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Abstract
The helicase-like transcription factor (HLTF) gene—a tumor suppressor in human colorectal cancer (CRC)—is regulated by alternative splicing and promoter hypermethylation. In this study, we used the AOM/DSS-induced mouse model to show Hltf-deletion caused poor survival concomitant with increased tumor multiplicity, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present during adenocarcinoma formation in controls. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p = 0.0062). Upregulation of gene expression, as validated with qRT-PCR, accompanied a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics.
Highlights
Colorectal cancer (CRC)—the second leading cause of cancer-related deaths in a combined population of men and women in the United States [1]—can originate proximal to the splenic flexure, or distal to that anatomic landmark
Monitoring revealed no evidence of bloody diarrhea in the cage bedding of either Hltf-deleted or control mice
Comparison of survival curves for male Hltf-deleted (n = 109) and control (n = 47) mice with the Logrank (Mantel-Cox) test (Chi square 12.27, p = 0.0005), and the Gehan-Breslow-Wilcoxon test (Chi square 11.88, p = 0.0006), indicated Hltf-deletion negatively effects the mortality of AOM/DSS-treated mice (Fig 1B) The hazard ratio indicated the risk of dying is 2.646-fold higher when Hltf is deleted
Summary
Colorectal cancer (CRC)—the second leading cause of cancer-related deaths in a combined population of men and women in the United States [1]—can originate proximal to the splenic flexure (right-sided CRC), or distal to that anatomic landmark (left-sided CRC). Increased left-sided CRC in men and women under the age of 50 drives poor survival statistics despite the availability of screening tools. Patients with inflammatory bowel disease that constitute the greatest at risk population are the only ones recommended for screening at this age. For these individuals, their CRC derives from the pro-neoplastic effects of severe, chronic inflammation [2].
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