title: miR-200c enhances sensitivity of drug-resistant non-small cell lung cancer to gefitinib by suppression of PI3K/Akt signaling pathway and inhibites cell migration via targeting ZEB1.
abstract: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. We explored the role of miR-200c in modulating the sensitivity of gefitinib-resistant NSCLC cells and examined the underlying mechanism. The gefitinib-resistant cell line PC-9-ZD and its parental PC-9 cells were used. Growth inhibition was detected by MTT assay. The cell apoptosis was detected by Annexin V/PI assay. Cell migration was assessed by wound-healing assay. RT-PCR was used to detected levels of miR-200c and ZEB1. The PI3k, Bcl-2, Bax, caspase-3 and ZEB1 protein expression were detected using Western blot analysis, and TUNEL, Immunohistochemistry for xenograft model. PC-9-ZD cells had low level of miR-200c expression compared to its parental PC-9 cells. PC-9-ZD cells with miR-200c transfection were more sensitive to gefitinib treatment. Apoptosis induced by gefitinib was observed in PC-9-ZD cells with miR-200c transfection significantly. The levels of phosphorylated-Akt and Bcl-2 expression decreased and levels of Bax and Caspase-3 expression increased in PC-9-ZD cells with miR-200c transfection. Cell migration was inhibited and ZEB1 mRNA level and protein expression were significantly decreased in PC-9-ZD cells with miR-200c transfection. Further in gefitinib resistant xenograft model, miR-200c enhanced sensitivity of gefitinib and induced apoptosis significantly through PI3K/Akt signaling pathway and targeting ZEB1. These results provided insights into the functions of miR-200c and offered an alternate approach in treating gefitinib-resistance NSCLC.
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Fangli
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Shuanglei
authors.initials: S
authors.lastname: Yue
authors.affiliation: Department of Oncology, Anji People's Hospital, Anji, Zhejiang 313399, PR China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Oncology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Hematology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, PR China. Electronic address: 522237197@qq.com.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011799:Quinazolines; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
keywords: Drug-resistance; NSCLC; PI3K; miR-200c