Identification of Target PTEN-Based miR-425 and miR-576 as Potential Diagnostic and Immunotherapeutic Biomarkers of Colorectal Cancer With Liver Metastasis.

Xiaoyun Hu,Kuo Li,Huizhe Wu,Boshi Fu,Haishan Zhao,Yalun Li,Qiuchen Chen,Minjie Wei,Hao Guo,Yu Chen

doi:10.3389/fonc.2021.657984

Abstract

A major complication of colorectal cancer (CRC), one of the most common and fatal types of cancers, is secondary liver metastasis. For patients with this fate, there are very few biomarkers available in clinical application, and the disease remains incurable. Recently, increasing studies demonstrated that tumorigenesis and development are closely related to immune escape, indicating that the roles of immune-related indicators might have been neglected in the past in colorectal cancer liver metastases (CRLM). Here, we unveil that elevated miR-425 and miR-576 promote CRLM through inhibiting PTEN-mediated cellular immune function. Specifically, miR-425 and miR-576 were identified for their significant upregulation in CRLM compared with the primary CRC tissues based on GSE81581 (n = 8) and GSE44121 (n = 18) datasets. Besides, we determined that the two microRNAs (miRNAs) coparticipated in restraining P53 and transforming growth factor beta (TGF-β) signaling pathways associated with tumor metastasis, and both shortened the overall survival of the patients with metastatic susceptibility. Notably, in situ hybridization on relatively large samples of paired CRC tissues (n = 157) not only substantiated that the expression of miR-425 and miR-576 was dramatically upregulated in CRLM but also revealed that they were closely related to tumor deterioration, especially liver metastases. Moreover, we further confirmed that the combination of miR-425 and miR-576 was an effective predictive model for liver metastases and poor clinical outcomes. Mechanically, downregulated PTEN (GSE81558, n = 6) was verified to be a shared target of miR-425 and miR-576 acting as metastasis-related oncogenes, on account of the presence of binding sites (+2928–+2934 and +4371–+4378, respectively) and the collaborative suppression of P53/TGF-β signaling in CRLM, which was further confirmed in CRC cells (HCT116 and SW480) based on systematic molecular biology experiments. Importantly, the target PTEN was strongly associated with microsatellite instability, tumor microenvironment, and immune cell infiltration. Thus, we speculate that miR-425 and miR-576 are novel biomarkers for CRLM prevention and immunotherapy and upstream inhibitors of the PTEN-P53/TGF-β function axis.

Highlights

Colorectal cancer (CRC) is the third most common cancer in the western world and represents a leading cause of death worldwide [1]
We investigated the metastasis-related roles that miR-425 and miR-576 collectively played, and P53 and transforming growth factor beta (TGF-b) signaling pathways were dramatically enriched based on Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis (Figure 1C and Supplementary Table S4)
High miR-425 and miR-576 expression shortened the overall survival time of rectum adenocarcinoma (READ) patients with either CD4+ or stage II, which both were closely related to CRC metastasis (Figure 1D)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer in the western world and represents a leading cause of death worldwide [1]. Surgical resection could provide these patients with an increase in 5-year survival, the heterogeneity of colorectal cancer liver metastases (CRLMs) leads to the fact that prediction and improvement of individual outcomes after surgery remain a challenge [3, 4]. One of the primary research focuses is still to excavate potential biomarkers and immunotherapeutic targets for both early evaluation and accurate treatment of CRLM. After their discovery, microRNAs (miRNAs) have been revealed to play crucial roles in cancer biology [6]. The exploration of the clinical values of the two miRNAs still stays in primary CRC [15, 16], while almost no liver metastasis is involved.

Methods

Results

Conclusion