Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways.
Background: While the exact mechanism remains unclear, type 2 diabetes mellitus (T2DM) has been shown to increase the risk of sarcopenia that is characterized by decreased muscle mass, strength, and function. This study aimed to identify the pathophysiological role of lncRNAs in diabetic sarcopenia. Methods: Whole-transcriptome RNA sequencing was performed on the gastrocnemius from the overt diabetes-induced sarcopenia model of db/db mice. Informatics and co-expression networks were performed to predict key lncRNAs and their potential regulation circuits in diabetes-induced sarcopenia. To determine the specific function of lncRNA Gm20743, the detection of Mito-Sox, reactive oxygen species, Ethynyl-2′-deoxyuridine, and myosin heavy chain was performed in overexpressed-Gm20743 C2C12 cells. Results: RNA-seq data and informatics revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. Meanwhile, we characterized three core candidate lncRNAs Gm20743, Gm35438, and 1700047G03Rik and their potential function. Furthermore, the results suggested lncRNA Gm20743 may be involved in regulating mitochondrial function, oxidative stress, cell proliferation, and myotube differentiation in skeletal muscle cells. Conclusion: These findings significantly improve our understanding of lncRNAs that may mediate muscle mass, strength, and function in diabetes and represent potential therapeutic targets for diabetes-induced sarcopenia.
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