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.