Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

Oduwole, Olayiwola; Isomaa, Veli; Nokelainen, Pasi; Stenbäck, Frej; Vihko, Pirkko

doi:10.1002/ijc.1567

Cited by 42 publications

(41 citation statements)

References 43 publications

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“…33 It has been shown that acid mucin is a major component of normal gastrointestinal epithelial cells whereas neutral mucins are found in adenomas and in early colonic malignancies with less differentiation. 34,35 The significance of this unexpected finding is as yet unclear, but raises a number of interesting possibilities. Fascin overexpression could be responsible for an increase in cell proliferation resulting in a less differentiated phenotype.…”

Section: Discussionmentioning

confidence: 99%

Fascin, an Actin-Bundling Protein, Modulates Colonic Epithelial Cell Invasiveness and Differentiation in Vitro

Jawhari¹,

Buda²,

Jenkins³

et al. 2003

The American Journal of Pathology

179

191

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In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phe- Epithelial cell differentiation is fundamentally influenced by cell-matrix and cell-cell interactions. [1][2][3] In colonic epithelial cells, both the integrin and cadherin superfamilies of adhesion molecules are important contributors to the establishment of cell polarity and epithelial cell differentiation, and have been shown to play a role in the control of colorectal differentiation in tumor cells. 4,5 This is partly achieved through the formation of intracellular protein assemblies that anchor cytoskeletal actin filaments at defined areas within the cell membrane. In epithelial cells, these zones correspond to integrin-dependent focal adhesions and cadherin-containing adherens junctions and desmosomes. 6 These assemblies also function as important links in the integration of multiple cell signaling pathways. 3 Cell-matrix and cell-cell adhesive interactions normally stabilize the epithelial cell layer and maintain the cells in a nonmigratory state. However, the malignant conversion of epithelial cells involves a phenotypic switch to a migratory state that enables tumor invasion beyond the basement membrane and metastasis. The process of cell migration is poorly understood in epithelial cells, but studies in many types of carcinoma cells have documented increased formation of cell protrusions at cell margins, release of cell-cell contacts, and group movement of sheets of cells. In the models of cell motility that have been developed from studies of fibroblasts, protru...

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Section: Discussionmentioning

confidence: 99%

Fascin, an Actin-Bundling Protein, Modulates Colonic Epithelial Cell Invasiveness and Differentiation in Vitro

Jawhari¹,

Buda²,

Jenkins³

et al. 2003

The American Journal of Pathology

179

191

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“…For example, in human colorectal cancer cell lines, estradiol has been shown to activate the mitogenactivated protein kinase cascade, a pathway that plays a key role in the stimulation of DNA and protein synthesis, which induces cell growth and proliferation (10,11). In addition, colorectal cancer tissue was found to have higher levels of estradiol activity compared with nonmalignant colorectal tissue (34,35), and a cross-sectional study of colon cancer patients reported that colon carcinoma tissue had a statistically significant twofold higher level of total estrogen compared with normal colon mucosa (36). Low concentrations of intratumoral estrogen were also statistically significantly associated with better prognosis (36), and higher levels of estrogen receptor beta expression were reported in colorectal carcinomas compared with normal colonic mucosa (37).…”

Section: Discussionmentioning

confidence: 99%

Reproductive history and risk of colorectal cancer in postmenopausal women.

Zervoudakis¹,

Schatzkin²,

Strickler³

et al. 2010

JCO

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Colorectal cancer is the fourth most common cancer and the second leading cause of cancer death in the United States, with approximately 142 570 new cases and 51 370 colorectal cancer-related deaths expected in 2010 (1). Observational and experimental evidence suggest that sex hormones, particularly estrogen, play a role in colorectal cancer pathogenesis (2). Most notably, a substantial body of epidemiological data supports an inverse relationship between postmenopausal oral hormone therapy use and the risk of colorectal cancer (3), an association that was confirmed by results of the Women's Health Initiative (WHI) Clinical Trial, which reported a statistically significant decreased risk of colorectal cancer among women using estrogen plus progestin formulations (but not among women using estrogen alone) compared with women using placebo (4,5).By contrast, two subsequent prospective studies reported a positive association between endogenous estrogen level and the risk of colorectal cancer in postmenopausal women. The first investigation, which was conducted in the WHI Observational Study, found that a high endogenous level of estrogen was associated with a 1.5-fold increased risk of developing colorectal cancer after adjustment for established colorectal cancer risk factors (6). Similarly, the New York University Women's Health Study reported a 60% increased risk of colorectal cancer for women in the highest quartile of circulating estrogen level compared with those in the lowest quartile (7). The positive associations between endogenous estrogen level and the risk of colorectal cancer reported by these investigations are consistent with laboratory data demonstrating the proliferative effects of exogenous estradiol in colorectal tissue and in colorectal cancer cell lines (8-11). The findings from these observational and experimental studies, when considered together with the data on hormone therapy use and colorectal cancer, suggest that endogenous and exogenous sex hormones may play different roles in colorectal tumorigenesis.

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“…6 In addition to this classic ligand-dependent pathway, ER function may also be modulated by extracellular signals in the absence of E2 or a ligandindependent manner. 7,8 ERs are members of the evolutionary conserved nuclear receptor superfamily of ligand-inducible transcription factors. ERa and ERb exhibit a modular structure consisting of 6 well-defined functional domains (A-F).…”

mentioning

confidence: 99%

Expression of Estrogen Receptor β in Colon Cancer Progression

Castiglione

Taddei²,

Degl’Innocenti³

et al. 2008

Diagnostic Molecular Pathology

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Colon cancer is the most frequent neoplasia of the intestine. This pathology is the third highest cause of death from cancer with 430,000 deaths globally per year. Estrogen has also been implicated in the development and progression of colon cancer. Also sex-specific differences have been suggested to be involved in the process. Previous studies have shown the estrogen b receptor to be the dominant receptor type in normal colonic tissue and its down-regulation along with the progression of colorectal cancer. The presence of estrogen receptors and products of estrogen-related genes in the colon suggests that estrogens have direct effects on the colonic tissue. However, the specific effect of estrogens on a normal colon and the role in the colon carcinogenesis are far from clear. The aim of this study is to analyze by real-time polymerase chain reaction, the relative quantitative expression of the estrogen receptors b, b1, b2, and b5 in colon adenocarcinomas and to compare this expression with the respective in normal tissues. Moreover, we evaluate a possible correlation between estrogen's receptor expressions and disease stages. Normal tissues show estrogen receptor b expression greater than pathologic tissues and the estrogen receptor b result as most expressed in the lower disease stages.

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Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

Cited by 42 publications

References 43 publications

Fascin, an Actin-Bundling Protein, Modulates Colonic Epithelial Cell Invasiveness and Differentiation in Vitro

Fascin, an Actin-Bundling Protein, Modulates Colonic Epithelial Cell Invasiveness and Differentiation in Vitro

Reproductive history and risk of colorectal cancer in postmenopausal women.

Expression of Estrogen Receptor β in Colon Cancer Progression

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