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.
Highlights
Abbreviations CD3 Cluster of differentiation 3 CD4 Cluster of differentiation 4 CD68 Cluster of differentiation 68 CD8 Cluster of differentiation 8 combined positive score (CPS) Combined positive score CRC Colorectal cancer ddPCR Droplet digital polymerase chain reaction epithelial–mesenchymal transition (EMT) Epithelial–mesenchymal transition Foxp[3] Forkhead box P3 intraclass correlations (ICCs) Intraclass correlation IHC Immunohistochemistry
We investigated nine different miRNAs that were previously reported to be related to EMT in solid tumors, namely miR-21-5p, 34a-5p, 138-5p, 200a-3p, 200b-5p, 200c-3p, 630, 1246, and 1290
After classifying the patients into two groups on the basis of their EMT status, we observed a significant difference between the groups in terms of their T cell densities in both tumor center (TC) and invasive margin (IM) tissues
Summary
Abbreviations CD3 Cluster of differentiation 3 CD4 Cluster of differentiation 4 CD68 Cluster of differentiation 68 CD8 Cluster of differentiation 8 CPS Combined positive score CRC Colorectal cancer ddPCR Droplet digital polymerase chain reaction EMT Epithelial–mesenchymal transition Foxp[3] Forkhead box P3 ICC Intraclass correlation IHC Immunohistochemistry. Multiagent approaches have been developed based on availability and not on the basis of validated and refined treatment algorithms[4]. To overcome such challenges, it is necessary to identify biomarkers that enable accurate prognosis and a personalized approach in the treatment of CRC. Downregulation of miR-21-5p has been reported to reverse EMT and the cancer stem cell phenotype[15]. The miR-200 family has been reported to target and downregulate ZEB1, an EMT activator[16]. These EMT-related miRNAs likely have several different targets and function at various levels
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