Reg4 Interacts with CD44 to Regulate Proliferation and Stemness of Colorectal and Pancreatic Cancer Cells.

Unlabelled: Regenerating Gene 4 (Reg4) is highly upregulated in gastrointestinal (GI) malignancies including colorectal and pancreatic cancers. Numerous studies demonstrated an association between higher Reg4 expression and tumor aggressiveness, intrinsic resistance to apoptotic death, and poor outcomes from GI malignancies. However, the precise receptor and underlying signaling mechanism have remained unknown.

Reg4 and its downstream transcriptional activator CD44ICD in stage II and III colorectal cancer.

Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression.

Quality metrics of screening colonoscopies performed by PAs.

Background: Many communities face a shortage of qualified endoscopists. Training physician assistants (PAs) to perform colonoscopies can expand the availability of colorectal cancer screening. This study examined screening colonoscopy metrics and quality indicators among gastroenterologists, supervised PAs, and gastroenterology fellows.

IDO1 and Kynurenine Pathway Metabolites Activate PI3K-Akt Signaling in the Neoplastic Colon Epithelium to Promote Cancer Cell Proliferation and Inhibit Apoptosis.

The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium.

Reg4-induced mitogenesis involves Akt-GSK3β-β-Catenin-TCF-4 signaling in human colorectal cancer.

Upregulation of regenerating gene 4 (Reg4) is observed in many human gastrointestinal malignancies including colorectal cancer (CRC). We previously reported a Reg4-mediated induction of epidermal growth factor receptor-Akt-AP1 signaling regulating CRC cell apoptosis. However, the role of Reg4 in the regulation of CRC cell division is poorly understood.

Toll-like receptor-7 ligand Imiquimod induces type I interferon and antimicrobial peptides to ameliorate dextran sodium sulfate-induced acute colitis.

Background: The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Certain stimulators of innate immunity (CpG DNA or GM-CSF) are reported to be anti-inflammatory in IBD. Toll-like receptor-7 (TLR7) is an important regulator of innate immunity and its activation plays a key role in induction of type I interferon (IFN).

RNA binding protein CUGBP2/CELF2 mediates curcumin-induced mitotic catastrophe of pancreatic cancer cells.

Background: Curcumin inhibits the growth of pancreatic cancer tumor xenografts in nude mice; however, the mechanism of action is not well understood. It is becoming increasingly clear that RNA binding proteins regulate posttranscriptional gene expression and play a critical role in RNA stability and translation. Here, we have determined that curcumin modulates the expression of RNA binding protein CUGBP2 to inhibit pancreatic cancer growth.

Dendritic cells produce CXCL13 and participate in the development of murine small intestine lymphoid tissues.

In the adult intestine, luminal microbiota induce cryptopatches to transform into isolated lymphoid follicles (ILFs), which subsequently act as sites for the generation of IgA responses. The events leading to this conversion are incompletely understood. Dendritic cells (DCs) are components of cryptopatches (CPs) and ILFs and were therefore evaluated in this process.

NOD2 status and human ileal gene expression.

Background: NOD2 single nucleotide polymorphisms have been associated with increased risk of ileal Crohn's disease (CD). This exploratory study was conducted to compare ileal mucosal gene expression in CD patients with and without NOD2 risk alleles.

Methods: Ileal samples were prospectively collected from 18 nonsmoking CD patients not treated with anti-TNF-α biologics and 9 nonsmoking control patients without inflammatory bowel disease undergoing initial resection and genotyped for the 3 major NOD2 risk alleles (Arg702Trp, Gly908Arg, Leu1007fs).

Reg IV regulates normal intestinal and colorectal cancer cell susceptibility to radiation-induced apoptosis.

Background & Aims: Regenerating (Reg) gene IV is predominantly expressed in gastrointestinal cells and highly up-regulated in many gastrointestinal malignancies, including colorectal cancer (CRC). Human CRC cells expressing higher levels of Reg IV gene and its protein product (Reg IV) are resistant to conventional therapies, including irradiation (IR). However, the underlying mechanism is not well defined.

Loss of p21Waf1/Cip1/Sdi1 enhances intestinal stem cell survival following radiation injury.

The microcolony assay following gamma irradiation (IR) is a functional assay of intestinal stem cell fate. The cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1/Sdi1) (p21) regulates cell cycle arrest following DNA damage. To explore the role of p21 on stem cell fate, we examined the effects of p21 deletion on intestinal crypt survival following IR and expression of the stem/progenitor cell marker Musashi-1 (Msi-1) and the antiapoptotic gene survivin.

Knockdown of RNA binding protein musashi-1 leads to tumor regression in vivo.

Background & Aims: In the gut, tumorigenesis is thought to arise from the stem cell population located near the base of intestinal and colonic crypts. The RNA binding protein musashi-1 (Msi-1) is a putative intestinal and progenitor/stem cell marker. Msi-1 expression is increased during rat brain development and in APC(min/+) mice tumors.

REG1A expression is a prognostic marker in colorectal cancer and associated with peritoneal carcinomatosis.

