Tissue miR-200c-3p and circulating miR-1290 as potential prognostic biomarkers for colorectal cancer

Abstract

Epithelial–mesenchymal transition (EMT)-related cancers generally elicit low immune responses. EMT is regulated by several microRNAs (miRNAs) in cancers. Thus, this study aimed to evaluate the prognostic potential of EMT-related miRNAs as biomarkers in colorectal cancer (CRC). Formalin-fixed paraffin-embedded tumor and normal tissue and plasma samples were obtained from 65 patients with pathologically confirmed CRC. In addition, plasma samples were obtained from 30 healthy volunteers. Immunohistochemical staining for E-cadherin, ZEB1, PD-1, PD-L1, CD3, CD4, CD8, Foxp3, and CD68 was conducted on tissue samples. Droplet digital polymerase chain reaction (ddPCR) analysis was performed to evaluate miR-21-5p, 34a-5p, 138-5p, 200a-3p, 200b-5p, 200c-3p, 630, 1246, and 1290 expression in tissue samples and miR-630, 1246, and 1290 expression in plasma samples. miR-21-5p, 34a-5p, 630, 1246, and 1290 expression was higher in tumor tissues than in normal tissues (P < 0.05). EMT was significantly associated with reduced tumor-infiltrating T cells. Moreover, miR-21-5p, miR-34a-5p, miR-200a-3p, and miR-200c-3p expression was negatively correlated with T cell density (P < 0.05). High tissue levels of miR-200c-3p were associated with poor overall survival (OS) (P < 0.001). CRC patients with the EMT phenotype had poor OS; however, PD-L1 positivity and abundant PD-1 positive immune cells were correlated with better OS (P < 0.05). miR-1246 and miR-1290 levels were significantly higher in the plasma of patients with CRC than in the plasma of healthy controls (P < 0.05). High plasma levels of miR-1290 were correlated with advanced stage and poor OS (P < 0.05). The tissue expression of miR-200c-3p and plasma levels of miR-1290 measured by ddPCR indicate their potential as prognostic biomarkers for CRC.

MicroRNAs Present in Malignant Pleural Fluid Increase the Migration of Normal Mesothelial Cells In Vitro and May Help Discriminate between Benign and Malignant Effusions

“…Additionally, extracellular vesicles from other biological matrices, such as supernatants of malignant ascites, had higher levels of miR-200c-3p than benign peritoneal fluid [ 35 ]. Both tumor-suppressive and tumor-promoting roles have been described for miR-200c-3p; this molecule suppresses EMT, migration, invasion, and drug resistance [ 36 ], and it promotes drug resistance and reduces T-cell infiltration [ 37 , 38 ]. Similarly, to our work, exposure of ovarian cancer spheroids and gastric cancer cells to miR-200c-3p and miR-200c-3p-rich supernatants of malignant ascites, respectively, increased cell migration [ 35 , 39 ].…”

MicroRNA mimics can distort physiological microRNA effects on immune checkpoints by triggering an antiviral interferon response

“…The initial aim of the study was to comprehensively characterize the miR-200 family as a potentially pivotal coordinator between EMT and immune evasion in BTC. This seemed intriguing, because [1] miR-200 family expression and EMT status are tightly connected [ 24 , 25 ]; [2] members of the miR-200 family have already been mentioned to influence the expression of several ICs [ 26 ]; [3] it has been reported that EMT status of cancer cells predicts the response of patients to IC blockade [ 16 ]; and [4] miR-200c-3p expression was identified as prognostic biomarker for colorectal cancer, suggesting a key role for this miRNA in regulating the EMT-immune crosstalk [ 39 ].…”

MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: targeting PD-1/PD-L1 and CTLA-4 pathways

“…The presence of a negative relationship between the levels of miR-22 and miR-24 and plasma PD-1 levels in patients who responded well to treatment for an extended period suggests that a network of miRNAs may play a role in suppressing the expression of immune checkpoints, primarily through the involvement of the miR-20 family (p < 0.05) [ 88 ]. The levels of miR-1290 in circulating plasma exhibited an inverse correlation with the presence of CD3-negative, CD8-negative, and PD-1-positive cells [ 89 , 90 ]. In a group of melanoma biopsies that had not been treated with PD-1 inhibitors, it was observed that higher levels of miR-100-5p (p-value = 0.036) and miR-125b-5p (p-value = 0.025) expression were linked to better results when treated with anti-PD-1 immunotherapy [ 91 ].…”

“…There was an inverse correlation observed between miR-200c-3p and the expression of immune cell markers, including CD3, CD4, and CD8. Additionally, miR-200c-3p displayed a negative correlation with the presence of PD-L1, an immune marker [ 89 , 101 ]. In the initial stage of clinical trials, the utilization of MRX34 , a newly developed synthetic version of miR-34a-5p , has demonstrated a notable reduction in the expression of PD-L1 in tumors.…”