Pseudogene KRT17P3 drives cisplatin resistance of human NSCLC cells by modulating miR‐497‐5p/mTOR

• Published in: Cancer science Vol. 112; no. 1; pp. 275 - 286
• Main Authors: Hou, Zhibo, Wang, Yi, Xia, Ning, Lv, Tangfeng, Yuan, Xiaoqin, Song, Yong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.01.2021; John Wiley and Sons Inc
• Subjects: Aged; Animals; Apoptosis; Bioinformatics; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell viability; Cell, Molecular, and Stem Cell Biology; Chemoresistance; Chemotherapy; Chromosome 5; Cisplatin; Cisplatin - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - genetics; Female; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Heterografts; Humans; Immunoprecipitation; Keratin; Keratin-17 - genetics; KRT17P3; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Male; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miR‐497‐5p; mTOR; Non-small cell lung carcinoma; non–small‐cell lung cancer; Original; Peripheral blood; Plasma; Plasmids; Polymerase chain reaction; Pseudogenes - genetics; Ribonucleic acid; RNA; Small cell lung carcinoma; Software; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; mTOR; KRT17P3; miR-497-5p; Cisplatin; non-small-cell lung cancer
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14733

Chemoresistance is a major obstacle in non–small cell lung cancer (NSCLC) treatment. The pseudogene keratin 17 pseudogene 3 (KRT17P3) has been previously shown to be upregulated in lung cancer tissues of patients with cisplatin resistance. In the present study, RT‐qPCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin‐resistant and 32 cisplatin‐sensitive patients. We found that the plasma level of KRT17P3 is upregulated in cisplatin‐resistant patients, and the increased expression of plasma KRT17P3 is associated with poor chemotherapy response. Functional studies demonstrated that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment in vitro and in vivo, while KRT17P3 knockdown has the opposite effect. Mechanistically, bioinformatics analysis, RNA immunoprecipitation, and dual luciferase reporter assay indicated that KRT17P3 acts as a molecular sponge for miR‐497‐5p and relieves the binding of miR‐497‐5p to its target gene mTOR. Rescue experiments validated the functional interaction between KRT17P3, miR‐497‐5p, and mTOR. Taken together, our findings indicate that KRT17P3/miR‐497‐5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin‐resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin. In the present study, we found the plasma level of KRT17P3 is upregulated in cisplatin‐resistant patients, and the increased expression of plasma KRT17P3 is associated with poor chemotherapy response. Functional studies demonstrated that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment in vitro and in vivo, while KRT17P3 knockdown has the opposite effect. Mechanistically, KRT17P3 acts as a molecular sponge for miR‐497‐5p and relieves the binding of miR‐497‐5p to its target gene mTOR.