Silencing of OGDHL promotes liver cancer metastasis by enhancing hypoxia inducible factor 1 α protein stability.

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases associated with a high rate of mortality. Frequent intrahepatic spread, extrahepatic metastasis, and tumor invasiveness are the main factors responsible for the poor prognosis of patients with HCC. Hypoxia-inducible factor 1 (HIF-1) has been verified to play a critical role in the metastasis of HCC. HIFs are also known to be modulated by small molecular metabolites, thus highlighting the need to understand the complexity of their cellular regulation in tumor metastasis. In this study, lower expression levels of oxoglutarate dehydrogenase-like (OGDHL) were strongly correlated with aggressive clinicopathologic characteristics, such as metastasis and invasion in three independent cohorts featuring a total of 281 postoperative HCC patients. The aberrant expression of OGDHL reduced cell invasiveness and migration in vitro and HCC metastasis in vivo, whereas the silencing of OGDHL promoted these processes in HCC cells. The pro-metastatic role of OGDHL downregulation is most likely attributed to its upregulation of HIF-1α transactivation activity and the protein stabilization by promoting the accumulation of L-2-HG to prevent the activity of HIF-1α prolyl hydroxylases, which subsequently causes an epithelial-mesenchymal transition process in HCC cells. These results demonstrate that OGDHL is a dominant factor that modulates the metastasis of HCC.

• Authors: Weiqi Dai, Yueyue Li, Weijie Sun, Meng Ji, Renjun Bao, Jianqing Chen, Shuqi Xu, Ying Dai, Yiming Chen, Wenjing Liu, Chao Ge, Wei Sun, Wenhui Mo, Chuanyong Guo, Xuanfu Xu
• Journal: Cancer science (Cancer Sci) Vol. 114 Issue 4 Pg. 1309-1323 (Apr 2023) ISSN: 1349-7006 [Electronic] England
• PMID: 36000493 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• OGDHL protein, human

Topics

• Humans
• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Gene Expression Regulation, Neoplastic
• Hypoxia-Inducible Factor 1 (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Liver Neoplasms (pathology)
• Prognosis
• Protein Stability