Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis
Open Access
- 28 July 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (37), 5639-5650
- https://doi.org/10.1038/s41388-021-01971-7
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.This publication has 41 references indexed in Scilit:
- Genetic and Functional Studies Implicate HIF1α as a 14q Kidney Cancer Suppressor GeneCancer Discovery, 2011
- Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligaseProceedings of the National Academy of Sciences of the United States of America, 2009
- The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapyKidney International, 2009
- Long non-coding RNAs: insights into functionsNature Reviews Genetics, 2009
- HIF-α Effects on c-Myc Distinguish Two Subtypes of Sporadic VHL-Deficient Clear Cell Renal CarcinomaCancer Cell, 2008
- The role of hypoxia-inducible factors in tumorigenesisCell Death & Differentiation, 2008
- HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional ActivityCancer Cell, 2007
- RACK1 Competes with HSP90 for Binding to HIF-1α and Is Required for O2-Independent and HSP90 Inhibitor-Induced Degradation of HIF-1αMolecular Cell, 2007
- Advanced Renal Cell CarcinomaDrugs, 2007
- Mechanism of regulation of the hypoxia-inducible factor-1alpha by the von Hippel-Lindau tumor suppressor proteinThe EMBO Journal, 2000