Metabolic reprogramming of the premalignant colonic mucosa is an early event in carcinogenesis

Mart Dela Cruz, Sarah Ledbetter, Sanjib Chowdhury, Ashish K. Tiwari, Navneet Momi, Ramesh K. Wali, Charles Bliss, Christopher Huang, David Lichtenstein, Swati Bhattacharya, Anisha Varma-Wilson, Vadim Backman, Hemant K. Roy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Background: Colorectal cancer (CRC) is the second leading cause of cancerrelated mortality in the United States. There is an increasing need for the identification of biomarkers of pre-malignant and early stage CRC to improve risk-stratification and screening recommendations. In this study, we investigated the possibility of metabolic and mitochondrial reprogramming early in the pre-malignant colorectal field. Methods: Rectal biopsies were taken from 81 patients undergoing screening colonoscopy, and gene expression of metabolic and mitochondrial markers were assessed using real time quantitative PCR. Validation studies were performed in two different animal models of colon carcinogenesis: Pirc rats and AOM-treated rats. Results: We found evidence of a Warburg effect in the normal-appearing rectal mucosa of patients harboring precancerous lesions elsewhere in the colon compared to control patients, with a significant increase in HIF1a, SLC2A1 (referred to as GLUT1), PKM2, and LDHA. We also found evidence of early mitochondrial changes in the colorectal field of patients harboring pre-cancerous lesions, with significantly increased mitochondrial gene expression of DRP1 (fission), OPA1 (fusion), PGC1-a (biogenesis), UCP2 (uncoupling) and mtND1 (copy number). Similar results were observed in the two different animal models. Conclusions: These results demonstrate for the first time evidence of early Warburg-like metabolic changes as well as changes in mitochondrial function, dynamics and mtDNA copy number in endoscopically normal premalignant colorectal mucosal field. These findings provide an opportunity for the development of metabolic biomarkers that could be used for improving screening recommendations and risk-stratification. This also provides a potential target for novel chemopreventive strategies in the pre-malignant colorectal field.

Original languageEnglish (US)
Pages (from-to)20543-20557
Number of pages15
JournalOncotarget
Volume8
Issue number13
DOIs
StatePublished - 2017

Keywords

  • Colorectal carcinoma
  • Field carcinogenesis
  • Metabolic reprogramming
  • Metabolism
  • Warburg effect

ASJC Scopus subject areas

  • Oncology

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