OncoTargets and Therapy (May 2019)
ODC1 promotes proliferation and mobility via the AKT/GSK3β/β-catenin pathway and modulation of acidotic microenvironment in human hepatocellular carcinoma
Abstract
Zi Ye,1 Zhirui Zeng,2,3 Yiyi Shen,4 Qiang Yang,1 Duidui Chen,1 Zubing Chen,1 Shiqiang Shen11Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, People’s Republic of China; 2Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Guiyang, Guizhou 550009, People’s Republic of China; 3Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550009, People’s Republic of China; 4Department of Liver-Biliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of ChinaPurpose: Ornithine decarboxylase 1 (ODC1)–an oncogene involved in the biosynthesis of polyamines–is commonly upregulated and associated with poor prognosis in numerous cancers. However, the role and mechanism of ODC1 in hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to investigate the role of ODC1 in HCC and clarify the latent molecular mechanisms.Material and methods: We used samples obtained from The Cancer Genome Atlas. The expression of ODC1 was also assessed in our additional HCC samples and HCC cell lines. The roles of ODC1 in HCC cell proliferation, migration and invasion in vitro were investigated using the cell-counting kit-8 assay, 5-ethynyl-2´-deoxyuridine assay, colony formation assay, flow cytometry, wound healing assay and transwell assay, respectively. The effect of ODC1 on HCC cell proliferation in vivo was investigated by constructing a xenotransplanted tumor model in nude mice. Quantitative real-time polymerase chain and western blotting were used to detect the expression levels of ODC1 in mimetic hypoxia, nutrient depleted, and acidotic microenvironment. The relationships between ODC1, the AKT/GSK3β/β-catenin pathway, and acidotic microenvironment were further investigated through western blotting, immunohistochemical staining, and immunofluorescence.Results: ODC1 was upregulated in HCC tissues and cell lines, and co-expressed with KI67 and PCNA (P<0.05). A decrease in the expression of ODC1 inhibits proliferation, migration, invasion, and induces cell cycle arrest in HCC cell lines in vitro, while suppressing HCC cell proliferation in vivo (P<0.05). Furthermore, the expression of ODC1 was increased in the mimetic acidotic microenvironment, while the interference with the expression of ODC1 reversed the effect of the acidotic microenvironment through regulation of AKT/GSK3β/β-catenin and related downstream proteins.Conclusion: ODC1 is an unfavorable gene in HCC patients,promoting HCC cell proliferation, migration and invasion via the AKT/GSK3β/β-catenin pathway and modulation of the acidotic microenvironment.Keywords: hepatocellular carcinoma, ornithine decarboxylase 1, acidotic, β-catenin
