TRANSCRIPTIONAL LANDSCAPE OF COLORECTAL CANCER FOR NOVEL BIOMARKER DISCOVERY AND TARGETED THERAPY

Abstract

Colorectal cancer (CRC) remains a global disease burden and a leading cause of cancer- related deaths worldwide and in the region. A better understanding of the disease and the development of novel diagnostic biomarkers and therapeutic targets is paramount. Transcriptome analyses of peripheral blood mononuclear cells (PBMCs) from CRC patients from this region identified differentially expressed mRNAs and their potential utilization as non-invasive biomarkers for CRC was confirmed using orthogonal partial least squares-discriminant analysis (OPLS-DA). Transcriptome analyses of mRNAs, lncRNAs, and miRNAs of CRC tumors and adjacent normal tissues in conjunction with Ingenuity Pathway Analysis (IPA) revealed activation of functional categories, including cellular movement, cellular proliferation, DNA replication, recombination and repair as the hallmark of CRC. In silico prediction algorithms and experimentally validated databases gave insight into the complex associations and interactions between aberrantly expressed mRNAs, miRNAs and lncRNAs in CRC. Functional studies revealed remarkable effects of targeted depletion of four selected CRC-essential genes, TPX2, TTK, LRP8, and DDX39A, on cellular proliferative and viability using HCT116 and HT-29 CRC cell models. Forced expression of downregulated miRNAs (hsa-miR-138-5p and hsa-miR-218-5p) led to substantial inhibition of CRC proliferation. To highlight plausible role for upregulated lncRNAs in CRC biology, CRISPR-Cas9 mediated MALAT1 promoter deletion led to significant inhibition of CRC cell proliferation, which was further enhanced when combined with 5-Fluorouracil (5-FU). Our data identified potential noninvasive biomarkers for CRC and provides thorough analysis of dysregulated protein-coding and non-coding RNAs in CRC from this region, highlighting numerous associations and regulatory networks, thus providing a better understanding of the disease for potential biomarker discovery and targeted therapy.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences