MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway.
Gefitinib is a first line anti-tumor drug used for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, the drug resistance to gefitinib limits its clinical application. Here, we observed the CSCs of PC9 are obviously resistant to gefitinib compared with the non-CSCs. Furthermore, we found the gefitinib failed to suppress the PI3K/AKT pathway in the PC9-CSCs. Mechanically, we showed significant down-regulation of miR-128 in the PC9-CSCs compared with the non-CSCs. Overexpression of miR-128 significantly increased the sensitivity of PC9-CSCs to gefitinib-induced apoptosis. In addition, the gene of c-met was proved to be directly inhibited by miR-128. Enforced expression of c-met could "rescue" the miR-128 promoted apoptosis and cleavage of caspases in PC9-CSCs treated with gefitinib. Thus, these results indicate that the miR-128/c-met pathway enhances the gefitinib sensitivity of the lung cancer stem cells by suppressing the PI3K/AKT pathway.
Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Jingjin
J
Jiang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Xiaoning
X
Feng
Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Wenjing
W
Zhou
Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Yue
Y
Wu
Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Yunmei
Y
Yang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
PC9-CSCs; PI3K/AKT; c-met; gefitinib; miR-128
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