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CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3

Authors
  • Yang, Lei1, 1
  • Chen, Yi1, 1
  • Liu, Ning1, 1
  • Lu, Yanwen1, 1
  • Ma, Wenliang1, 1
  • Yang, Zhenhao2
  • Gan, Weidong3
  • Li, Dongmei1, 1
  • 1 Nanjing University, Nanjing, Jiangsu, 210093, China , Nanjing (China)
  • 2 Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210008, China , Nanjing (China)
  • 3 The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210008, China , Nanjing (China)
Type
Published Article
Journal
Molecular Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jan 18, 2022
Volume
21
Issue
1
Identifiers
DOI: 10.1186/s12943-022-01497-w
Source
Springer Nature
Keywords
Disciplines
  • Research
License
Green

Abstract

BackgroundFunctions of CircMET (hsa_circ_0082002) which is a circular RNA and derived from MET gene remain understood incompletely. In the present study, Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (NONO-TFE3 tRCC) with up-regulated CircMET was employed to investigate its mechanism in cancer progression and post-transcriptional regulation.MethodsFISH and real-time PCR were performed to explore the expression and localization circMET in NONO-TFE3 tRCC tissues and cells. The functions of circMET in tRCC were investigated by proliferation analysis, EdU staining, colony and sphere formation assay. The regulatory mechanisms among circMET, CDKN2A and SMAD3 were investigated by luciferase assay, RNA immunoprecipitation, RNA pulldown and targeted RNA demethylation system.ResultsThe expression of circMET was upregulated by NONO-TFE3 fusion in NONO-TFE3 tRCC tissues and cells, and overexpression of circMET significantly promoted the growth of NONO-TFE3 tRCC. Mechanistic studies revealed that circMET was delivered to cytosol by YTHDC1 in N6-methyladenosine (m6A)-depend manner. CircMET enhances mRNA decay of CDKN2A by direct interaction and recruitment of YTHDF2. Meanwhile, circMET competitively absorbed miR-1197 and prevented those from SMAD3 mRNA.ConclusionsCircMET promotes the development of NONO-TFE3 tRCC, and the regulation to both CDKN2A and SMAD3 of circMET was revealed. CircMET has the potential to serve as a novel target for the molecular therapy of NONO-TFE3 tRCC as well as the other cancer with high-expressing circMET.

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