Suppression of HELLS by miR-451a represses mTOR pathway to hinder aggressiveness of SCLC

Abstract

Background

Uncovering molecular pathogenesis and mechanisms of small cell lung cancer (SCLC) will contribute to SCLC therapy. Multiple studies demonstrated that miR-451a acts as an anti-tumor miRNA in non-small cell lung cancer. However, the mechanism of miR-451a in SCLC was ambiguous.

Objective

We aimed to explore the function of miR-451a in SCLC and decipher the underlying mechanisms.

Methods

TargetScan and dual-luciferase reporter assays were used to analyze the target genes of miR-451a. Cell counting kit-8 and colony formation assays were performed to assess the roles of miR-451a on cell growth. Gene set enrichment analysis (GSEA) was utilized to enrich biological pathways. Western blot was used to measure protein expression.

Results

MiR-451a expression was reduced dramatically in SCLC tissues and cell lines (NCI-H1688 and NCI-H446). Helicase, Lymphoid Specific (HELLS) was proved to be a target gene of miR-451a. In addition, cell proliferation assays in SCLC cells transfected with miR-451a mimic and/or HELLS revealed that miR-451a inhibited cell proliferation via targeting HELLS. Moreover, the roles of miR-451a/HELLS in expression of key proteins in mTOR and apoptosis signaling pathways suggested that miR-451a inactivated mTOR and activated apoptosis signaling pathway via directly silencing HELLS.

Conclusions

Our study indicated that miR-451a hinders SCLC cell proliferation in vitro through regulating mTOR and apoptosis signaling pathways via silencing HELLS, suggesting that miR-451a could be a promising tumor suppressor in SCLC. And there is a potential for miR-451a to be a drug target and biomarker for SCLC.

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Conceptualization: Jiyun Cui and Dianjie Lin; Methodology: Jiyun Cui and Jing Wang; Formal analysis and investigation: Yuyao Shen; Writing - original draft preparation: Jiyun Cui, Jing Wang and Yuyao Shen; Writing - review and editing: Dianjie Lin; Approval of the manuscript: All authors.

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Correspondence to Dianjie Lin.

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Jiyun Cui, Jing Wang, Yuyao Shen and Dianjie Lin declare that they have no conflict of interest.

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Cui, J., Wang, J., Shen, Y. et al. Suppression of HELLS by miR-451a represses mTOR pathway to hinder aggressiveness of SCLC. Genes Genom 43, 105–114 (2021). https://doi.org/10.1007/s13258-020-01028-1

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Keywords

  • Small cell lung cancer
  • miR-451a
  • Prognostic biomarker
  • Tumor suppressor