title: Gα12gep oncogene inhibits FOXO1 in hepatocellular carcinoma as a consequence of miR-135b and miR-194 dysregulation.
abstract: The high mortality rate of hepatocellular carcinoma (HCC) is associated with its fast-growing malignancy. In tumor microenvironments, certain GPCRs are coupled to Gα12 for signal transduction. Given the role of forkhead box O1 (FOXO1) in the inhibition of various tumors, this study investigated whether increase of Gα12 in HCC causes FOXO1 repression, and if so, whether this event occurs through microRNA dysregulation. Overexpression of an active mutant of Gα12 (Gα12QL) decreased FOXO1 levels, whereas knockdown of Gα12 had the opposite effect. Of the microRNAs targeting FOXO1, miR-135b levels were markedly increased by Gα12 signaling, which led to FOXO1 repression as shown by the experiments using mimic, antisense oligonucleotide or siRNA. Gα12QL increased the primary form of miR-135b by activating JunB (or c-Jun)/AP-1. Consistently, knockdown of JunB (or c-Jun) decreased miR-135b levels, thereby increasing FOXO1. Moreover, Gα12QL induced MDM2, the deficiency of which facilitated FOXO1 accumulation. In addition, Gα12QL repressed miR-194 cluster gene products (194/192/215), which contributed to MDM2-mediated FOXO1 repression. In functional assays, Gα12QL facilitated tumor cell growth with alterations in cell cycle-associated protein levels, which was antagonized by enforced expression of FOXO1. In human HCCs, FOXO1 levels were decreased as compared with the surrounding liver tissue. Moreover, decrease of FOXO1 or miR-194 was statistically significant between stages T1 and T2, whereas increase of miR-135b discriminated tumor stage T3a versus T1/T2. In conclusion, Gα12gep oncogene inhibits FOXO1, which may result from the inhibition of FOXO1 de novo synthesis by miR-135b in conjunction with MDM2-mediated destabilization of FOXO1.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Jung
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Yu-Ri
authors.initials: YR
authors.lastname: Seo
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Yoon Mee
authors.initials: YM
authors.lastname: Yang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ja Hyun
authors.initials: JH
authors.lastname: Koo
authors.affiliation: Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: An
authors.affiliation: College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Kang Mo
authors.initials: KM
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: sgk@snu.ac.kr.
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005347:Fibroblasts; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C581727:JunB protein, human; C544965:MIRN135 microRNA, human; C554846:MIRN194 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D048031:JNK Mitogen-Activated Protein Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13
keywords: FOXO1; GPCR; Gα(12); Liver cancer; Non-coding small RNA