Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis

Long noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2 alpha accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2 alpha. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2 alpha protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2 alpha bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2 alpha specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2 alpha positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

Automated summary

In this study, the oncogenic lncRNA PVT1 was found to promote the development of ccRCC by stabilizing HIF2 alpha, forming a positive feedback loop. High expression of PVT1 was associated with poor prognosis in ccRCC patients, and PVT1 enhanced cell proliferation, migration, invasion, and tumor angiogenesis. The interaction between PVT1 and HIF2 alpha played a key role in tumorigenesis and progression of ccRCC.