title: miR-222 induces Adriamycin resistance in breast cancer through PTEN/Akt/p27kip1pathway.
abstract: The high resistant rate of Adriamycin (Adr) is associated with a poor prognosis of breast cancer in women worldwide. Since miR-222 might contribute to chemoresistance in many cancer types, in this study, we aimed to investigate its efficacy in breast cancer through PTEN/Akt/p27kip1pathway. Firstly, in vivo, we verified that miR-222 was upregulated in chemoresistant tissues after surgery compared with the paired preneoadjuvant samples of 21 breast cancer patients. Then, human breast cancer Adr-resistant cell line (MCF-7/Adr) was constructed to validate the pathway from the parental sensitive cell line (MCF-7/S). MCF-7/Adr and MCF-7/S were transfected with miR-222 mimics, miR-222 inhibitors, or their negative controls, respectively. The results showed that inhibition of miR-222 in MCF-7/Adr significantly increased the expressions of PTEN and p27kip1and decreased phospho-Akt (p-Akt) both in mRNA and protein levels (p < 0.05) by using quantitative real-time PCR (qRT-PCR) and western blot. MTT and flow cytometry suggested that lower expressed miR-222 enhanced apoptosis and decreased the IC50 of MCF-7/Adr cells. Additionally, immunofluorescence demonstrated that the subcellular location of p27kip1was dislocated resulting from the alteration of miR-222. Conversely, in MCF-7/S transfected with miR-222 mimics, upregulation of miR-222 is associated with decreasing PTEN and p27kip1and increasing Akt accompanied by less apoptosis and higher IC50. Importantly, Adr resistance induced by miR-222 overexpression through PTEN/Akt/p27 was completely blocked by LY294002, an Akt inhibitor. Taken together, these data firstly elucidated that miR-222 could reduce the sensitivity of breast cancer cells to Adr through PTEN/Akt/p27kip1signaling pathway, which provided a potential target to increase the sensitivity to Adr in breast cancer treatment and further improved the prognosis of breast cancer patients.
authors.affiliation: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Shen
authors.affiliation: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Long-Ji
authors.initials: LJ
authors.lastname: Luo
authors.affiliation: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China.
authors.forename: Shan-Liang
authors.initials: SL
authors.lastname: Zhong
authors.affiliation: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China. jsccljhzhao@126.com.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Baiziting 42, Nanjing, 210009, China. jinhangtangjsch@163.com.
authors.forename: Jin-Hai
authors.initials: JH
authors.lastname: Tang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; C436291:CDKN1B protein, human; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Adr resistance; Breast cancer; PTEN/Akt/p27 pathway; miR-222