OncoTargets and Therapy (2020-05-01)

Circ-OXCT1 Suppresses Gastric Cancer EMT and Metastasis by Attenuating TGF-β Pathway Through the Circ-OXCT1/miR-136/SMAD4 Axis

  • Liu J,
  • Dai X,
  • Guo X,
  • Cheng A,
  • Mac SM,
  • Wang Z

Journal volume & issue
Vol. Volume 13
pp. 3987 – 3998

Abstract

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Jianjun Liu, Xinglong Dai, Xiong Guo, Anqi Cheng, Sandrie Mariella Mac, Ziwei Wang Department of Gastrointestinal Surgery, Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of ChinaCorrespondence: Ziwei Wang Tel +86 13098681910Email [email protected]: Circular RNAs (circRNAs) have been proven to play important roles in tumorigenesis. However, the mechanism by which circRNAs act on gastric cancer (GC) through epithelial-to-mesenchymal transition (EMT) is unclear. In this study, we identified circ-OXCT1 and elucidated its function on EMT in GC.Methods: Tissue circRNA microarray analysis and qRT-PCR were utilized to determine the expression level of circ-OXCT1 in GC. Luciferase reporter assay and FISH were employed to confirm the interaction between circ-OXCT1 and miR-136. CCK-8, cloning formation, transwell, wound healing, nude mice experiment, circ-OXCT1 overexpression and silencing were conducted to elucidate the function of circ-OXCT1 in vivo and in vitro. Western blot and rescue experiment were carried out to evaluate the changes of EMT-related proteins induced by circ-OXCT1 overexpression or silencing.Results: Circ-OXCT1 was downregulated in GC tissues and cell lines. Its expression level was significantly associated with lymph node metastasis, pathologic stage and overall survival rate through clinicopathologic data analysis. Circ-OXCT1 silencing downregulated SMAD4 expression and accordingly regulated expression of E-cadherin, N-cadherin and vimentin through the transforming growth factor-beta (TGF-β)/Smad signaling pathway by a circ-OXCT1/miR-136/SMAD4 axis, resulting in enhancement of EMT and subsequent boost of cell migration, invasion and nude mice lung metastasis.Conclusion: Our data showed that circ-OXCT1 suppresses gastric cancer EMT and metastasis through TGF-β/Smad signaling pathway. The clinicopathologic data analysis revealed that circ-OXCT1 overexpression could be a novel treatment for advanced GC especially with distant metastasis by targeting the circ-OXCT1/miR-136/SMAD4 axis.Keywords: gastric cancer, GC, circ-OXCT1, miR-136, SMAD4, EMT

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