Fei Cao1, Li-Xue Yin2. 1. School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, P.R. China. 2. School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, P.R. China; Key Laboratory of Ultrasonic Cardiac Electrophysiology and Biomechanics of Sichuan Province, Department of Cardiovascular Ultrasound and Non-invasive Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, P.R. China. Electronic address: yinlixue68@163.com.
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the primary causes of cancer-related death and resistance to cytotoxic chemotherapy is the major cause of mortality in HCC patients. miR-122 is a liver specific miRNA and is found to be reduced in HCC, however, the function of miR-122 in HCC chemosensitivity remains elusive. METHODS: We used qRT-PCR to measure expressions of miR-122, β-catenin and MDR1 in four HCC cell lines. And we assessed the effects of miR-122 or β-catenin on cell viability and apoptosis upon oxaliplatin (OXA) treatment by MTT assay and flow cytometry. In addition, we validated the interactions of miR-122/β-catenin and β-catenin/MDR1 by dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). Western blotting was used to determine the protein levels of β-catenin, Wnt1 and MDR1. In the end, we verified the anti-tumor effect of miR-122 in vivo by using mouse tumor xenograft model. RESULTS: We found that miR-122 was down-regulated in HCC cells. Up-regulation of miR-122 or inhibition of Wnt/β-catenin signaling promoted HCC cells apoptosis and increased the sensitivity of HCC cells to OXA. On the molecular level, we showed that miR-122 directly targeted and suppressed Wnt/β-catenin pathway while β-catenin bound with MDR1 promoter and activated its transcription. Overexpression of miR-122 inhibited MDR1 expression via directly suppressing Wnt/β-catenin pathway. CONCLUSION: Our study fully demonstrated that miR-122 inhibits MDR1 expression via suppression of Wnt/β-catenin pathway, thereby enhancing HCC sensitivity to OXA. Therefore, miR-122 could serve as a novel potential therapeutic target for HCC.
BACKGROUND:Hepatocellular carcinoma (HCC) is one of the primary causes of cancer-related death and resistance to cytotoxic chemotherapy is the major cause of mortality in HCC patients. miR-122 is a liver specific miRNA and is found to be reduced in HCC, however, the function of miR-122 in HCC chemosensitivity remains elusive. METHODS: We used qRT-PCR to measure expressions of miR-122, β-catenin and MDR1 in four HCC cell lines. And we assessed the effects of miR-122 or β-catenin on cell viability and apoptosis upon oxaliplatin (OXA) treatment by MTT assay and flow cytometry. In addition, we validated the interactions of miR-122/β-catenin and β-catenin/MDR1 by dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). Western blotting was used to determine the protein levels of β-catenin, Wnt1 and MDR1. In the end, we verified the anti-tumor effect of miR-122 in vivo by using mousetumor xenograft model. RESULTS: We found that miR-122 was down-regulated in HCC cells. Up-regulation of miR-122 or inhibition of Wnt/β-catenin signaling promoted HCC cells apoptosis and increased the sensitivity of HCC cells to OXA. On the molecular level, we showed that miR-122 directly targeted and suppressed Wnt/β-catenin pathway while β-catenin bound with MDR1 promoter and activated its transcription. Overexpression of miR-122 inhibited MDR1 expression via directly suppressing Wnt/β-catenin pathway. CONCLUSION: Our study fully demonstrated that miR-122 inhibits MDR1 expression via suppression of Wnt/β-catenin pathway, thereby enhancing HCC sensitivity to OXA. Therefore, miR-122 could serve as a novel potential therapeutic target for HCC.
Authors: Bei Xie; Linjing Li; Zhewen Zhang; Lei Zhao; Juan Cheng; Cunmin Zhou; Jie Cheng; Jing Yan; Jing Chen; Juan Yi; Bei Wang; Suya Jin; Hulai Wei Journal: J Cancer Date: 2021-05-13 Impact factor: 4.207