Pro-neoplastic effects of amphiregulin in colorectal carcinogenesis.

Purpose: Epidermal growth factor (EGF) family plays critical roles in intestinal epithelial growth and transformation. Amphiregulin (AREG) is a member of the EGF family, and has been suggested to be more important to tumor versus normal growth. The precise roles of AREG in colorectal carcinogenesis have not been thoroughly elucidated.

Amphiregulin promotes intestinal epithelial regeneration: roles of intestinal subepithelial myofibroblasts.

Epidermal growth factor family plays critical roles in intestinal epithelial proliferation and differentiation. The precise function of amphiregulin (AREG), a member of the epidermal growth factor family, in intestinal biology is largely unknown. The present study attempted to address the functional roles of AREG in intestinal epithelial regeneration.

Autotaxin expression and its connection with the TNF-alpha-NF-kappaB axis in human hepatocellular carcinoma.

Background: Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive.

NF-kappaB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy.

Nuclear factor-kappaB (NF-kappaB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-kappaBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-kappaBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells.

Prostaglandin E2 and Krüppel-like transcription factors synergistically induce the expression of decay-accelerating factor in intestinal epithelial cells.

The decay-accelerating factor (DAF) prevents the intestinal mucosa from bystander killing by complement. Prostaglandin E(2) (PGE(2)) induces the expression of DAF that may protect the tumour environment from complement attack. In the present study, we demonstrate synergistic actions of PGE(2) and two Krüppel-like factors (KLFs), which are zinc finger-containing transcription factors, in DAF regulation.

Krüppel-like factor 5 mediates cellular transformation during oncogenic KRAS-induced intestinal tumorigenesis.

Background & Aims: Krüppel-like factor 5 (KLF5) is a zinc finger-transcription factor that regulates cell proliferation. Oncogenic KRAS mutations are commonly found in colorectal cancers. We aimed to determine whether KLF5 mediates KRAS functions during intestinal tumorigenesis.

Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin.

The persistent activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is oncogenic and involved in colorectal neoplasia. Mutations of both regulatory subunit and catalytic subunit of PI3K have been demonstrated in colon cancers. In the present study, we show that heterozygous disruption of the phosphatase and tensin homolog (PTEN) tumor suppressor gene promoted tumor progression in APC(min/+) mice.

PTEN expression contributes to the regulation of muscle protein degradation in diabetes.

Objective: Conditions accelerating muscle proteolysis are frequently associated with defective phosphatidylinositol 3-kinase (PI3K)/Akt signaling and reduced PI3K-generated phosphatidylinositol 3,4,5-triphosphate (PIP(3)). We evaluated the control of muscle protein synthesis and degradation in mouse models of type 1 and 2 diabetes to determine whether defects besides PI3K/Akt activities affect muscle metabolism.

Research Design And Methods: We evaluated the expression and activity of PTEN, the phosphatase converting PIP(3) to inactive phosphatidylinositol 4,5-bisphosphate, and studied how PTEN influences muscle protein in diabetic wild-type mice and in mice with partial deficiency of PTEN(+/-).

Prostaglandin E2 induces the expression of IL-1alpha in colon cancer cells.

PGE(2) has been shown to exert pro-oncogenic effects in colorectal neoplasia through producing autocrine or paracrine growth factors. In the present study, we demonstrate that PGE(2) induced the expression of IL-1alpha in colon cancer cells, which plays critical roles in tumor metastasis and neoangiogenesis in a variety of cancers. PGE(2) increased the levels of both IL-1alpha mRNA and protein, suggesting a positive feedback loop between the IL-1 pathway and PGE(2) signaling.

Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis.

Prostaglandins (PG) are produced throughout the gastrointestinal tract and are critical mediators for a complex array of physiologic and pathophysiologic processes in the intestine. Intestinal myofibroblasts, which express cyclooxygenase (COX) and generate PGE(2), play important roles in intestinal epithelial proliferation, differentiation, inflammation, and neoplasia through secreting growth factors and cytokines. Here, we show that PGE(2) activated human intestinal subepithelial myofibroblasts (18Co) through Gs protein-coupled E-prostanoid receptors and the cyclic AMP/protein kinase A pathway.

