MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation
BackgroundHepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways via their targeting of down...
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Frontiers Media S.A.
2021-03-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.642030/full |
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doaj-dcd43bfb2def46988680dea0f4cbfc27 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yinghui Hong Yinghui Hong Mingliang Ye Mingliang Ye Fan Wang Fan Wang Jun Fang Jun Fang Chun Wang Chun Wang Jie Luo Jie Luo Jialiang Liu Jialiang Liu Jing Liu Jing Liu Lan Liu Lan Liu Qiu Zhao Qiu Zhao Ying Chang Ying Chang |
spellingShingle |
Yinghui Hong Yinghui Hong Mingliang Ye Mingliang Ye Fan Wang Fan Wang Jun Fang Jun Fang Chun Wang Chun Wang Jie Luo Jie Luo Jialiang Liu Jialiang Liu Jing Liu Jing Liu Lan Liu Lan Liu Qiu Zhao Qiu Zhao Ying Chang Ying Chang MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation Frontiers in Oncology MiR-21-3p hepatocellular carcinoma SMAD7 YAP1 prognosis |
author_facet |
Yinghui Hong Yinghui Hong Mingliang Ye Mingliang Ye Fan Wang Fan Wang Jun Fang Jun Fang Chun Wang Chun Wang Jie Luo Jie Luo Jialiang Liu Jialiang Liu Jing Liu Jing Liu Lan Liu Lan Liu Qiu Zhao Qiu Zhao Ying Chang Ying Chang |
author_sort |
Yinghui Hong |
title |
MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation |
title_short |
MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation |
title_full |
MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation |
title_fullStr |
MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation |
title_full_unstemmed |
MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 Regulation |
title_sort |
mir-21-3p promotes hepatocellular carcinoma progression via smad7/yap1 regulation |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2021-03-01 |
description |
BackgroundHepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways via their targeting of downstream genes. MiR-21-3p, a liver-enriched miRNA, and SMAD7, the negative regulator of the TGF-β signaling pathway, likely exert a vital influence on HCC progression.AimsHere, we explore the role of the miR-21-3p-SMAD7/YAP1 axis on HCC pathogenesis.MethodsMiRNA microarray analysis was performed for miRNA screening. The dual-luciferase assay was adopted for target verification. Expression of miRNA and related genes were quantified via qRT-PCR, western blotting, and immunohistochemical staining. Flow cytometry and the transwell migration assay were used to detail cell apoptosis, invasion and metastases. Rat models were established to explore the role of the miR-21-3p-SMAD7/YAP1 axis in hepatocarcinogenesis. Bioinformatics analysis was conducted for exploring genes of clinical significance.ResultsMiR-21-3p levels were found to be significantly elevated in hepatocellular carcinoma and indicate poor overall survival. High miR-21-3p levels were associated with advanced tumor stages (P = 0.029), in particular T staging (P = 0.026). Low SMAD7/high YAP1 levels were confirmed in both HCC and rat models with advanced liver fibrosis and cirrhosis. Besides, SMAD7 was demonstrated to be the direct target of miR-21-3p. The effect of MiR-21-3p on tumor phenotypes and YAP1 upregulation could be partly reversed via the restoration of SMAD7 expression in HCC cell lines. Overexpression of YAP1 after miR-21-3p upregulation promoted expression of nuclear transcription effector connective tissue growth factor. Co-survival analysis indicated that lower miR-21-3p/higher SMAD7 (P = 0.0494) and lower miR-21-3p/lower YAP1 (P = 0.0379) group patients had better overall survival rates. Gene Set Variation Analysis revealed that gene sets related to miR-21-3p and SMAD7 were significantly associated with the TGF-β signaling pathway in HCC.ConclusionMiR-21-3p promotes migration and invasion of HCC cells and upregulation of YAP1 expression via direct inhibition of SMAD7, underscoring a major epigenetic mechanism in the pathogenesis of HCC. |
topic |
MiR-21-3p hepatocellular carcinoma SMAD7 YAP1 prognosis |
url |
https://www.frontiersin.org/articles/10.3389/fonc.2021.642030/full |
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doaj-dcd43bfb2def46988680dea0f4cbfc272021-03-08T05:46:02ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-03-011110.3389/fonc.2021.642030642030MiR-21-3p Promotes Hepatocellular Carcinoma Progression via SMAD7/YAP1 RegulationYinghui Hong0Yinghui Hong1Mingliang Ye2Mingliang Ye3Fan Wang4Fan Wang5Jun Fang6Jun Fang7Chun Wang8Chun Wang9Jie Luo10Jie Luo11Jialiang Liu12Jialiang Liu13Jing Liu14Jing Liu15Lan Liu16Lan Liu17Qiu Zhao18Qiu Zhao19Ying Chang20Ying Chang21Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaDepartment of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, ChinaClinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan University, Wuhan, ChinaBackgroundHepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways via their targeting of downstream genes. MiR-21-3p, a liver-enriched miRNA, and SMAD7, the negative regulator of the TGF-β signaling pathway, likely exert a vital influence on HCC progression.AimsHere, we explore the role of the miR-21-3p-SMAD7/YAP1 axis on HCC pathogenesis.MethodsMiRNA microarray analysis was performed for miRNA screening. The dual-luciferase assay was adopted for target verification. Expression of miRNA and related genes were quantified via qRT-PCR, western blotting, and immunohistochemical staining. Flow cytometry and the transwell migration assay were used to detail cell apoptosis, invasion and metastases. Rat models were established to explore the role of the miR-21-3p-SMAD7/YAP1 axis in hepatocarcinogenesis. Bioinformatics analysis was conducted for exploring genes of clinical significance.ResultsMiR-21-3p levels were found to be significantly elevated in hepatocellular carcinoma and indicate poor overall survival. High miR-21-3p levels were associated with advanced tumor stages (P = 0.029), in particular T staging (P = 0.026). Low SMAD7/high YAP1 levels were confirmed in both HCC and rat models with advanced liver fibrosis and cirrhosis. Besides, SMAD7 was demonstrated to be the direct target of miR-21-3p. The effect of MiR-21-3p on tumor phenotypes and YAP1 upregulation could be partly reversed via the restoration of SMAD7 expression in HCC cell lines. Overexpression of YAP1 after miR-21-3p upregulation promoted expression of nuclear transcription effector connective tissue growth factor. Co-survival analysis indicated that lower miR-21-3p/higher SMAD7 (P = 0.0494) and lower miR-21-3p/lower YAP1 (P = 0.0379) group patients had better overall survival rates. Gene Set Variation Analysis revealed that gene sets related to miR-21-3p and SMAD7 were significantly associated with the TGF-β signaling pathway in HCC.ConclusionMiR-21-3p promotes migration and invasion of HCC cells and upregulation of YAP1 expression via direct inhibition of SMAD7, underscoring a major epigenetic mechanism in the pathogenesis of HCC.https://www.frontiersin.org/articles/10.3389/fonc.2021.642030/fullMiR-21-3phepatocellular carcinomaSMAD7YAP1prognosis |