miR-301a promotes lung tumorigenesis by suppressing Runx3

Abstract

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 Kras LA2 and miR-301a −/− ; Kras LA2 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 −/− ; Kras LA2 mice compared to WT-Kras LA2 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.

Disruption of super-enhancer-driven tumor suppressor gene RCAN1.4 expression promotes the malignancy of breast carcinoma

“…5 c, d). As RUNX3 is located in 1p36, a region often deleted in breast cancer [ 29 , 30 ], we focus this study on the regulatory role of this transcription factor. Additionally, the transcriptional levels of RCAN1.1 and RCAN1.2 were not changed when RUNX3 was knocked down (Additional file 3 : Fig.…”

Evaluation of miR‐130 family members as circulating biomarkers for the diagnosis of bladder cancer

“…miR‐130b‐3p also plays a role in tumorigenesis and development, such as endometrial cancer 37 and non‐small cell lung cancer 18 . Research on miR‐301a‐3p and miR‐301b‐3p has focused on pancreatic, 38 colorectal, 39 hepatocellular, 16 and lung cancer 17 . These miRNAs are upregulated and play a pro‐cancer role in many cancers, and high expression in tumor tissues is often associated with poor prognosis.…”

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MicroRNA-183-5p contributes to malignant progression through targeting PDCD4 in human hepatocellular carcinoma

“…In recent years, an increasing number of scientific researches have proposed that miRNAs could exert the biological roles through direct binding to the 3′UTR of their downstream target mRNAs [ 17 , 18 , 21 ]. In order to clarify the possible molecular mechanisms underlying the oncogenic effects of miR-183-5p in HCC, we carried out further mechanistic studies.…”