Prostaglandin E2 Stimulates the beta-catenin/T cell factor-dependent transcription in colon cancer.

Cyclooxygenase and its derived prostaglandin E2 (PGE2) have been shown to stimulate the growth of cancer cells and promote tumor angiogenesis. Here, we show that PGE2 activated the beta-catenin/T cell factor-dependent transcription in colon cancer cells through the cAMP/protein kinase A pathway. The expression of cyclin D1 and vascular endothelial growth factor was induced by PGE2 in LS-174T cells.

Up-regulation of the enzymes involved in prostacyclin synthesis via Ras induces vascular endothelial growth factor.

Background And Aims: The constitutive activation of Ras is an important step in the development and progression of several different cancers and is known to increase the level of cyclooxygenase 2 (COX-2). Prostaglandins are the downstream bioactive lipid mediators produced by the COX-2 enzyme. We sought to determine the role of Ras-induced up-regulation of the enzymes involved in prostacyclin biosynthesis in nontransformed rat intestinal epithelial cells (IECs).

Prostaglandin E2 synergistically enhances receptor tyrosine kinase-dependent signaling system in colon cancer cells.

Cyclooxygenase (COX)-generated prostaglandin E(2) (PGE(2)) plays critical roles in colorectal carcinogenesis. Recently, we have shown that PGE(2) and transforming growth factor-alpha synergistically induces the expression of amphiregulin (AR) in colon cancer cells (Shao, J., Evers, B.

Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal epithelial cells.

Phosphatidylinositol 3'-kinase (PI3K) activity is required for Ras- mediated transformation of intestinal epithelial cells (IECs). The mammalian target of rapamycin (mTOR) and its downstream pathways control the translation of specific mRNAs that are required for cell proliferation and transformation. Here, we elucidated the roles of PI3K and mTOR in K-Ras-mediated transformation of IECs (IEC-6).

Prostaglandin E2 stimulates the growth of colon cancer cells via induction of amphiregulin.

Prostaglandin E(2) (PGE(2)), a major product of cyclooxygenase enzymes, is implicated in colorectal carcinogenesis and has been shown to stimulate the growth of human colorectal carcinoma cells. Here, we show that PGE(2) activated the cyclic AMP/protein kinase A pathway, which induced the expression of amphiregulin (AR), an epidermal growth factor family member, through activation of a cyclic AMP-responsive element in the AR promoter. AR exerted a mitogenic effect on LS-174 cells and partially mediated the PGE(2)-induced growth stimulation.

Intestinal transformation results in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions.

Background: An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-beta 1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-beta 1 in colorectal carcinogenesis is not clear. We have previously described in detail the changes in cell proliferation and differentiation caused by chronic exposure to TGF-beta 1.

Peroxisome proliferator-activated receptors modulate K-Ras-mediated transformation of intestinal epithelial cells.

Activation of peroxisome proliferator-activated receptors (PPARs) exerts diverse effects on neoplastic cells. Recent work has shown that PPARdelta is up-regulated after loss of adenomatous polyposis coli tumor suppressor gene function and that transcriptional activation of the PPARgamma nuclear receptor can lead to inhibition of carcinoma growth. In this study, we elucidate the regulation and functional importance of PPARgamma and delta after K-Ras-transformation of intestinal epithelial cells.

Cyclin D3 is essential for intestinal epithelial cell proliferation.

Intestinal epithelium is a complex organ that undergoes continuous proliferation. D-type cyclins bind cyclin-dependent kinases (Cdk4 and Cdk6) and are expressed during the transition from G0 into the S phase. Previously, we reported that cyclins D1 and D3 are induced by growth factors in two rat intestinal epithelial cell lines, IEC-6 and RIE-1.