Tumor suppressor miRNA-204-5p regulates growth, metastasis, and immune microenvironment remodeling in breast cancer

Bok Sil Hong, Han Suk Ryu, Namshin Kim, Jisun Kim, Eunshin Lee, Hyunhye Moon, Kyoung Hyoun Kim, Min Sun Jin, Nam Hoon Kwon, Sunghoon Kim, Donghyun Kim, Doo Hyun Chung, Kyeonghun Jeong, Kwangsoo Kim, Ki Yoon Kim, Han Byoel Lee, Wonshik Han, Jihui Yun, Jong Il Kim, Dong Young NohHyeong Gon Moon

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1520-1534
Number of pages15
JournalCancer Research
Volume79
Issue number7
DOIs
Publication statusPublished - 2019 Apr 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Tumor suppressor miRNA-204-5p regulates growth, metastasis, and immune microenvironment remodeling in breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Hong, B. S., Ryu, H. S., Kim, N., Kim, J., Lee, E., Moon, H., Kim, K. H., Jin, M. S., Kwon, N. H., Kim, S., Kim, D., Chung, D. H., Jeong, K., Kim, K., Kim, K. Y., Lee, H. B., Han, W., Yun, J., Kim, J. I., ... Moon, H. G. (2019). Tumor suppressor miRNA-204-5p regulates growth, metastasis, and immune microenvironment remodeling in breast cancer. Cancer Research, 79(7), 1520-1534. https://doi.org/10.1158/0008-5472.CAN-18-0891