title: Depletion of intermediate filament protein Nestin, a target of microRNA-940, suppresses tumorigenesis by inducing spontaneous DNA damage accumulation in human nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is a major malignant tumor of the head and neck region in southern China. The understanding of its underlying etiology is essential for the development of novel effective therapies. We report for the first time that microRNA-940 (miR-940) significantly suppresses the proliferation of a variety of cancer cell lines, arrests cells cycle, induces caspase-3/7-dependent apoptosis and inhibits the formation of NPC xenograft tumors in mice. We further show that miR-940 directly binds to the 3'-untranslated regions of Nestin mRNA and promotes its degradation. Likewise, depletion of Nestin inhibits tumor cell proliferation, arrest cells at G2/M, induces apoptosis and suppresses xenograft tumor formation in vivo. These functions of miR-940 can be reversed by ectopic expression of Nestin, suggesting that miR-940 regulates cell proliferation and survival through Nestin. Notably, we observed reduced miR-940 and increased Nestin levels in NPC patient samples. Protein microarray revealed that knockdown of Nestin in 5-8F NPC cells alters the phosphorylation of proteins involved in the DNA damage response, suggesting a mechanism for the miR-940/Nestin axis. Consistently, depletion of Nestin induced spontaneous DNA damage accumulation, delayed the DNA damage repair process and increased the sensitivity to irradiation and the chemotherapeutic agent doxorubicin. Collectively, our findings indicate that Nestin, which is downregulated by miR-940, can promote tumorigenesis in NPC cells through involvement in the DNA damage response. The levels of microRNA-940 and Nestin may serve as indicators of cancer status and prognosis.
authors.affiliation: 1] Institute of Genetic Engineering, Jinan University, National Engineering Research Center of Genetic Medicine, Key Lab for Genetic Medicine of Guangdong Province, Guangzhou, People's Republic of China [2] Central Laboratory, Shanghai 10th People's Hospital of Tongji University, Shanghai, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Medical Laboratory, Shanghai 10th People's Hospital of Tongji University, Shanghai, People's Republic of China.
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.affiliation: Central Laboratory, Shanghai 10th People's Hospital of Tongji University, Shanghai, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Shanghai 10th People's Hospital of Tongji University, Shanghai, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Central Laboratory, Shanghai 10th People's Hospital of Tongji University, Shanghai, People's Republic of China.
authors.forename: Q
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: G
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Yao
authors.affiliation: Institute of Genetic Engineering, Jinan University, National Engineering Research Center of Genetic Medicine, Key Lab for Genetic Medicine of Guangdong Province, Guangzhou, People's Republic of China.
authors.forename: A
authors.initials: A
authors.lastname: Hong
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: An
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005720:Gamma Rays; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D064231:Nestin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; C000594732:MIRN940 microRNA, human; D035683:MicroRNAs; D064231:Nestin; D004317:Doxorubicin