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. 2022 Oct;92(4):1008-1016.
doi: 10.1038/s41390-021-01860-5. Epub 2022 Jan 28.

Circ-ITCH overexpression promoted cell proliferation and migration in Hirschsprung disease through miR-146b-5p/RET axis

Ren-Peng Xia  1 , Fan Zhao  1 , Ti-Dong Ma  1 , Chan-Juan Zou  1 , Guang Xu  1 , Chong-Gao Zhou  2
Affiliations

Circ-ITCH overexpression promoted cell proliferation and migration in Hirschsprung disease through miR-146b-5p/RET axis

Ren-Peng Xia et al. Pediatr Res. 2022 Oct.

Abstract

Background: Hirschsprung disease (HSCR) is a congenital intestinal disease caused by the abnormal proliferation and migration of enteric nerve cells (ENCC). Research suggested critical roles for circular RNA (circRNA) itchy E3 ubiquitin protein ligase (ITCH) in gastrointestinal malignancies progression. However, the function of circ-ITCH in HSCR remains poorly defined.

Methods: The related genes expression in 30 HSCR patients and 30 controls without HSCR were detected using qRT-PCR. Cell proliferation was assessed by CCK-8 assay and EdU assay. Cell migration was detected with wound-healing assay and transwell assay. The interactions among circ-ITCH, miR-146b-5p, and RET were confirmed by Dual luciferase reporter assay.

Results: Circ-ITCH and RET expressions were downregulated in HSCR patients and cells, while the miR-146b-5p expression was upregulated. Circ-ITCH overexpression facilitated cell proliferation, migration, and activated MAPK pathway, which were reversed by circRNA-ITCH knockdown. Circ-ITCH negatively regulated miR-146b-5p expression. MiR-146b-5p overexpression abolished the promoting effects of circ-ITCH overexpression on cell proliferation and migration. MiR-146b-5p inhibited RET expression. RET overexpression eliminated the inhibitory effects of miR-146b-5p overexpression on cell proliferation and migration.

Conclusion: Circ-ITCH overexpression facilitated cell proliferation and migration in HSCR by regulating miR-146b-5p/RET/MAPK axis.

Impact: The expressions of Circ-ITCH and RET were markedly reduced in HSCR, while miR-146b-5p expression was increased in HSCR. Circ-ITCH overexpression enhanced the proliferative and migratory abilities of SH-SY5Y and 293T cells. Circ-ITCH negatively regulated miR-146b-5p expression.

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