Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

c-Yes is a member of the c-Src family of tyrosine kinases and has been implicated in intracellular signaling, cell morphology, and adhesion. Changes in its expression have also been associated with the aggressiveness of human breast and colon cancer cells. In MDA-MB-231 human breast cancer cells, overexpression of the small heat shock protein 27 (hsp27) results in a downregulation of c-Yes levels, concomitant with increased in vitro invasiveness and in vivo metastatic behavior. Very little is known, however, about the mechanisms regulating c-Yes expression. Here, we demonstrate that hsp27-induced c-Yes downregulation is not due to a reduction in transcriptional activity. However, the 3'-untranslated region (3'-UTR) of the c-Yes gene may be involved in its own regulation, since this region affects heterologous reporter gene activity in transactivation assays. This down-regulatory effect maps to three adenine/uridine-rich elements (AREs) that bind to cellular HuR and AUF1 (hnRNP D), two ARE-binding proteins (ARE-BPs) implicated in accelerated mRNA degradation. Our results suggest that the c-Yes 3'-UTR contains at least three newly identified AREs which are bound specifically by ARE-BPs, and provide a structural basis for post-transcriptional regulation of c-Yes expression.
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PMID:The c-Yes 3'-UTR contains adenine/uridine-rich elements that bind AUF1 and HuR involved in mRNA decay in breast cancer cells. 1628 64

Maspin, a member of the Serpin protease inhibitor family, is overexpressed in poorly differentiated colorectal tumors and more frequently found in tumors with microsatellite instability. Immunohistochemical nuclear Maspin staining is predominantly seen in tumor cells at the invasion front of such cancers, suggesting that this molecule is associated with local tumor cell infiltration and aggressiveness. In a retrospective study, we studied nuclear Maspin expression as a potential prognostic tool in a total of 172 primary stage III colon cancers by immunohistochemistry. Of those 172 patients, 76 were treated by surgery only, and 96 patients received additional adjuvant 5-fluorouracil (5-FU) based chemotherapy. Nuclear Maspin expression was an independent adverse prognostic factor for overall survival in our patient cohort (hazard ratio 2.08; 95% CI, 1.13-3.81; p = 0.018). However, patients with primary tumors expressing Maspin in the nucleus showed a significant treatment benefit from 5-FU chemotherapy (hazard ratio 0.384; 95% CI, 0.188-0.784; p = 0.009) compared to adjuvantly treated patients whose tumors did not express this molecule. Nuclear Maspin expression is highly predictive of 5-FU chemotherapy response in patients with advanced stage colon cancer. Patients with negative immunohistochemical Maspin expression do not benefit from 5-FU treatment and may be candidates for an alternative (non-5-FU based) adjuvant therapy regime.
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PMID:Nuclear Maspin expression is associated with response to adjuvant 5-fluorouracil based chemotherapy in patients with stage III colon cancer. 1633 19

The pathogenesis of colon cancer is not well understood. This common type of cancer is generally believed to occur in a multistep process which involves alterations of various tumor suppressor genes and oncogenes during the progression through benign lesions towards carcinoma. TFF3 is a product of the colonic epithelium and has been implicated in colonic mucosal protection and also in the aggressiveness of colon cancer cells. The aim of this study was to analyze the expression of TFF3 during propagation towards cancer development in the human colon. Colonic tissues representing colitis, adenomatous polyposis, tubulovillous adenoma, and mucoid/adeno-carcinomas were processed for immunohistochemistry using an antibody specific for human TFF3. The results were correlated with those of PCNA-labeling, quantified, and compared with those of control tissues obtained from the safe margin of macroscopically normal colonic mucosa of patients with colon cancer. The data showed marked down-regulation of TFF3 expression in adenomatous polyposis, then TFF3 expression returns to about control level during adenoma and remains high during mucoid- and adeno-carcinomas. Colonic tissues with highly invasive cancer cells were characterized by statistically significant down-regulation of TFF3 expression. The changes observed in expression of TFF3 showed an inverse correlation with cell proliferation and suggest that it might play a protective role against colon carcinogenesis.
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PMID:Expression of TFF3 during multistep colon carcinogenesis. 1745 48

