Induction of Cyclooxygenase-2 and Invasiveness by Transforming Growth Factor-β1 in Immortalized Mouse Colonocytes Expressing Oncogenic Ras

Roman, Christopher D.; Morrow, Jason D.; Whitehead, Robert H.; Beauchamp, R. Daniel

doi:10.1016/s1091-255x(01)00041-5

Cited by 14 publications

(12 citation statements)

References 38 publications

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“…Recent evidence has ascribed the TGF-␤-induced malignant conversion of epithelial cells to the up-regulation of COX-2 (23)(24)(25)(26)36). Shao et al (23) found that the TGF-␤-immunostaining pattern in metastatic human colon cancers was similar to that observed for COX-2.…”

Section: Discussionmentioning

confidence: 86%

“…Shao et al (23) found that the TGF-␤-immunostaining pattern in metastatic human colon cancers was similar to that observed for COX-2. Several studies have demonstrated that TGF-␤ collaborates with oncogenic Ras to induce the expression of COX-2 mRNA and protein in rodent colonocytes (24,26,36). Therefore, we compared the immunointensity of the COX-2 protein in TGF-␤1-positive and -negative human gastric carcinomas; however, COX-2 overexpression was rare in TGF-␤1-positive tumors.…”

Section: Discussionmentioning

confidence: 97%

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Concomitant Overexpression of Cyclooxygenase-2 in HER-2–Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome

Okano¹,

Shinohara²,

Miyamoto³

et al. 2004

Clinical Cancer Research

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Purpose: The expression of cyclooxygenase-2 (COX-2) is known to be involved in gastric carcinogenesis and tumor progression, but little is known about the mechanisms responsible for the up-regulation of COX-2. We examined the involvement of two growth factor-signaling systems, HER-2 and transforming growth factor (TGF)-␤, in the induction of COX-2 in human gastric cancer tissue.Experimental Design: COX-2 expression was detected by immunohistochemistry in surgical specimens obtained from 166 patients with advanced gastric cancer; possible correlations between the expression of COX-2 and the expression of HER-2, TGF-␤1, and Smad4, an intracellular mediator that transmits the TGF-␤ signal, were then analyzed.Results: COX-2 protein was overexpressed in 91 (54.8%) tumors; COX-2 overexpression was correlated with a differentiated histologic type, deep invasion, and positive lymph node metastasis. COX-2 was frequently overexpressed in HER-2-positive tumors (19 of 22, 86.4%) and in Smad4-reduced tumors (67 of 104, 64.4%) but irrelevant to the TGF-␤1 expression status. The expression levels of COX-2 and HER-2 and the reduction in Smad4 were all associated with a poor patient outcome. A multivariate analysis demonstrated a significantly poor outcome for the concomitant overexpression of COX-2 in patients with Smad4-reduced tumors.Conclusions: These results support the possibility that signal transduction via HER-2 and the TGF-␤/Smad system may be implicated in COX-2 expression and that the reduction of Smad4 may be, in part, of causal significance in the TGF-␤-initiated overexpression of COX-2, which is associated with a poor prognosis for patients with gastric cancer.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Concomitant Overexpression of Cyclooxygenase-2 in HER-2–Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome

Okano¹,

Shinohara²,

Miyamoto³

et al. 2004

Clinical Cancer Research

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“…RIE-1 cells were derived from normal small intestinal crypts from rats (36), and YAMC cells were derived from murine colon crypts conditionally immortalized with a temperature-sensitive simian virus 40 large T antigen (37). Both cell types display properties of normal intestinal epithelial cells (e.g., polarized growth, formation of tight adherens junctions, contact-mediated growth inhibition, and TGF-␤-mediated growth inhibition) and rapid ARE-mRNA turnover (21,22,38).…”

Section: Tgf-␤ Promotes P-body Formationmentioning

confidence: 99%

Transforming Growth Factor β Regulates P-Body Formation through Induction of the mRNA Decay Factor Tristetraprolin

Blanco

Sanduja

Deane

et al. 2014

Molecular and Cellular Biology

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dTransforming growth factor ␤ (TGF-␤) is a potent growth regulator and tumor suppressor in normal intestinal epithelium. Likewise, epithelial cell growth is controlled by rapid decay of growth-related mRNAs mediated through 3= untranslated region (UTR) AU-rich element (ARE) motifs. We demonstrate that treatment of nontransformed intestinal epithelial cells with TGF-␤ inhibited ARE-mRNA expression. This effect of TGF-␤ was promoted through increased assembly of cytoplasmic RNA processing (P) bodies where ARE-mRNA localization was observed. P-body formation was dependent on TGF-␤/Smad signaling, as Smad3 deletion abrogated P-body formation. In concert with increased P-body formation, TGF-␤ induced expression of the ARE-binding protein tristetraprolin (TTP), which colocalized to P bodies. TTP expression was necessary for TGF-␤-dependent P-body formation and promoted growth inhibition by TGF-␤. The significance of this was observed in vivo, where colonic epithelium deficient in TGF-␤/Smad signaling or TTP expression showed attenuated P-body levels. These results provide new insight into TGF-␤'s antiproliferative properties and identify TGF-␤ as a novel mRNA stability regulator in intestinal epithelium through its ability to promote TTP expression and subsequent P-body formation.

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“…In the mouse mammary epithelial cell lines RAC311 and C57MG, Wnt-1 expression induced stabilization of cytosolic β-catenin, morphological transformation and transcriptional up-regulation of the COX-2 gene, resulting in increased levels of COX-2 mRNA and protein [27]. Roman et al [28] found that induction of COX-2 and the release of prostaglandins E2 and I2 from mouse colonocytes was augmented by activated Ras and transforming growth factor (TGF)-β 1 . It has also been demonstrated that up-regulation of COX-2 is a downstream effect of Ras-mediated transformation in fibroblasts [29], intestinal epithelial cells [30], mammary epithelial cells [31] and non-small cell lung cancer cells [32].…”

Section: Regulation Of Cox-2 Expressionmentioning

confidence: 99%

Cyclooxygenase‐2 modulates cellular growth and promotes tumorigenesis

Trifan

Hla

2003

J Cellular Molecular Medi

162

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Cyclooxygenase (COX) -2 and the prostaglandins resulting from its enzymatic activity have been shown to play a role in modulating cell growth and development of human neoplasia. Evidence includes a direct relationship between COX-2 expression and cancer incidence in humans and animal models, increased tumorigenesis after genetic manipulation of COX-2, and significant anti-tumor properties of non-steroidal anti-inflammatory drugs in animal models and in some human cancers. Recent data showed that COX-2 and the derived prostaglandins are involved in control of cellular growth, apoptosis, and signal through a group of nuclear receptors named peroxisome proliferator-activated receptors (PPARs). In this article we will review some of the findings suggesting that COX-2 is involved in multiple cellular mechanisms that lead to tumorigenesis.

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Induction of Cyclooxygenase-2 and Invasiveness by Transforming Growth Factor-β1 in Immortalized Mouse Colonocytes Expressing Oncogenic Ras

Cited by 14 publications

References 38 publications

Concomitant Overexpression of Cyclooxygenase-2 in HER-2–Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome

Concomitant Overexpression of Cyclooxygenase-2 in HER-2–Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome

Transforming Growth Factor β Regulates P-Body Formation through Induction of the mRNA Decay Factor Tristetraprolin

Cyclooxygenase‐2 modulates cellular growth and promotes tumorigenesis

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