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miR-122 enhances sensitivity of hepatocellular carcinoma to oxaliplatin via inhibiting MDR1 by targeting Wnt/β-catenin pathway
- Source :
- Experimental and Molecular Pathology. 106:34-43
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- 0301 basic medicine
ATP Binding Cassette Transporter, Subfamily B
Carcinoma, Hepatocellular
Clinical Biochemistry
Down-Regulation
Mice, Nude
Apoptosis
Real-Time Polymerase Chain Reaction
Pathology and Forensic Medicine
Flow cytometry
Mice
03 medical and health sciences
0302 clinical medicine
Genes, Reporter
Cell Line, Tumor
MiR-122
medicine
Animals
Humans
MTT assay
RNA, Neoplasm
Viability assay
Antineoplastic Agents, Alkylating
Wnt Signaling Pathway
neoplasms
Molecular Biology
beta Catenin
medicine.diagnostic_test
Chemistry
Liver Neoplasms
Wnt signaling pathway
Xenograft Model Antitumor Assays
digestive system diseases
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Oxaliplatin
MicroRNAs
030104 developmental biology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Catenin
Cancer research
Chromatin immunoprecipitation
Subjects
Details
- ISSN :
- 00144800
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- Experimental and Molecular Pathology
- Accession number :
- edsair.doi.dedup.....19311bb7045aa22e33e74f3515a559a2