J Cancer 2020; 11(22):6737-6747. doi:10.7150/jca.48132

Research Paper

Reciprocal regulation of HIF-1α and Uroplakin 1A promotes glycolysis and proliferation in Hepatocellular Carcinoma

Yang Song1,2#, Hui Wang1#, Xue-Jing Zou2, Ya-Xuan Zhang1, Ze-Qin Guo1, Li Liu2, De-Hua Wu1✉, Dong-Yan Zhang1✉

1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, GuangDong Province, 510515, China.
2. Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, GuangDong Province, 510515, China.
#These authors contribute equally to this work.

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Citation:
Song Y, Wang H, Zou XJ, Zhang YX, Guo ZQ, Liu L, Wu DH, Zhang DY. Reciprocal regulation of HIF-1α and Uroplakin 1A promotes glycolysis and proliferation in Hepatocellular Carcinoma. J Cancer 2020; 11(22):6737-6747. doi:10.7150/jca.48132. Available from http://www.jcancer.org/v11p6737.htm

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Abstract

Uroplakin 1A (UPK1A) has recently been found dysregulation in many cancers. However, the functions of UPK1A and its underlying mechanisms in hepatocellular carcinoma (HCC) remain poorly understand. In the present study, we found that UPK1A was highly expressed in HCC tumor tissues compared with adjacent non-tumor tissues. Datasets from the Cancer Genome Atlas project (TCGA) and Gene expression Omnibus confirmed that UPK1A was highly expressed in HCC. High expression of UPK1A predicted poor overall survival (OS) in patients with HCC. Univariate and multivariate analysis showed that UPK1A was a significant and independent prognostic predictor for OS of patients with HCC. Functionally, silencing UPK1A suppressed HCC cell glycolysis and proliferation. Mechanistically, hypoxia-inducible factor 1α (HIF-1α) directly bound to the hypoxia response elements (HRE) of UPK1A promoter region, which led to the up-regulation of UPK1A under hypoxia. Furthermore, downregulation of UPK1A reduced key enzyme of glycolysis via regulating HIF-1α. Taken together, these data indicates the existence of a positive feedback loop between HIF-1α and UPK1A that modulates glycolysis and proliferation under hypoxia in HCC cells.

Keywords: UPK1A, HIF-1α, glycolysis, proliferation, Hepatocellular carcinoma