Nicotine‑induced miR‑21‑3p promotes chemoresistance in lung cancer by negatively regulating FOXO3a

Zhang,Yong-Qing; Chen,Rui-Lin; Shang,Li-Qun; Yang,Shu-Mei

doi:10.3892/ol.2022.13380

Nicotine‑induced miR‑21‑3p promotes chemoresistance in lung cancer by negatively regulating FOXO3a

Authors:
- Yong-Qing Zhang
- Rui-Lin Chen
- Li-Qun Shang
- Shu-Mei Yang
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Affiliations: Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
Published online on: June 14, 2022 https://doi.org/10.3892/ol.2022.13380
Article Number: 260
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer is the leading cause of cancer‑related mortality worldwide and cigarette smoking is reported to contribute to the lung cancer‑related mortality. The present study aimed to investigate the molecular mechanism underlying nicotine‑induced chemoresistance in lung cancer. The expression of microRNA (miR)‑21‑3p and its predicted target FOXO3a in lung cancer cells was detected via reverse transcription‑quantitative PCR, in the presence or absence of nicotine. The regulatory effect of miR‑21‑3p and FOXO3a on lung cancer cell proliferation and apoptosis induced by docetaxel or cisplatin treatment was evaluated by performing Cell Counting Kit‑8 and Annexin V/PI staining assays, respectively. The interaction between miR‑21‑3p and FOXO3a was analyzed by performing luciferase reporter assays and western blotting. FOXO3a overexpression rescue experiments were conducted in vitro and in vivo using a xenograft mouse model to assess the function of miR‑21‑3p/FOXO3a in lung cancer. Nicotine induced miR‑21‑3p expression in lung cancer cells in a dose‑dependent manner. miR‑21‑3p downregulated FOXO3a expression by directly binding to the 3'‑untranslated region of FOXO3a. Moreover, miR‑21‑3p knockdown sensitized lung cancer cells to docetaxel or cisplatin treatment. Mechanistically, FOXO3a was predicted as a direct target of miR‑21‑3p. FOXO3a overexpression promoted the chemosensitivity of lung cancer cells to docetaxel or cisplatin treatment. Furthermore, FOXO3a overexpression antagonized the regulatory function of miR‑21‑3p on docetaxel‑ or cisplatin‑treated lung cancer cells. In the docetaxel‑ or cisplatin‑treated lung cancer xenograft mouse model, miR‑21‑3p promoted chemoresistance via negatively regulating FOXO3a. Therefore, the present study demonstrated that nicotine‑induced miR‑21‑3p promoted chemoresistance to docetaxel or cisplatin treatment via negatively regulating FOXO3a, which may serve as a novel therapeutic strategy for the treatment of patients with chemoresistant lung cancer.

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