diagnostic and prognostic molecular markers but also as promising therapeutic agents. In this context, this review provides an examination of the most frequently deregulated microRNAs (miRNAs) in PDAC and their putative molecular targets involved in the signaling pathways of pancreatic
carcinogenesis. Additionally, it is presented a summary of gene therapy clinical trials involving miRNAs and it is illustrated the therapeutic potential associated to these small non-coding RNAs, for PDAC treatment. The facts presented here constitute a strong evidence of the remarkable opportunity associated to the application of microRNA-based therapeutic strategies as a novel approach for cancer therapy.
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Dong D, Gong Y, Zhang D, Bao H, Gu G. miR-874 suppresses the proliferation and metastasis of osteosarcoma by targeting E2F3. Tumour Biol 2016; 37:6447-55. [PMID: 26631042 DOI: 10.1007/s13277-015-4527-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 11/26/2015] [Indexed: 01/01/2023] Open
Abstract
Increasing evidence indicates that microRNAs (miRNAs) play critical roles in osteosarcoma (OS) occurrence and development. MicroRNA-874 (miR-874) has proven to be dysregulated in several human cancers. However, the biological function and underlying molecular mechanism of miR-874 in OS remain unclear. In this study, we aimed to investigate the biological role and potential mechanism of miR-874 in OS. Here, we found that miR-874 expression was significantly decreased in OS cell lines and tissues by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and its expression was correlated with tumor-node-metastasis (TNM) stage, tumor size, and lymph node metastasis (all P < 0.01). Functional study revealed that overexpression of miR-874 in OS cells could remarkably inhibit proliferation, migration, and invasion and induce cell apoptosis. In addition, E2F transcription factor 3 (E2F3) was confirmed as a target of miR-874 in OS cells. E2F3 mRNA expression was upregulated and was inversely correlated with the level of miR-874 in OS tissues. Importantly, downregulation of E2F3 mimicked the effect of overexpression miR-874 in OS cells, and E2F3 overexpression partially attenuated the tumor-suppressive effects of miR-874 in OS cells. Taken together, these findings suggested that miR-874 might suppress the growth and metastasis of OS cells partially by targeting E2F3.
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Affiliation(s)
- Dong Dong
- Department of Radiology, The First Hospital of Jilin University, No.71 Xinmin Street, Changchun, 130021, Jilin, China
| | - Yubao Gong
- Department of Joint Surgery, The First Hospital of Jilin University, No. 71 Xinmin Street, Changchun, 130021, Jilin, China
| | - Debao Zhang
- Department of Joint Surgery, The First Hospital of Jilin University, No. 71 Xinmin Street, Changchun, 130021, Jilin, China
| | - Huricha Bao
- Department of Joint surgery, Inner Monggolia People's Hospital, Huhehaote, 010000, Inner Monggolia, China
| | - Guishan Gu
- Department of Joint Surgery, The First Hospital of Jilin University, No. 71 Xinmin Street, Changchun, 130021, Jilin, China.
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microRNA-217 inhibits tumor progression and metastasis by downregulating EZH2 and predicts favorable prognosis in gastric cancer. Oncotarget 2016; 6:10868-79. [PMID: 25869101 PMCID: PMC4484425 DOI: 10.18632/oncotarget.3451] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 02/25/2015] [Indexed: 01/18/2023] Open
Abstract
microRNA-217 (miR-217) is frequently dysregulated in cancer. Here, we report that miR-217 levels were lower in tumor tissue compared with the adjacent normal tissue. Low levels of miR-217 were associated with aggressive tumor phenotypes and poor overall survival in gastric cancer patients. The ectopic expression of miR-217 inhibited cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas knockdown of endogenous miR-217 increased cell proliferation and invasion. Further experiments revealed that Polycomb group protein enhancer of zeste homolog 2 (EZH2) was a direct target of miR-217 in gastric cancer cells. Knockdown of EZH2 mimicked the tumor-suppressive effects of miR-217 in gastric cancer cells, whereas the reintroduction of EZH2 abolished its effects. Taken together, these results demonstrated that miR-217 may be used as a prognostic marker, and the newly identified miR-217-EZH2 axis may be a potential target in the development of therapeutic strategies for gastric cancer patients.
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