Project description:Background. One of the major limitations associated to the platinum use is the resistance that almost invariably will progress in lung and ovarian cancers. In the current study, we sought to identify epigenetically regulated miRNAs as novel biomarkers of platinum-resistance in those tumor types. Methods. We combined transcriptomic data from miRNA and mRNA under the influence of an epigenetic reactivation treatment, followed by qRT-PCR and epigenteic validations for an accurate candidate selection in 23 human cancer cell lines. Functional analysis were performed to study their biological and therapeutic implications, that were further tested in 257 primary samples obtained from lung and ovarian tumors. Results. We identified a group of 9 miRNAs belonging to the CM19 cluster and 7 potential miRNA-targets potentially involved in resistance development, in both tumor types. Deregulation of miR-7, -132, -335 and -148a may be a common event in the development of CDDP-resistance. miR-7 presented specific methylation in the resistant subtypes and its reexpression, decreased cell viability, suggesting a possible cell sensitization to cisplatin. Our translational approach indicated that miR-7 methylation is a frequent event that may play an important role in the early establishment of NSCLC tumorigenesis, and seems to play an additional platinum-predictive role in ovarian cancer. Conclusions. miR-7 is a novel potential epigenetic biomarker tool for the selection of ovarian cancer patients with higher risk to earlier relapse and worst response to platinum-based chemotherapy. Funding. FIS (ISCIII): PI12/00386, PI13/01450, PI15/00186, and FEDER/FSE (Una manera de hacer Europa).
Project description:Background. One of the major limitations associated to the platinum use is the resistance that almost invariably will progress in lung and ovarian cancers. In the current study, we sought to identify epigenetically regulated miRNAs as novel biomarkers of platinum-resistance in those tumor types. Methods. We combined transcriptomic data from miRNA and mRNA under the influence of an epigenetic reactivation treatment, followed by qRT-PCR and epigenteic validations for an accurate candidate selection in 23 human cancer cell lines. Functional analysis were performed to study their biological and therapeutic implications, that were further tested in 257 primary samples obtained from lung and ovarian tumors. Results. We identified a group of 9 miRNAs belonging to the CM19 cluster and 7 potential miRNA-targets potentially involved in resistance development, in both tumor types. Deregulation of miR-7, -132, -335 and -148a may be a common event in the development of CDDP-resistance. miR-7 presented specific methylation in the resistant subtypes and its reexpression, decreased cell viability, suggesting a possible cell sensitization to cisplatin. Our translational approach indicated that miR-7 methylation is a frequent event that may play an important role in the early establishment of NSCLC tumorigenesis, and seems to play an additional platinum-predictive role in ovarian cancer. Conclusions. miR-7 is a novel potential epigenetic biomarker tool for the selection of ovarian cancer patients with higher risk to earlier relapse and worst response to platinum-based chemotherapy. Funding. FIS (ISCIII): PI12/00386, PI13/01450, PI15/00186, and FEDER/FSE (Una manera de hacer Europa).
Project description:To evaluate the ability of epithelial-to-mesenchymal transition-related microRNAs (miRNAs) as serum biomarkers for prognosis and prediction of metastasis in patients with colorectal cancer (CRC).Epithelial-to-mesenchymal transition-related miRNAs drive CRC progression and metastasis. However, their potential as serum biomarkers in CRC has not been studied.This was a 3-phase study using 446 colorectal specimens. In the first phase, we selected candidate miRNAs associated with metastasis by analyzing the expression of 4 miR-200 family members (miR-200b, -200c, -141, and -429) in serum samples from 12 patients with stage I and IV CRC. The second phase involved independent validation of candidate miRNAs in serum from 182 patients with CRC and 24 controls. Finally, we analyzed expression in matched 156 tumor tissues from 182 patients with CRC and an independent set of 20 matched primary CRC and corresponding liver metastases to identify the source of circulating miRNAs.After initial screening, miR-200c was selected as the candidate serum miRNA best associated with metastasis. Validation analysis revealed that serum miR-200c levels were significantly higher in stage IV than in stage I-III CRCs. High serum miR-200c demonstrated a significant positive correlation with lymph node metastasis, distant metastasis, and prognosis (P = 0.0026, P = 0.0023, and P = 0.0064, respectively). More importantly, serum miR-200c was an independent predictor for lymph node metastasis (odds ratio: 4.81, 95% confidence interval: 1.98-11.7, P = 0.0005) and tumor recurrence (hazard ratio: 4.51, 95% confidence interval: 1.56-13.01, P = 0.005) and emerged as an independent prognostic marker for CRC (hazard ratio: 2.67, 95% confidence interval: 1.28-5.67, P = 0.01).Serum miR-200c has strong potential to serve as a noninvasive biomarker for CRC prognosis and predicting metastasis.