The EXO1/Polη/Polι axis as a promising target for miR-3163-mediated attenuation of cancer stem-like cells in non-small cell lung carcinoma.

Autor: Mandal T; Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Shukla D; Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India., Khan MMA; Structural Biology & Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India., Ganesan SK; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.; Structural Biology & Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India., Srivastava AK; Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, WB, India. amit@iicb.res.in.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. amit@iicb.res.in.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2024 Nov; Vol. 131 (10), pp. 1668-1682. Date of Electronic Publication: 2024 Oct 05.
DOI: 10.1038/s41416-024-02840-2
Abstrakt: Background: Cancer stem-like cells (CSLCs) drive tumour progression and chemoresistance. The concerted efforts of EXO1 and TLS polymerases safeguard DNA integrity against chemotherapeutic drugs. In absence of potential drug targets, non-small cell lung carcinoma (NSCLC) patients have few therapeutic options. In current scenario, microRNAs offer a potential avenue for eradicating CSLCs.
Methods: EXO1 downregulation impact on CSLCs expansion was assessed via flow cytometry. Co-localisation of EXO1, Polη and Polι was validated through co-immunoprecipitation and confocal-imaging. The effects of co-downregulation of Polη and Polι on CSLC survival, repair synthesis, and mutagenesis were evaluated using flow cytometry and immunohistochemistry in cell lines and xenografts. MicroRNA targeting EXO1 was studied for its role in CSLCs regulation.
Results: EXO1 downregulation in NSCLC CSLCs induces DNA lesions, triggering apoptosis and enhances cisplatin sensitivity. It collaborates with Polη and Polι in DNA repair, contributing to cisplatin resistance in CSLCs. Absence of Polη and Polι impairs repair and reduces cisplatin-induced mutagenesis. Co-downregulation of Polη and Polι in xenografts reduces tumour proliferation significantly. MiR-3163 overexpression sensitises CSLCs to cisplatin via targeting EXO1/Polη/Polι axis, as shown in mechanistic studies.
Conclusion: This study unveils a novel regulatory pathway involving EXO1/Polη/Polι axis and miR-3163, providing insights into CSLCs regulation in NSCLC. EXO1/Polη/Polι axis targeted by miR-3163, resulting in the inhibition of cell growth and induction of apoptosis in NSCLC CSLCs.
Competing Interests: Competing interests The authors declare no competing interests. Ethical approval All animal protocols were approved by the CSIR-IICB-Animal ethics committee (IICB/AEC/Meeting/July/2020/1). All methods are reported following the ARRIVE guidelines (https://arriveguidelines.org) for animal experiment reporting, with ethics approval.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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