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.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and women worldwide [1]
Methylation levels of Uc160 and Uc346 gradually increased from hyperplastic polyps to adenomas and to in situ carcinomas, while in infiltrative adenocarcinomas methylation levels decreased, but they were still elevated compared to hyperplastic polyps (Figure 1)
Lower methylation levels of Uc160 were observed in hyperplastic polyps compared to tubulovillous (p = 0.044) and serrated adenomas (p = 0.038), while lower levels of methylation were observed between hyperplastic polyps and tubular adenomas compared to infiltrative adenocarcinomas (p = 0.011 and p = 0.002, respectively)
Summary
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and women worldwide [1]. The classical pathway of colorectal tumorigenesis is characterized by the adenoma–carcinoma sequence, which can last decades, and it is determined by specific molecular pathways, including genetic alterations of tumor suppressor genes [2]. In this context, classical adenomas are precursor lesions, which are characterized from proliferative and dysplastic epithelial cells with increased potential for malignant transformation [2]. Ultra-conserved regions (UCRs) are 481 genomic regions longer than 200 bp, which are 100%. Transcriptional deregulation of T-UCRs has been attributed mainly to hypermethylation of the promoters, as well as to their interaction with microRNAs (miRNAs) [7,8]
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