miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling
INFLAMMATORY BOWEL DISEASES
Authors: Pekow, Joel; Hutchison, Alan L.; Meckel, Katherine; Harrington, Kymberly; Deng, Zifeng; Talasila, Nitya; Rubin, David T.; Hanauer, Stephen B.; Hurst, Roger; Umanskiy, Konstantin; Fichera, Alessandro; Hart, John; Dinner, Aaron R.; Bissonnette, Marc
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: MicroRNA (miRNA) and mRNA expression was examined in nondysplastic 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 and through examination of expression in UC-cancers. Results: There were 101 significantly up-regulated and 98 down-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 nondysplastic tissue remote from UC-neoplasia and 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 30 untranslated region compared with a mutant 30 untranslated region for all 3 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 nondysplastic 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.
Association analysis between thrombospondin-2 gene polymorphisms and intervertebral disc degeneration in a Chinese Han population
MEDICINE
Authors: Yuan, Baisheng; Ji, Wei; Fan, Bing; Zhang, Binglei; Zhao, Yulin; Li, Jianmin
Abstract
The aim of this study is to determine the contribution of 2 single nucleotide polymorphisms (SNPs) in thrombospondin 2 (THBS2) gene to the development of intervertebral disc degeneration (IDD) in a Chinese Han population. We studied 138 patients with radiographically proven IDD and 136 healthy volunteers with no history of back problems. Magnetic resonance images (MRIs) were obtained for all the patients and controls. Image evaluation for IDD was performed to evaluate the severity of IDD. All patients and controls were genotyped for rs6422747 and rs6422748. Associations between genotypes and development of IDD were analyzed. We found that 2 SNPs in the intron region of THBS2 gene (rs6422747 and rs6422748) were associated with susceptibility of IDD. However, they were not related with severity of IDD, including the total number of degenerative disc and level of IDD. G allele in both SNPs was associated with a higher risk of IDD. The 2 SNPs (rs6422747 and rs6422748) in the THBS2 gene were associated with susceptibility of IDD but not severity of IDD in a Chinese Han population. Our results indicated that THBS2 gene polymorphisms might be the risk factors for IDD. More studies with larger sample size need to be perfected to make sure the functions of THBS2 gene polymorphisms in IDD development.
COA
Certificate of Analysis
