FXR silencing in human colon cancer by DNA methylation and KRAS signaling

Ann M. Bailey, Le Zhan, Dipen Maru, Imad Shureiqi, Curtis R. Pickering, Julie Izzo, Nan He, Caimiao Wei, Veerabhadran Baladandayuthapani, Han Liang, Scott Kopetz, Garth Powis, Grace Guo

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue (n = 238), polyps (n = 32), and adenocarcinomas, staged I-IV (n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl- DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Kiras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ~12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume306
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

DNA Methylation
Colonic Neoplasms
Epithelial-Mesenchymal Transition
Atlases
Neoplasms
Methylation
Colon
Adenocarcinoma
Immunohistochemistry
Genome
Polymerase Chain Reaction
Protein Array Analysis
DNA
Methyltransferases
Human Development
Cytoplasmic and Nuclear Receptors
Polyps
Bile Acids and Salts
Oncogenes
Immunoprecipitation

All Science Journal Classification (ASJC) codes

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Keywords

  • Bile acids
  • Colon cancer
  • Farnesoid X receptor
  • Nuclear receptor
  • Promoter methylation

Cite this

Bailey, Ann M. ; Zhan, Le ; Maru, Dipen ; Shureiqi, Imad ; Pickering, Curtis R. ; Izzo, Julie ; He, Nan ; Wei, Caimiao ; Baladandayuthapani, Veerabhadran ; Liang, Han ; Kopetz, Scott ; Powis, Garth ; Guo, Grace. / FXR silencing in human colon cancer by DNA methylation and KRAS signaling. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2014 ; Vol. 306, No. 1.
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Bailey, AM, Zhan, L, Maru, D, Shureiqi, I, Pickering, CR, Izzo, J, He, N, Wei, C, Baladandayuthapani, V, Liang, H, Kopetz, S, Powis, G & Guo, G 2014, 'FXR silencing in human colon cancer by DNA methylation and KRAS signaling', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 306, no. 1. https://doi.org/10.1152/ajpgi.00234.2013

FXR silencing in human colon cancer by DNA methylation and KRAS signaling. / Bailey, Ann M.; Zhan, Le; Maru, Dipen; Shureiqi, Imad; Pickering, Curtis R.; Izzo, Julie; He, Nan; Wei, Caimiao; Baladandayuthapani, Veerabhadran; Liang, Han; Kopetz, Scott; Powis, Garth; Guo, Grace.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 306, No. 1, 01.01.2014.

Research output: Contribution to journalArticle

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AU - Bailey, Ann M.

AU - Zhan, Le

AU - Maru, Dipen

AU - Shureiqi, Imad

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AU - Izzo, Julie

AU - He, Nan

AU - Wei, Caimiao

AU - Baladandayuthapani, Veerabhadran

AU - Liang, Han

AU - Kopetz, Scott

AU - Powis, Garth

AU - Guo, Grace

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