miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling

Abstract

Background As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population. Methods miRNA and mRNA expression was examined in non-dysplastic rectosigmoid mucosa from UC patients with (n=19) or without remote colon neoplasia (n=23). We developed a method to identify miRNA-regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling, was further evaluated in vitro as well as through examination of expression in UC-cancers. Results There were 101 significantly down-regulated and 97 up-regulated miRNAs (adjusted p<0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down-regulation of miR-4728-3p in non-dysplastic tissue remote from UC-neoplasia as well as in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3′ UTR compared to a mutant 3′ UTR for all three genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes. Conclusions Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in non-dysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor-suppressor in UC-associated colon carcinogenesis.

TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

“…8a). Among the miRNAs, we mainly focus on miR-125a-5p [35,36], miR-760 [37,38], miR-4728-5p [39,40] and miR-6785-5p [40], knowing that they are closely correlated with other malignancies.…”

Systematic Investigation of the Efficacy of Sinitang Decoction Against Ulcerative Colitis

“…CRP and COL12A1, which were among the 78 SNT-related differentially regulated proteins, did not directly interact but they may interact through their downstream/upstream proteins, such as FBLN2, LAMA5, THBS2 (which may play a crucial role in UC progression and may be a novel prognostic biomarker ( Chang et al, 2016 ; Pekow et al, 2017 ), and APOE [which may increase susceptibility to UC ( Keshen et al, 2009 )].…”

Comprehensive analysis of differential circular RNA expression in a mouse model of colitis‐induced colon carcinoma

“…Among the enriched signaling pathways, activation of the Ras‐Raf‐MAPK pathway was reported to be involved in the pathogenesis, progression, and oncogenesis of human colorectal cancer . Other studies found that miR‐4728‐3p functions as a tumor suppressor in colitis‐associated colorectal neoplasia through the regulation of focal adhesion signaling …”

“…[39][40][41] Other studies found that miR-4728-3p functions as a tumor suppressor in colitis-associated colorectal neoplasia through the regulation of focal adhesion signaling. 42…”