The Intestinal Nuclear Receptor Signature With Epithelial Localization Patterns and Expression Modulation in Tumors

Background & Aims

The WNT–adenomatous polyposis coli system controls cell fate in the intestinal epithelium, where compartment-specific genes tightly regulate proliferation, migration, and differentiation. Nuclear receptors are transcription factors functioning as sensors of hormones and nutrients that are known to contribute to colon cancer progression. Here we mapped the messenger RNA (mRNA) abundance and the epithelial localization of the entire nuclear receptor family in mouse and human intestine.

Methods

We used complementary high-resolution in situ hybridization and systematic real-time quantitative polymerase chain reaction in samples of normal distal ileum and proximal colon mucosa and tumors obtained from mouse and human adenomatous polyposis coli–initiated tumor models (ie, Apc^Min/+ mice and familial adenomatous polyposis patients) and in cellular models of human colon cancer.

Results

We first defined for each receptor an expression pattern based on its transcript localization in the distal ileum and the proximal colon. Then, we compared the mRNA levels between normal intestinal epithelium and neoplastic intestinal tissue. After analyzing the correspondence between mouse and human tumor samples plus genetically modified human colon cancer cells, we used complementary graphic and statistical approaches to present a comprehensive overview with several classification trees for the nuclear hormone receptor intestinal transcriptome.

Conclusions

We defined the intestinal nuclear hormone receptor map, which indicates that the localization pattern of a receptor in normal intestine predicts the modulation of its expression in tumors. Our results are useful to select those nuclear receptors that could be used eventually as early diagnostic markers or targeted for clinical intervention in intestinal polyposis and cancer.

Abbreviations used in this paper: APC, adenomatous polyposis coli, AR, androgen receptor, CAR, constitutive androstane receptor, CKI, casein kinases I, COUP-TF, Chicken ovalbumin upstream promoter-transcription factor, CRC, colo-rectal cancer, DAX-1, Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1, ER, estrogen receptor, ERR, estrogen-related receptor, FAP, Familial Adenomatous Polyposis, FXR, farnesoid X receptor, GCNF, germ cell nuclear factor, GR, glucocorticoid receptor, GSK3β, glycogen synthase kinase 3β, HNF, hepatocyte nuclear factor, KLF4, Krüppel-like factor 4, LRH-1, liver receptor homolog 1, LXR, liver X receptor, MR, mineralocorticoid receptor, NGFIB, neuronal growth factor 1B, NOR1, neuron-derived orphan receptor 1, NR, nuclear receptors, QPCR, quantitative real-time PCR, PNR, photoreceptor-specific nuclear receptor, PPAR, peroxisome proliferator-activated receptor, PR, progesterone receptor, PXR, pregnane X receptor, RAR, retinoic acid receptor, ROR, RAR-related orphan receptor, RXR, retinoid X receptor, SF1, steroidogenic factor 1, SHP, small heterodimer partner, TCF-4, T-cell factor 4, TF, transcription factors, TLX, human homologue of the drosophila tailless gene, TR, thyroid receptor, TR2, 4, testicular receptor 2, 4, VDR, vitamin D receptor