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 language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Gastrointestinal and Liver Physiology |
| Volume | 306 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2014 |
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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
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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 journal › Article
TY - JOUR
T1 - FXR silencing in human colon cancer by DNA methylation and KRAS signaling
AU - Bailey, Ann M.
AU - Zhan, Le
AU - Maru, Dipen
AU - Shureiqi, Imad
AU - Pickering, Curtis R.
AU - Izzo, Julie
AU - He, Nan
AU - Wei, Caimiao
AU - Baladandayuthapani, Veerabhadran
AU - Liang, Han
AU - Kopetz, Scott
AU - Powis, Garth
AU - Guo, Grace
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
KW - Bile acids
KW - Colon cancer
KW - Farnesoid X receptor
KW - Nuclear receptor
KW - Promoter methylation
UR - http://www.scopus.com/inward/record.url?scp=84891538213&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891538213&partnerID=8YFLogxK
U2 - https://doi.org/10.1152/ajpgi.00234.2013
DO - https://doi.org/10.1152/ajpgi.00234.2013
M3 - Article
C2 - 24177031
VL - 306
JO - The American journal of physiology
JF - The American journal of physiology
SN - 0002-9513
IS - 1
ER -