title: Tumor suppressor miR-29c regulates radioresistance in lung cancer cells.
abstract: Radiotherapy is an important treatment option for non-small cell lung carcinoma patients. Despite the appropriate use of radiotherapy, radioresistance is a biological behavior of cancer cells that limits the efficacy of this treatment. Deregulation of microRNAs contributes to the molecular mechanism underlying resistance to radiotherapy in cancer cells. Although the functional roles of microRNAs have been well described in lung cancer, their functional roles in radioresistance are largely unclear. In this study, we established a non-small cell lung carcinoma Calu-1 radioresistant cell line by continuous exposure to therapeutic doses of ionizing radiation as a model to investigate radioresistance-associated microRNAs. Our data show that 50 microRNAs were differentially expressed in Calu-1 radioresistant cells (16 upregulated and 34 downregulated); furthermore, well-known and novel microRNAs associated with resistance to radiotherapy were identified. Gene ontology and enrichment analysis indicated that modulated microRNAs might regulate signal transduction, cell survival, and apoptosis. Accordingly, Calu-1 radioresistant cells were refractory to radiation by increasing cell survival and reducing the apoptotic response. Among deregulated microRNAs, miR-29c was significantly suppressed. Reestablishment of miR-29c expression in Calu-1 radioresistant cells overcomes the radioresistance through the activation of apoptosis and downregulation of Bcl-2 and Mcl-1 target genes. Analysis of The Cancer Genome Atlas revealed that miR-29c is also suppressed in tumor samples of non-small cell lung carcinoma patients. Notably, we found that low miR-29c levels correlated with shorter relapse-free survival of non-small cell lung carcinoma patients treated with radiotherapy. Together, these results indicate a new role of miR-29c in radioresistance, highlighting their potential as a novel biomarker for outcomes of radiotherapy in lung cancer.
authors.affiliation: 1 Departamento de Ciencias Naturales, Universidad Autonoma Metropolitana, Unidad Cuajimalpa, Mexico City, Mexico.
authors.forename: Elena
authors.initials: E
authors.lastname: Arechaga-Ocampo
authors.affiliation: 2 Posgrado en Ciencias Genomicas, Universidad Autonoma de la Ciudad de Mexico, Mexico City, Mexico.
authors.forename: Cesar
authors.initials: C
authors.lastname: Lopez-Camarillo
authors.affiliation: 3 Departamento de Biomedicina Molecular, Centro de Investigacion y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Villegas-Sepulveda
authors.affiliation: 1 Departamento de Ciencias Naturales, Universidad Autonoma Metropolitana, Unidad Cuajimalpa, Mexico City, Mexico.
authors.forename: Claudia H
authors.initials: CH
authors.lastname: Gonzalez-De la Rosa
authors.affiliation: 1 Departamento de Ciencias Naturales, Universidad Autonoma Metropolitana, Unidad Cuajimalpa, Mexico City, Mexico.
authors.forename: Isidro X
authors.initials: IX
authors.lastname: Perez-Añorve
authors.affiliation: 1 Departamento de Ciencias Naturales, Universidad Autonoma Metropolitana, Unidad Cuajimalpa, Mexico City, Mexico.
authors.forename: Reynalda
authors.initials: R
authors.lastname: Roldan-Perez
authors.affiliation: 2 Posgrado en Ciencias Genomicas, Universidad Autonoma de la Ciudad de Mexico, Mexico City, Mexico.
authors.forename: Ali
authors.initials: A
authors.lastname: Flores-Perez
authors.affiliation: 4 Departamento de Oncología Medica, Instituto Nacional de Cancerologia, Mexico City, Mexico.
authors.forename: Omar
authors.initials: O
authors.lastname: Peña-Curiel
authors.affiliation: 5 Unidad de Radioterapia, Instituto Nacional de Cancerologia, Mexico City, Mexico.
authors.forename: Oscar
authors.initials: O
authors.lastname: Angeles-Zaragoza
authors.affiliation: 6 Laboratorio de Oncologia Celular, UMIEZ, FES Zaragoza, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico.
authors.forename: Rosalva
authors.initials: R
authors.lastname: Rangel Corona
authors.affiliation: 7 Laboratorio de Medicina Genomica, Hospital Regional 1º de Octubre, Mexico City, Mexico.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Gonzalez-Barrios
authors.affiliation: 3 Departamento de Biomedicina Molecular, Centro de Investigacion y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico.
authors.forename: Raul
authors.initials: R
authors.lastname: Bonilla-Moreno
authors.affiliation: 8 Laboratorio de Biomedicina Molecular, Unidad Academica de Ciencias Quimico Biologicas, Universidad Autonoma de Guerrero, Chilpancingo, Mexico.
authors.forename: Oscar
authors.initials: O
authors.lastname: Del Moral-Hernandez
authors.affiliation: 9 Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerologia and Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Herrera
authors.affiliation: 10 Laboratorio de Virus y Cancer, Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerologia and Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Mexico City, Mexico.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garcia-Carranca
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy*; D035683:MicroRNAs / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011836:Radiation Tolerance / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C579095:MCL1 protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: MicroRNAs; biomarkers; lung cancer; radioresistance; radiotherapy