miR-204 suppresses cancer stemness and enhances osimertinib sensitivity in non-small cell lung cancer by targeting CD44

Shang-Gin Wu; Tzu-Hua Chang; Meng-Feng Tsai; Yi-Nan Liu; Yen-Lin Huang; Chia-Lang Hsu; Han-Nian Jheng; Jin-Yuan Shih

Molecular Therapy: Nucleic Acids (Mar 2024)

miR-204 suppresses cancer stemness and enhances osimertinib sensitivity in non-small cell lung cancer by targeting CD44

Shang-Gin Wu,
Tzu-Hua Chang,
Meng-Feng Tsai,
Yi-Nan Liu,
Yen-Lin Huang,
Chia-Lang Hsu,
Han-Nian Jheng,
Jin-Yuan Shih

Affiliations

Shang-Gin Wu: Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University, Taipei 10672, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
Tzu-Hua Chang: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
Meng-Feng Tsai: Department of Biomedical Sciences, Da-Yeh University, Changhua 51591, Taiwan
Yi-Nan Liu: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
Yen-Lin Huang: Department of Pathology, National Taiwan University Cancer Center, National Taiwan University, Taipei 10672, Taiwan; Department of Pathology, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
Chia-Lang Hsu: Department of Medical Research, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
Han-Nian Jheng: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
Jin-Yuan Shih: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan; Corresponding author: Jin-Yuan Shih, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan.

Journal volume & issue: Vol. 35, no. 1
p. 102091

Abstract

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Osimertinib is an effective treatment option for patients with advanced non-small cell lung cancer (NSCLC) with EGFR activation or T790M resistance mutations; however, acquired resistance to osimertinib can still develop. This study explored novel miRNA–mRNA regulatory mechanisms that contribute to osimertinib resistance in lung cancer. We found that miR-204 expression in osimertinib-resistant lung cancer cells was markedly reduced compared to that in osimertinib-sensitive parental cells. miR-204 expression levels in cancer cells isolated from treatment-naive pleural effusions were significantly higher than those in cells with acquired resistance to osimertinib. miR-204 enhanced the sensitivity of lung cancer cells to osimertinib and suppressed spheroid formation, migration, and invasion of lung cancer cells. Increased miR-204 expression in osimertinib-resistant cells reversed resistance to osimertinib and enhanced osimertinib-induced apoptosis by upregulating BIM expression levels and activating caspases. Restoration of CD44 (the direct downstream target gene of miR-204) expression reversed the effects of miR-204 on osimertinib sensitivity, recovered cancer stem cell and mesenchymal markers, and suppressed E-cadherin expression. The study demonstrates that miR-204 reduced cancer stemness and epithelial-to-mesenchymal transition, thus overcoming osimertinib resistance in lung cancer by inhibiting the CD44 signaling pathway.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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