OIP5, a target of miR-15b-5p, regulates hepatocellular carcinoma growth and metastasis through the AKT/mTORC1 and β-catenin signaling pathways.
Opa interacting protein 5 (OIP5) is upregulated in some types of human cancers, but the biological implications of its upregulation have not yet been clarified in human hepatocellular carcinoma (HCC). In this study, the signaling pathway downstream of OIP5 was analyzed by proteome kinase profiling. A putative microRNA targeting OIP5 was identified using a miRNA PCR array. Tumorigenicity and metastatic ability were examined in an orthotopic animal model. OIP5 expression was strongly detected in early and advanced tumors via gene expression profiling and immunohistochemical staining analyses. Cells with knockdown of OIP5 via target shRNA exhibited reduced hepatic mass formation and metastatic tumor nodules in an orthotopic mouse model. OIP5-induced AKT activation was mediated by both mTORC2 and p38/PTEN activation. AKT activation was linked to mTORC1 and GSK-3β/β-catenin signaling, which are primarily associated with tumor cell growth and metastasis, respectively. miR-15b-5p, which targets OIP5, efficiently inhibited OIP5-mediated mTORC1 and GSK-3β/β-catenin signaling. These findings suggest that OIP5 may be involved in HCC growth and metastasis and that miR-15b-5p inhibits OIP5-mediated oncogenic signaling in HCC.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine, Biomedical Research Institute Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Hua
H
Li
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine, Biomedical Research Institute Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Jun
J
Zhang
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine, Biomedical Research Institute Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Mi-Jin
MJ
Lee
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine, Biomedical Research Institute Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Goung-Ran
GR
Yu
Department of Infectious Disease, Yanbian University Hospital, Yanji, Jilin Province, China.
Xueji
X
Han
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Research Institute of Clinical Medicine, Biomedical Research Institute Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
Dae-Ghon
DG
Kim
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; C517146:OIP5 protein, human; D051176:beta Catenin; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
OIP5; hepatocellular carcinoma; metastasis; miR-15b-5p; tumor growth