Tumor Suppressor miRNA-204-5p Regulates Growth, Metastasis, and Immune Microenvironment Remodeling in Breast Cancer
| Autor: | Jisun Kim, HG Moon, Nam Hoon Kwon, Donghyun Kim, Han Suk Ryu, Eunshin Lee, Wonshik Han, Dong Young Noh, Sunghoon Kim, Doo Hyun Chung, Kwangsoo Kim, Jong Il Kim, Ki Yoon Kim, Hyeong-Gon Moon, Bok Sil Hong, Kyeonghun Jeong, Jihui Yun, Kyoung Hyoun Kim, Han-Byoel Lee, Namshin Kim, Min Sun Jin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Class I Phosphatidylinositol 3-Kinases Breast Neoplasms Metastasis Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Breast cancer Immune system Cell Line Tumor microRNA Tumor Microenvironment medicine Animals Humans Neoplasm Metastasis Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Tumor microenvironment business.industry medicine.disease Survival Analysis MicroRNAs 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Heterografts Female business Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer Research. 79:1520-1534 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Various 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 with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, 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 patients with breast cancer showed a nonlinear 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 anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, 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. Significance: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer. |
| Databáze: | OpenAIRE |
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