title: Hypoxia-induced miR-424 decreases tumor sensitivity to chemotherapy by inhibiting apoptosis.
abstract: Chemotherapy resistance of tumor cells is a big challenge. Adaption to hypoxia is an essential cellular response that is controlled by the master oxygen-sensitive transcription factor HIF1 (hypoxia-inducible factor 1). The mechanism by which tumor cells acquire resistance to chemotherapy under hypoxic conditions is not fully understood. In this study, we found that hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 enhanced apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples. These results suggest that miR-424 is a potential molecular target for tumor therapy.
authors: 1] Department of Biochemistry & Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China [2] Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors: D
authors: D
authors: Zhang
authors: Department of Biochemistry & Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Z
authors: Z
authors: Shi
authors: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors: M
authors: M
authors: Li
authors: Department of Biochemistry & Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: J
authors: J
authors: Mi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C554214:MIRN424 microrna, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; D005047:Etoposide; D004317:Doxorubicin