Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients

Abstract

Deregulation of the transcribed ultra-conserved regions (T-UCRs) Uc160, Uc283, and Uc346 has been reported in colorectal cancer (CRC) recently. Here, we investigated promoter methylation of these T-UCRs during the adenoma–carcinoma sequence and their clinical significance in CRC patients. Methylation levels were assessed in CRC, adenomas, infiltrated lymph nodes, and metastatic tissue specimens. In situ hybridization was performed in representative tissue specimens. T-UCRs expression levels were also evaluated in HT-29 colon cancer cells before and after the acquired resistance to 5-fluorouracil (5-FU) and oxaliplatin. A gradual increase in T-UCRs methylation levels from hyperplastic polyps to adenomas and to in situ carcinomas (ISC) and a gradual decrease from ISC to infiltrative and metastatic carcinomas was observed (p < 0.001 for Uc160 and Uc283, p = 0.018 for Uc346). Uc160 and Uc283 methylation was associated with the grade of dysplasia in adenoma specimens (p = 0.034 and p = 0.019, respectively). Furthermore, higher Uc160 methylation, mainly in stage III and IV patients, was related to improved overall survival (OS) in univariate (p = 0.009; HR, 0.366) and multivariate analysis (p = 0.005; HR, 0.240). Similarly, higher methylation of Uc283 was associated with longer OS (p = 0.030). Finally, T-UCRs expression was significantly reduced in HT-29 cells after resistance to chemotherapy. This study suggests that promoter methylation of Uc160, Uc283, and Uc346 is altered during CRC development and that Uc160 and Uc283 methylation may have prognostic significance for CRC patients.

Differential Expression Analysis Revealing CLCA1 to Be a Prognostic and Diagnostic Biomarker for Colorectal Cancer

“…To our knowledge, our work is the first to combine RRA analysis of GEO datasets with WGCNA of TCGA datasets to explore the significant genes associated with CRC. Some diseases of the intestinal tract, such as intestinal polyps (33) and inflammatory bowel disease (34), can have symptoms similar to those of CRC and can also develop into cancer. To explore potential DEGs between tumor tissue and noncancerous tissue, we compared normal tissue, normal matched tissue and paratumor tissue with CRC tissue as control tissue.…”

Overexpression of the transcribed ultraconserved region Uc.138 accelerates colon cancer progression

“…Zhang et al reported that uc.338 was upregulated in human colorectal cancer and increased cell proliferation by activation of the PI3K/AKT pathway 25 . The methylation status and expression levels of uc.160, uc.283, and uc.346 were dysregulated in neoplastic tissues from colorectal cancer, and uc.160 and uc.346 enhanced colorectal cancer cell progression 26 .…”

Long noncoding RNA uc.230/CUG-binding protein 1 axis sustains intestinal epithelial homeostasis and response to tissue injury

“…Like the downregulation of protein-coding genes, the loss of adequate T-UCR expression has been linked to the presence of CpG island promoter hypermethylation (36). Almost half of the T-UCR-associated CpG island in all tissues is unmethylated, while the other half shows tissue-specific T-UCR CpG island methylation (43)(44)(45). Epigenetic inactivation by CpG island hypermethylation of several T-UCRs such as uc.160, uc.283 + A, and uc.346 + occurs in a wide spectrum of human cancer cells and these changes in promoter methylation modulate the expression of T-UCRs (46).…”