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

Abstract

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 HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. 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 HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

Downregulation of lncRNA APCDD1L-AS1 due to DNA hypermethylation and loss of VHL protein expression promotes the progression of clear cell renal cell carcinoma

“…NICI was highly expressed in ccRCC, and its expression could be regulated by VHL 34 . PVT1 interacted with HIF2α protein to enhance its stability by protecting it from ubiquitin-dependent degradation, thereby contributing to the development and metastasis of ccRCC 16 . During this study, our result determined that overexpression of VHL upregulated the expression of APCDDL-AS1 and knockdown of VHL inhibited APCDD1L-AS1 expression.…”

“…Moreover, lncRNAs also play important roles in the development of ccRCC. For example, ZNF582-AS1 restrained the growth and metastasis of ccRCC by regulating the N(6)-methyladenosine modification of MT-RNR1 15 , and PVT1 promoted the tumorigenesis and metastasis of ccRCC by stabilizing HIF2α 16 . APCDD1L-AS1 was a novel lncRNA and located at Chromosome 20: 58,515,379-58,619,888.…”

A Computationally Constructed lncRNA-Associated Competing Triplet Network in Clear Cell Renal Cell Carcinoma

“…Furthermore, we also verified lncRNA PVT1 to be an oncogenic lncRNA in ccRCC. It has been reported that ccRCC has the strongest upregulated expression of PVT1 among all cancer types and served as a prognostic factor of renal cancer [ 42 , 43 ].…”

lncRNA PVT1: a novel oncogene in multiple cancers

“…Recently, Zhang et al. [ 175 ] found that HIF-2α promotes PVT1 expression by binding to the PVT1 enhancer; similarly, PVT1 can protect HIF-2α from ubiquitin-dependent degradation. This PVT1/HIF-2α loop promotes tumorigenesis and metastasis in RCC (Fig.…”