Extracellular vesicle mir-200c enhances gefitinib sensitivity in heterogeneous egfr-mutant nsclc

Chien Chung Lin, Chin You Wu, Joseph Ta Chien Tseng, Chun Hua Hung, Shang Yin Wu, Yu Ting Huang, Wei Yuan Chang, Po Lan Su, Wu Chou Su

研究成果: Article同行評審

6 引文 斯高帕斯(Scopus)

摘要

Intratumoral heterogeneity in epidermal growth factor receptor (EGFR)-mutant mutant non-small-cell lung cancer (NSCLC) explains the mixed responses to EGFR-tyrosine kinase in-hibitors (TKIs). However, some studies showed tumors with low abundances of EGFR mutation still respond to EGFR-TKI, and the mechanism remained undetermined. Extracellular vesicles (EVs) can transmit antiapoptotic signals between drug-resistant and drug-sensitive cells. Herein, we pro-filed EVs from EGFR-mutant cells to identify a novel mechanism explaining why heterogenous EGFR-mutant NSCLC patients still respond to EGFR-TKIs. We first demonstrated that the EVs from EGFR-mutant changes the wild-type cells’ sensitivity to gefitinib by adding EV directly or coculturing EGFR wild-type (CL1-5) cells and EGFR-mutant (PC9) cells. In animal studies, only the combined treatment of PC9 EV and gefitinib delayed the tumor growth of CL1-5 cells. MicroRNA analysis comparing EV miRNAs from PC9 cells to those from CL1-5 cells showed that mir200 family members are most abundant in PC9 EVs. Furthermore, mir200a and mir200c were found upregulated in plasma EVs from good responders to EGFR-TKIs. Finally, the transfection of CL1-5 cells with miR200c inactivates downstream signaling pathways of EGFR, the EMT pathway, and enhances gefi-tinib sensitivity. Overall, our results suggest that in heterogeneous EGFR-mutant NSCLC, tumor cells transmit EV miRNAs that may affect sensitivity to EGFR-TKIs and provide potential prognostic biomarkers for EGFR-mutant NSCLC.

原文English
文章編號243
期刊Biomedicines
9
發行號3
DOIs
出版狀態Published - 2021 3月

All Science Journal Classification (ASJC) codes

  • 醫藥(雜項)
  • 一般生物化學,遺傳學和分子生物學

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