title: Upregulation of miR-137 reverses sorafenib resistance and cancer-initiating cell phenotypes by degrading ANT2 in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. More than 80% of patients with HCC are not good candidates for curative surgical resection due to advanced liver cirrhosis caused by underlying chronic hepatitis virus (B or C) infection. Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced HCC. Although, sorafenib currently sets the new standard for advanced HCC treatment, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical. In the present study, we found that adenine nucleotide translocator 2 (ANT2) was upregulated in sorafenib‑resistant HCC Huh7 cells (Huh7-R) and its overexpression promoted sorafenib resistance. ANT2 induced the formation of cancer-initiating cell (CIC) phenotypes and promoted metastasis-associated traits in the Huh7 cells. Silencing of miR-137 upregulated ANT2 protein expression in the Huh7 cells. miR-137 was downregulated in the Huh7-R cells, compared with that in the Huh7 cells and its restoration reversed sorafenib resistance in the Huh7-R cells. Restoration of miR-137 inhibited formation of CIC traits and attenuated the abilities of migration and invasion in the Huh7-R cells. Moreover, we demonstrated that high-intensity focused ultrasound (HIFU) in unresectable HCC upregulated serum miR-137. Combining HIFU and sorafenib may be a wise option for advanced and unresectable HCC.
authors.affiliation: Department of Ultrasound, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
authors.forename: Ai-Qing
authors.initials: AQ
authors.lastname: Lu
authors.affiliation: Department of Ultrasound, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Gastrointestinal Surgery, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Neonatal Intensive Care Unit, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Wang
authors.affiliation: The First Intensive Care Unit, The First People's Hospital of Jining, Jining, Shandong 272100, P.R. China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Cao
mesh_terms: D020413:3' Untranslated Regions; D033742:Adenine Nucleotide Translocator 2 / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D057086:High-Intensity Focused Ultrasound Ablation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D033742:Adenine Nucleotide Translocator 2; C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib