Association of MALAT1 and PVT1 Variants, Expression Profiles and Target miRNA-101 and miRNA-186 with Colorectal Cancer: Correlation with Epithelial-Mesenchymal Transition.

Abdullah F Radwan,Mahmoud A Senousy,Olfat G Shaker,Noha A El-Boghdady

doi:10.3390/ijms22116147

Abdullah F Radwan, Mahmoud A Senousy + Show 2 more

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https://doi.org/10.3390/ijms22116147

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Abstract

The influence of PVT1 and MALAT1 variants on colorectal cancer (CRC) susceptibility and their impact on PVT1/miRNA-186/epithelial-mesenchymal transition (EMT) and MALAT1/miRNA-101/EMT axes in CRC are unknown. We investigated the influence of PVT1 rs13255292 and MALAT1 rs3200401 on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs PVT1 and MALAT1 expression and their target miRNA-186, miRNA-101/E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. rs3200401 was associated with increased CRC risk, whereas rs13255292 was protective. Serum PVT1 and MALAT1 were upregulated in CRC and AP patients versus healthy controls, whereas, miRNA-186, miRNA-101 and E-cadherin were downregulated in CRC versus non-CRC groups. MALAT1 showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. PVT1, MALAT1, miRNA-186 and miRNA-101 levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. rs3200401CC genotype carriers showed higher E-cadherin levels than CC + CT carriers. rs3200401 was correlated with lymph node status. For the first time, rs13255292 and rs3200401 are potential genetic CRC predisposition markers, with rs3200401 possibly impacting the EMT process. Serum PVT1, MALAT1, miRNA-186 and miRNA-101 are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.

Highlights

Colorectal cancer (CRC) is among the most frequently diagnosed cancers worldwide, and it is a leading cause of cancer-related deaths around the world [1]
We explored the relationship of these polymorphisms with MALAT1 and plasmacytoma variant translocation 1 (PVT1) expression and their target miRNA-101 and miRNA-186, respectively, in CRC
Carcinoembryonic antigen (CEA), the current conventional tumor marker in CRC management, is most elevated in the late metastatic stages. It has low sensitivity and specificity when used to distinguish early non-metastatic stages [23]; it is recommended to be used as a biomarker for already confirmed metastasized diagnosed CRC

Summary

Introduction

Colorectal cancer (CRC) is among the most frequently diagnosed cancers worldwide, and it is a leading cause of cancer-related deaths around the world [1]. Advanced cases of CRC have poor prognosis and unsatisfactory survival rates [2]. We must make advances in the early detection and therapy of CRC to increase patient survival. Because of the wide variety of biological processes that they play a part in, non-coding RNAs (ncRNAs) such as long ncRNAs (lncRNAs) and microRNAs (miRNAs) have recently received enough attention to merit mentioning. Mutations or the unnatural expression of ncRNAs are closely associated with many diseases, cancer [3]. The crosstalk research between lncRNAs, miRNAs, and their master regulated proteins has become a newfangled passion for deciphering cancer’s molecular mechanism, including CRC

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