RESUMO
Radioresistance of tumor cells gives rise to local recurrence and disease progression in many patients. MicroRNAs (miRNAs) are master regulators of gene expression that control oncogenic pathways to modulate the radiotherapy response of cells. In the present study, differential expression profiling assays identified 16 deregulated miRNAs in acquired radioresistant breast cancer cells, of which miR-122 was observed to be up-regulated. Functional analysis revealed that miR-122 has a role as a tumor suppressor in parental cells by decreasing survival and promoting radiosensitivity. However, in radioresistant cells, miR-122 functions as an oncomiR by promoting survival. The transcriptomic landscape resulting from knockdown of miR-122 in radioresistant cells showed modulation of the ZNF611, ZNF304, RIPK1, HRAS, DUSP8 and TNFRSF21 genes. Moreover, miR-122 and the set of affected genes were prognostic factors in breast cancer patients treated with radiotherapy. Our data indicate that up-regulation of miR-122 promotes cell survival in acquired radioresistant breast cancer and also suggest that miR-122 differentially controls the response to radiotherapy by a dual function as a tumor suppressor an and oncomiR dependent on cell phenotype.
Assuntos
Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Genes Supressores de Tumor , MicroRNAs/biossíntese , RNA Neoplásico/biossíntese , Tolerância a Radiação , Regulação para Cima/efeitos da radiação , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Feminino , Humanos , Células MCF-7 , MicroRNAs/genética , Proteínas de Neoplasias , RNA Neoplásico/genéticaRESUMO
Cervical cancer (CC) is one of the most common cancers diagnosed in women worldwide, and it is estimated that ~500,000 new patients are diagnosed with cervical cancer annually and that ~270,000 deaths occur each year. Patients with cervical cancer are treated with different radiotherapy schedules, either alone or with adjuvant chemotherapy. Unfortunately, nearly 50% of all patients with cervical cancer do not respond to standard treatment due to tumor radioresistance. In this scenario, several microRNAs (miRNAs) have been associated with the acquisition of the radioresistance phenotype. The aim of the present study was to evaluate the possible role of miR125a in the acquisition of radioresistance in cervical cancer. The expression of miR125a was assessed by means of RTqPCR in 30 cervical cancer samples from patients receiving standard treatment and 3 induced radioresistant cervical cancer cell lines. In addition, we employed miR125a mimics and inhibitors to evaluate its function in the induction of radioresistance. We showed that miR125a was downregulated in patients with cervical cancer who did not respond to standard treatment. Concordantly, radioresistant SiHa, CaSki and HeLa cell lines had low levels of miR125a with respect to the sensitive cell lines. Finally, we demonstrated that overexpression of miR125a sensitized cervical cancer cells to radiation therapy through the downregulation of CDKN1A. Our data corroborate previously published studies in which it was demonstrated that miRNAs could play a role in the regulation of the process of radioresistance. Additionally, we showed that overexpression of miR125a could be used as a radioresistance biomarker in patients with cervical cancer.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Tolerância a Radiação/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Células HeLa , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/metabolismoRESUMO
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.
