Tumor suppressor microRNA-204-5p regulates growth, metastasis, and immune microenvironment remodeling in breast cancer
Menée à l'aide de lignées cellulaires de cancer mammaire et à l'aide de modèles murins, cette étude démontre que le micro-ARN miR-204-5p, un suppresseur de tumeur, régule la croissance tumorale, le processus métastatique et le remodelage du micro-environnement immunitaire
Various microRNAs (miRNAs) play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared to normal breast tissues, and its expression levels were associated with increased survival outcome in breast cancer patients. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. Additionally, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of breast cancer patients showed a non-linear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anti-cancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. Additionally, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cell-autonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis.
Cancer Research 2019