1. Gankyrin Promotes Tumor-Suppressor Protein Degradation to Drive Hepatocyte Proliferation
- Author
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Yanjun Jiang, Meenasri Kumbaji, Amber M. D'Souza, Sheeniza Shah, Leila Valanejad, Ashley Cast, Rebekah Karns, Mary Wright, David B. Smithrud, Soona Shin, Kyle Lewis, and Nikolai A. Timchenko
- Subjects
Hepatoblastoma ,Male ,0301 basic medicine ,Tumor-Suppressor Proteins ,Gankyrin ,Proliferation ,C/EBP, CCAAT/enhancer binding protein ,GLKO, Gankyrin liver-specific knock-out ,BrdU, bromodeoxyuridine ,Mice ,Genes, Tumor Suppressor ,Rb, retinoblastoma ,Carbon Tetrachloride ,Original Research ,Cancer ,Mice, Knockout ,Liver injury ,Benzenesulfonates ,Liver Neoplasms ,Gastroenterology ,Progenitor Cells ,Opn, osteopontin ,mRNA, messenger RNA ,3. Good health ,Gene Expression Regulation, Neoplastic ,Editorial ,medicine.anatomical_structure ,Liver ,Hepatocyte ,Liver cancer ,RT-PCR, reverse-transcriptase polymerase chain reaction ,Carcinoma, Hepatocellular ,PH, partial hepatectomy ,PCNA, proliferating cell nuclear antigen ,Down-Regulation ,Protein degradation ,Biology ,LKO, liver-specific knock-out ,HNF4α, hepatocyte nuclear factor 4α ,cDNA, complementary DNA ,03 medical and health sciences ,FXR, farnesoid X receptor ,UPS, ubiquitin proteasome system ,TSP, tumor-suppressor protein ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:RC799-869 ,CUGBP1, CUG triplet repeat binding protein 1 ,Cell Proliferation ,Hepatology ,Oncogene ,Tumor Suppressor Proteins ,Triazoles ,medicine.disease ,WT, wild-type ,MicroRNAs ,030104 developmental biology ,2D, 2-dimensional ,Cancer cell ,Hepatocytes ,Cancer research ,biology.protein ,lcsh:Diseases of the digestive system. Gastroenterology ,Gank, Gankyrin ,HCC, hepatocellular carcinoma ,Co-IP, co-immunoprecipitation ,Transcription Factors ,DEN, diethylnitrosamine - Abstract
Background & Aims Uncontrolled liver proliferation is a key characteristic of liver cancer; however, the mechanisms by which this occurs are not well understood. Elucidation of these mechanisms is necessary for the development of better therapy. The oncogene Gankyrin (Gank) is overexpressed in both hepatocellular carcinoma and hepatoblastoma. The aim of this work was to determine the role of Gank in liver proliferation and elucidate the mechanism by which Gank promotes liver proliferation. Methods We generated Gank liver-specific knock-out (GLKO) mice and examined liver biology and proliferation after surgical resection and liver injury. Results Global profiling of gene expression in GLKO mice showed significant changes in pathways involved in liver cancer and proliferation. Investigations of liver proliferation after partial hepatectomy and CCl4 treatment showed that GLKO mice have dramatically inhibited proliferation of hepatocytes at early stages after surgery and injury. In control LoxP mice, liver proliferation was characterized by Gank-mediated reduction of tumor-suppressor proteins (TSPs). The failure of GLKO hepatocytes to proliferate is associated with a lack of down-regulation of these proteins. Surprisingly, we found that hepatic progenitor cells of GLKO mice start proliferation at later stages and restore the original size of the liver at 14 days after partial hepatectomy. To examine the proliferative activities of Gank in cancer cells, we used a small molecule, cjoc42, to inhibit interactions of Gank with the 26S proteasome. These studies showed that Gank triggers degradation of TSPs and that cjoc42-mediated inhibition of Gank increases levels of TSPs and inhibits proliferation of cancer cells. Conclusions These studies show that Gank promotes hepatocyte proliferation by elimination of TSPs. This work provides background for the development of Gank-mediated therapy for the treatment of liver cancer. RNA sequencing data can be accessed in the NCBI Gene Expression Omnibus: GSE104395., Graphical abstract
- Published
- 2018