By expression profiling of early staged colon carcinomas, we found regenerating islet-derived 1 alpha (REG1A) to be upregulated in patients with an unfavorable clinical outcome. For validation, REG1A expression was quantified in another colorectal cancer (CRC) patient cohort by Taqman PCR. Aside from tumor and normal tissue from 63 nonpretreated CRC patients, 31 mucosa biopsies from healthy individuals as well as 22 adenomas were included in the investigation.

Gastrin-mediated interleukin-8 and cyclooxygenase-2 gene expression: differential transcriptional and posttranscriptional mechanisms.

Background & Aims: Gastrin induces the expression of cyclooxygenase (COX)-2 and interleukin (IL)-8; however, the mechanism(s), especially in gastric epithelial cells, is not well understood. Here, we have determined the intracellular mechanisms mediating gastrin-dependent gene expression.

Methods: AGS-E human gastric cancer cell line stably expressing cholecystokinin-2 receptor was treated with amidated gastrin-17.

Diphenyl difluoroketone: a curcumin derivative with potent in vivo anticancer activity.

Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was reported to inhibit proliferation of a variety of cancer cells in vitro. However, the efficacy and in vivo mechanism of action of EF24 in gastrointestinal cancer cells have not been investigated. Here, we assessed the in vivo therapeutic effects of EF24 on colon cancer cells.

Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis.

Background: Sargramostim, granulocyte macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Clinical trials show that sargramostim induces clinical response and remission in patients with active Crohn's disease. To study the mechanism, we examined the effects of GM-CSF in the dextran sulfate sodium (DSS)-induced acute colitis model.

Characterization of cecal gene expression in a differentially susceptible mouse model of bacterial-induced inflammatory bowel disease.

Background: A/JCr mice develop typhlitis in response to Helicobacter hepaticus infection, whereas C57BL/6 mice coexist with this bacterium in a "commensal" relationship and do not develop disease even during prolonged colonization.

Methods: To determine mechanisms that control this balance between responsiveness and nonresponsiveness, the mucosal response of A/JCr and C57BL/6 mice to acute H. hepaticus colonization was evaluated using genome-wide profiling.

Expression of the genes dual oxidase 2, lipocalin 2 and regenerating islet-derived 1 alpha in Crohn's disease.

Objective: A global gene expression profile of non-inflamed colonic mucosal cells from patients with Crohn's disease (CD) and of colonic mucosal cells from controls was performed.

Material And Methods: Tissue specimens from macroscopically non-inflamed descending colon were obtained colonoscopically from 33 CD patients and from 17 control subjects. All controls and 10 CD patients were medication-free at the time of colonoscopy.

Functional antagonism between RNA binding proteins HuR and CUGBP2 determines the fate of COX-2 mRNA translation.

Background And Aims: Cyclooxygenase-2 (COX-2) expression is regulated at the levels of messenger RNA (mRNA) stability and translation by AU-rich elements (ARE) located in its 3' untranslated region (3'UTR). Although structurally homologous RNA binding proteins HuR and CUGBP2 stabilize COX-2 mRNA, HuR induces whereas CUGBP2 inhibits COX-2 mRNA translation. This study aimed to determine the antagonism between these proteins on COX-2 expression.

Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes.

Expression of anti-apoptotic genes is frequently elevated in tumors, where they increase resistance to chemotherapeutic agents and predict poor patient outcomes. However, key cellular factors regulating anti-apoptotic genes in tumors remain unknown. Increased expression of the regenerating (Reg) genes is commonly observed in gastrointestinal (GI) malignancies including colorectal cancer (CRC).

Growth factors as treatment options for intestinal inflammation.

On the basis of several studies that have been completed to date, some growth factors appear promising for the treatment of inflammatory bowel disease: keratinocyte-like growth factor-2 (KGF-2), epidermal growth factor (EGF) enemas used in combination with oral mesalamine, somatropin (human growth hormone), and sargramostim (recombinant human GM-CSF). The results of these studies are highlighted and suggest that new insights into the regulation of intestinal immunity may provide effective synergistic or single-agent treatment alternatives to immunosuppression for inflammatory bowel disease. These data focus on the reparative components of mucosal homeostasis.

Pancreatic regenerating protein (reg I) and reg I receptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis.

Aim: Pancreatic regenerating protein (reg I) stimulates pancreatic regeneration after pancreatectomy and is mitogenic to ductal and beta-cells. This suggests that reg I and its receptor may play a role in recovery after pancreatic injury. We hypothesized that reg I and its receptor are induced in acute pancreatitis.

Molecular biology of the small intestine.

Purpose Of Review: A concise report of published research is presented here that has provided new insights into the molecular and cell biology of the small intestine.

Recent Findings: The precise control of cell renewal lineage commitment, differentiation and apoptosis along the crypt-villus axis are regulated by paracrine and autocrine signaling pathways that include Wnt, Hedgehog and Notch ligands. The downstream signaling pathways and transcriptional control of gene expression are being elucidated.

Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas.

Background & Aims: Reg IV, a secreted protein and member of the Reg multigene family, is up-regulated in malignancies of the human gastrointestinal tract, including colorectal carcinoma (CRC). However, in vitro signal transduction pathway(s) utilized by Reg IV are not yet known.

Methods: To determine the signaling pathway(s) responsive to Reg IV, we examined the effects of purified recombinant human Reg IV (rhR4) on HCT116 and HT29 colon adenocarcinoma cells.