The Role of a Western Diet in Regulating Expression of Farnesoid X Receptor and Colorectal Cancer Progression

Shaili Tapiavala

Introduction. Colorectal cancer is the third most common cancer in the Western world (1,4).  Today, colorectal cancer patients have an improving prognosis due to early detection, but colorectal cancer is still the third-leading cause of cancer-related deaths in America (1,4).  Colorectal cancer has been correlated with a high fat/high carbohydrate/low fiber diet, commonly found in Western countries (1,4).  High fat diets promote the hepatic synthesis of bile acids and increase delivery to the lumen of the colon (1,4).  The Farnesoid X Receptor (FXR) is the nuclear receptor for bile acids found in both the liver and intestines (2,3).  FXR regulates bile acid homeostasis through the upregulation of bile acid transporters (IBABP, OSTα and OSTβ, and ASBT) and also represses the production of inflammation inducers (TNF-α, IL-1, and IL-6) (2,3).  Studies have shown the microRNAS both regulate and are regulated by FXR, specifically microRNA-192 and microRNA-22 (5-7).  Methods. Two binding sites within the NR1H4-3’ UTR were examined in vitro by luciferase reporter assays (5).  Two different cells lines were used, Huh-7 and Caco-2 cells (5).  These cell lines were transfected with miR-192-3p and miR-192-5p mimics to examine the effects of miR-192 on the expression of FXR (5).  Another study utilized FXR KO mice compared to WT mice to compare the levels of miR-22 and CCNA2 expression (7).  The RNA was quantified through PCR after extraction with TRIzol reagent and reverse transcription (7).  Results. FXR protein expression was decreased after transfection with miR-192-3p and miR-192-5p in Caco-2 cells (5.  MiR-192 also decreased the expression of FXR inducible bile transporters, specifically OSTα and OSTβ (5).  Another study showed that chenodeoxycholic acid decreased miR-22 level through FXR regulation (7).  FXR transcriptionally regulates miR-22 by directly binding to the invert repeat 1 motif (7).  MiR-22, in return, targets Cyclin A2 (CCNA2). CCNA2 induces the cell cycle by activating cyclin-dependent kinase (2,7).  The study shows that levels of miR-22 in the ileum were significantly reduced in the FXR KO mice (7).  Increased expression of CCNA2 was found in FXR KO mice compared to the WT mice (7).  Conclusions. Colorectal cancer cells show decreased FXR expression and are unable to regulate the increased bile acids found in a Western diet (3).  Restoring FXR expression or using FXR agonists can be further studied for those at high risks for colorectal cancer (2,3).  Studies with microRNA-22 and microRNA-192 show potential as novel targets to inhibit colonic carcinogenesis (5,7).

 

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