title: miR-345 inhibits tumor metastasis and EMT by targeting IRF1-mediated mTOR/STAT3/AKT pathway in hepatocellular carcinoma.
abstract: MicroRNAs (miRNAs) have been reported to play critical roles in tumor progression including hepatocellular carcinoma (HCC). Thus, the underlying mechanisms need further investigation. Previous study reported that loss of miR-345 expression indicated a poor prognosis of HCC patients. This study evaluated whether loss of miR-345 could promote the tumor metastasis and epithelial-mesenchymal-transition (EMT) of HCC by targeting interferon regulatory factor 1 (IRF1)-mediated mTOR/STAT3/AKT signaling. Underexpression of miR-345 was identified in 65 cases of human HCC compared to matched tumor-adjacent tissues by qRT-PCR. Moreover, we found that reduced expression of mi-345 was observed in HCC cell lines. The restoration of miR-345 inhibited cell migration and invasion in HCCLM3 cells, while its loss facilitated the cell mobility of HepG2 cells. Furthermore, miR-345 over-expression reduced lung metastases of HCC cells in nude mice. Notably, miR-345 overexpression prohibited, while its knockdown enhanced the EMT process of HCC cell lines in vitro. Bioinformatics software predicted that IRF1 was a direct target of miR-345. We then observed the negative regulation of miR-345 on IRF1 protein expression and the direct binding between them was further verified by dual-luciferase assays in HCC cells. In addition, over-expression of IRF1 mRNA was inversely correlated with the level of miR-345 in HCC specimens. Restoration of IRF1 resulted in promoted EMT and cell mobility in miR-345 overexpressing HCCLM3 cells. It was found that mTOR/STAT3/AKT pathway and its downstream targets including Slug, Snail and Twist may be involved in IRF1 mediated EMT process. In conclusion, miR-345 acts as an inhibitor of EMT process in HCC cells by targeting IRF1 and this study highlights the potential effects of miR-345 on prognosis and treatment of HCC.
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Huanzhou
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Meng
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Jiangkun
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Tian
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C561417:MIRN345 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases