Butyrate-Induced In Vitro Colonocyte Differentiation Network Model Identifies ITGB1, SYK, CDKN2A, CHAF1A, and LRP1 as the Prognostic Markers for Colorectal Cancer Recurrence

Nutr Cancer. 2019;71(2):257-271. doi: 10.1080/01635581.2018.1540715. Epub 2018 Nov 26.

Abstract

Numerous mechanisms are believed to contribute to the role of dietary fiber-derived butyrate in the protection against the development of colorectal cancers (CRCs). To identify the most crucial butyrate-regulated genes, we exploited whole genome microarray of HT-29 cells differentiated in vitro by butyrate treatment. Butyrate differentiates HT-29 cells by relaxing the perturbation, caused by mutations of Adenomatous polyposis coli (APC) and TP53 genes, the most frequent mutations observed in CRC. We constructed protein-protein interaction network (PPIN) with the differentially expressed genes after butyrate treatment and extracted the hub genes from the PPIN, which also participated in the APC-TP53 network. The idea behind this approach was that the expression of these hub genes also regulated cell differentiation, and subsequently CRC prognosis by evading the APC-TP53 mutational effect. We used mRNA expression profile of these critical hub genes from seven large CRC cohorts. Logistic Regression showed strong evidence for association of these common hubs with CRC recurrence. In this study, we exploited PPIN to reduce the dimension of microarray biologically and identified five prognostic markers for the CRC recurrence, which were validated across different datasets. Moreover, these five biomarkers we identified increase the predictive value of the TNM staging for CRC recurrence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Butyrates / pharmacology*
  • Cell Differentiation / drug effects
  • Chromatin Assembly Factor-1 / metabolism
  • Colon / cytology*
  • Colon / drug effects
  • Colon / metabolism
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Computational Biology / methods
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gene Expression Profiling
  • Humans
  • Integrin beta1 / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasm Recurrence, Local / pathology*
  • Prognosis
  • Protein Interaction Maps / drug effects
  • Syk Kinase / metabolism

Substances

  • Biomarkers, Tumor
  • Butyrates
  • CDKN2A protein, human
  • CHAF1A protein, human
  • Chromatin Assembly Factor-1
  • Cyclin-Dependent Kinase Inhibitor p16
  • Integrin beta1
  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • SYK protein, human
  • Syk Kinase