HIF-1α/LAPTM5/STAT1 axis promotes the malignant progression of clear cell renal cell carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cell carcinoma with poor prognosis and high mortality. Mutation-mediated inactivation of Von Hippel Lindau (VHL) is a hallmark feature of ccRCC, and it leads to the accumulation of hypoxia-inducible factors (HIFs) and cancer progression. Therefore, further elucidation of the network that regulates the VHL/HIF-1α pathway will provide potential therapeutic targets for the treatment of ccRCC. The results of the current study demonstrated that lysosomal-associated protein transmembrane 5 (LAPTM5) is a novel transcriptional target of HIF-1α and that HIF-1α positively regulates the expression of LAPTM5 in ccRCC cells. Furthermore, the maximum overexpression of LAPTM5 in ccRCC tissues compared with corresponding normal tissues was observed in the pan-cancer analysis. In addition, LAPTM5 overexpression was closely related to metastasis and poor outcomes in ccRCC patients. In addition, LAPTM5 promoted the proliferation, migration and invasion of ccRCC cells. Mechanistically, LAPTM5 regulated the K63-linked ubiquitination of STAT1, enhanced the interaction between STAT1 and JAK2, and induced the phosphorylation of STAT1 at Y701, ultimately promoting the progression of ccRCC. This study reveals a novel HIF-1α/LAPTM5/STAT1 signalling pathway that promotes ccRCC progression and provides potential therapeutic strategies for the treatment of ccRCC.