miR-301a promotes lung tumorigenesis by suppressing Runx3

Autor: Zhujuan Huang, Yong Li, Ming Liu, Zhi Cao, Mingtian Zhong, Lei Wang, Fengxue Zhang, Jiexuan Wang, Xiaodong Ma, Xun Li, Zhanwen Lin
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Lung Neoplasms
T cell
Cell
Down-Regulation
CD8-Positive T-Lymphocytes
Biology
CD8+ T cells
medicine.disease_cause
lcsh:RC254-282
Proto-Oncogene Proteins p21(ras)
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
miR-301a
Cell Line
Tumor
Runx3
medicine
Animals
Humans
Neoplasm Metastasis
IFN-γ
Cell Proliferation
Tumor microenvironment
Sequence Analysis
RNA
Cell growth
Gene Expression Profiling
Research
High-Throughput Nucleotide Sequencing
Cell migration
Cell cycle
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
digestive system diseases
Gene Expression Regulation
Neoplastic
MicroRNAs
Core Binding Factor Alpha 3 Subunit
030104 developmental biology
medicine.anatomical_structure
Oncology
A549 Cells
030220 oncology & carcinogenesis
Kras
Cancer research
Molecular Medicine
Carcinogenesis
Neoplasm Transplantation
Zdroj: Molecular Cancer, Vol 18, Iss 1, Pp 1-15 (2019)
Molecular Cancer
ISSN: 1476-4598
Popis: Background Our previous report demonstrated that genetic ablation of miR-301a reduces Kras-driven lung tumorigenesis in mice. However, the impact of miR-301a on host anti-tumor immunity remains unexplored. Here we assessed the underlying molecular mechanisms of miR-301a in the tumor microenvironment. Methods The differentially expressed genes were identified by using deep sequencing. The immune cell counts, and cytokines expression were analyzed by realtime PCR, immunohistochemistry and flow cytometry. The role of miR-301a/Runx3 in lung tumor was evaluated on cell growth, migration and invasion. The function of miR-301a/Runx3 in regulating tumor microenvironment and tumor metastasis were evaluated in Kras transgenic mice and B16/LLC1 syngeneic xenografts tumor models. Results In this work, we identified 1166 up-regulated and 475 down-regulated differentially expressed genes in lung tumor tissues between KrasLA2 and miR-301a−/−; KrasLA2 mice. Immune response and cell cycle were major pathways involved in the protective role of miR-301a deletion in lung tumorigenesis. Overexpression of the miR-301a target, Runx3, was an early event identified in miR-301a−/−; KrasLA2 mice compared to WT-KrasLA2 mice. We found that miR-301a deletion enhanced CD8+ T cell accumulation and IFN-γ production in the tumor microenvironment and mediated antitumor immunity. Further studies revealed that miR-301a deficiency in the tumor microenvironment effectively reduced tumor metastasis by elevating Runx3 and recruiting CD8+ T cells, whereas miR-301a knockdown in tumor cells themselves restrained cell migration by elevating Runx3 expression. Conclusions Our findings further underscore that miR-301a facilitates tumor microenvironment antitumor immunity by Runx3 suppression in lung tumorigenesis. Electronic supplementary material The online version of this article (10.1186/s12943-019-1024-0) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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