RESUMO
OBJECTIVE: In this study, we aimed to investigate the underlying mechanisms of MGP downregulation in chemoresistant ER+ breast cancer cells and its association with survival outcomes in breast cancer patients. MATERIALS AND METHODS: Microarray data of dysregulated genes in chemoresistant ER+ breast cancer cells were searched in GEO datasets. MGP expression in breast cancer patients and its DNA methylation status were analyzed in TCGA database. MGP promoter methylation was assessed using Methylation-Specific PCR (MSP) assay. The association between MGP expression and survival outcomes in different sub-types of breast cancer patients after systemic therapy was analyzed by data mining in Kaplan Meier plotter and in Breast Cancer Gene-Expression Miner Version 4.0 (bc-GenExMiner 4.0). RESULTS: MGP is significantly downregulated in MCF-7/ADR cells compared to the parental MCF-7 cells. MCF-7/ADR cells had a significantly higher level of methylation in MGP promoter than MCF-7 cells. Demethylation treatment significantly restored MGP expression at both mRNA and protein levels. High MGP expression is associated with better relapse-free survival (RFS) in luminal A and luminal B breast cancer patients, but the association was not observed in HER2+ and basal-like subtype breast cancer patients. High MGP expression was associated with significantly lower risk of any event (AE) and also lower risk of metastatic relapse (MR). Survival curve showed that high MGP expression was associated to both better AE-free survival and MR-free survival. CONCLUSIONS: MGP is downregulated due to promoter hypermethylation in chemoresistant ER+ breast cancer cells. High MGP expression may predict better survival outcomes among ER+ breast cancer patients.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Metilação de DNA , Proteínas da Matriz Extracelular/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Bases de Dados Factuais , Intervalo Livre de Doença , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Recidiva Local de Neoplasia , Regiões Promotoras Genéticas , Receptores de Estrogênio/metabolismo , Proteína de Matriz GlaRESUMO
OBJECTIVE: Long non coding RNA (LncRNA) urothelial carcinoma-associated 1 (UCA1) is an oncogene in breast cancer. However, the detailed mechanism has not been fully revealed. This study explored whether UCA1 can directly interact with miR-143, a tumor suppressor in breast cancer and whether the UCA1-miR-143 axis is involved in regulation of cancer cell growth and apoptosis. PATIENTS AND METHODS: miRNA microarray was performed to identify the most dysregulated miRNAs between tumor and adjacent normal tissues of breast cancer. QRT-PCR analysis was performed to assess the expression of UCA1 and miR-143. The binding between UCA1 and miR-143 was verified using dual luciferase and RNA binding protein immunoprecipitation (RIP) assay. MTT assay and flow cytometry analysis were performed to study the role of UCA1-miR-143 axis in cell proliferation, cell cycle and apoptosis. RESULTS: UC1 was significantly upregulated, while miR-143 was significantly downregulated in the tumor tissues than in the adjacent normal tissues. There are direct interactions between miR-143 and the miRNA recognition sites of UCA1. UCA1 is present in Ago2-containing RNA-induced silencing complex (RISC), through association with miR-143. Through downregulating miR-143, UCA1 can modulate breast cancer cell growth and apoptosis. CONCLUSIONS: UCA1 can directly interact with miR-143, lower its expression and affect its downstream regulation. Therefore, the UCA1-miR-143 axis constitutes a part of the oncogenic role of UCA1 in breast cancer.