Hypermethylation and Downregulation of UTP6 Are Associated With Stemness Properties, Chemoradiotherapy Resistance, and Prognosis in Rectal Cancer: A Co-expression Network Analysis.

Background: To identify the hub genes associated with chemoradiotherapy resistance in rectal cancer and explore the potential mechanism.

Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify the gene modules correlated with the chemoradiotherapy resistance of rectal cancer.

Results: The mRNA expression of 31 rectal cancer patients receiving preoperative chemoradiotherapy was described in our previous study. Through WGCNA, we demonstrated that the chemoradiotherapy resistance modules were enriched for translation, DNA replication, and the androgen receptor signaling pathway. Additionally, we identified and validated UTP6 as a new effective predictor for chemoradiotherapy sensitivity and a prognostic factor for the survival of colorectal cancer patients using our data and the GSE35452 dataset. Low UTP6 expression was correlated with significantly worse disease-free survival (DFS), overall survival (OS), and event- and relapse-free survival both in our data and the R2 Platform. Moreover, we verified the UTP6 expression in 125 locally advanced rectal cancer (LARC) patients samples by immunohistochemical analysis. The results demonstrated that low UTP6 expression was associated with worse DFS and OS by Kaplan-Meier and COX regression model analyses. Gene set enrichment and co-expression analyses showed that the mechanism of the UTP6-mediated chemoradiotherapy resistance may involve the regulation of FOXK2 expression by transcription factor pathways.

Conclusion: Low expression of the UTP6 was found to be associated with chemoradiotherapy resistance and the prognosis of colorectal cancer possibly via regulating FOXK2 expression by transcription factor pathways.