DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer

• DOI: 10.1186/s13148-024-01663-5
• Publication Date: 2024-04-15T17:01:40Z
• Authors: Qing Yuan; Rubo Wang; Xiang Li; Fei Sun; Jiazhi Lin; Zhimin Fu; Jiansong Zhang
• Keywords: 0301 basic medicine; Lung Neoplasms; Cancer stem cells; Research; R; DNA Methyltransferase 1; QH426-470; DNA Methylation; Gene Expression Regulation, Neoplastic; MicroRNAs; 03 medical and health sciences; Non-small cell lung cancer; Cell Movement; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; miR-152-3p; Genetics; Neoplastic Stem Cells; Medicine; Humans; SOS1; Cell Proliferation

Abstract Background CSLCs(Cancer stem cell-like cells), which are central to tumorigenesis, are intrinsically influenced by epigenetic modifications. This study aimed to elucidate the underlying mechanism involving the DNMT1/miR-152-3p/SOS1 axis in regulating the self-renewal and tumor growth of LCSLCs (lung cancer stem-like cells).

Materials and methods Target genes of miR-152-3p were predicted using TargetScan Human 8.0. Self-renewal and tumor growth of LCSLC were compared in suspension-cultured non-small cell lung cancer (NSCLC) cell lines H460 and A549 cell-derived globe cells. Functional effects of the DNMT1/miR-152-3p/SOS1 axis were assessed through gain-of-function experiments in vitro and in vivo. Additionally, luciferase reporter assays were employed to analyze the interaction among DNMT1, miR-152-3p, and SOS1.

Results Our findings highlight a negative interaction between DNMT1 and miR-152-3p, resulting in reduced miR-152-3p level. This, in turn, leads to the alleviation of the inhibitory effect of miR-152-3p on the target gene SOS1, ultimately activating SOS1 and playing an essential role in self-renewal and tumor growth of LCSLC. However, the alteration of SOS1 does not affect DNMT1/miR-152-3p regulation. Therefore, it is reasonable to infer that the DNMT1/miR-152-3p negative feedback loop critically sustains self-renewal and tumor growth of LCSLC through SOS1.

Conclusions This study reveals a novel mechanism underpinning self-renewal and tumor growth of CSLC (cancer stem cell) in NSCLC and identifies potential therapeutic targets for NSCLC treatment.