Proteins secreted (the secretome) from cancer cells are potentially useful as biomarkers of the disease. Using LC-MS/MS, the secreted proteomes from a series of isogenic breast cancer cell lines varying in aggressiveness were analyzed by mass spectrometry: nontumorigenic MCF10A, premalignant/tumorigenic MCF10AT, tumorigenic/locally invasive MCF10 DCIS.com, and tumorigenic/metastatic MCF 10CA cl. D. Proteomes were obtained from conditioned serum-free media, partially fractionated using a small reverse phase C2 column, and digested with trypsin for analysis by LC-MS/MS, using a method previously shown to give highly enriched secreted proteomes (Mbeunkui et al. J. Proteome Res. 2006, 5, 899-906). The search files produced from five analyses (three separate preparations) were combined for database searching (Mascot) which produced a list of over 250 proteins from each cell line. The aim was to discover highly secreted proteins which changed significantly in abundance corresponding with aggressiveness. The most apparent changes were observed for alpha-1-antichymotrypsin and galectin-3-binding protein which were highly secreted proteins from MCF10 DCIS.com and MCF10CA cl. D, yet undetected in the MCF10A and MCF10AT cell lines. Other proteins showing increasing abundance in the more aggressive cell lines included alpha-1-antitrypsin, cathepsin D, and lysyl oxidase. The S100 proteins, often associated with metastasis, showed variable changes in abundance. While the cytosolic proteins were low (e.g., actin and tubulin), there was significant secretion of proteins often associated with the cytoplasm. These proteins were all predicted as products of nonclassical secretion (SecretomeP, Center for Biological Sequence Analysis). The LC-MS/MS results were verified for five selected proteins by western blot analysis, and the relevance of other significant proteins is discussed. Comparisons with two other aggressive breast cancer cell lines are included. The protein with consistent association with aggressiveness in all lines, and in unrelated cancer cells, was the galectin-3-binding protein which has been associated with breast, prostate, and colon cancer earlier, supporting the approach and findings. This analysis of an isogenic series of cell lines suggests the potential usefulness of the secretome for identifying prospective markers for the early detection and aggressiveness/progression of cancer.
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PMID:Identification of differentially secreted biomarkers using LC-MS/MS in isogenic cell lines representing a progression of breast cancer. 1760 9

Apoptosis is a genetically programmed process of controlled and orderly cell suicide, which is critical for multicellular organisms during development and tissue homeostasis. In cancer, the ratio of apoptosis to cell division is altered, resulting in a net gain of malignant tissue. Tumor cells may acquire resistance to apoptosis by the expression of anti-apoptotic proteins, or by the down-regulation or mutation of pro-apoptotic mediators. In the classic pathway of apoptosis, this process is primarily coordinated by activation of caspases. Decreased expression of caspases inversely correlates with the aggressiveness of cancer. Increased activity of caspases renders cancer cells susceptible to chemoradiotherapeutic modalities. Thus, caspase activity is pivotal in carcinogenesis. The functions of activated caspases are inhibited by the binding of inhibitors of apoptosis (IAPs). The function of IAPs is regulated by pro-apoptotic protein Second Mitochondria-Derived Activator of Caspases (Smac) or Direct IAP Binding Protein with low isoelectric point, pI (DIABLO). Induction of apoptosis leads to increased mitochondrial permeability to Smac/DIABLO, which adheres to IAPs inhibiting their caspase-binding activity. The role of Smac/DIABLO, therefore, may have significant diagnostic and therapeutic features in carcinogenesis. The role of Smac/DIABLO in colorectal carcinogenesis is ill defined. Data continues to accumulate to suggest that decreased levels of Smac/DIABLO may be important in chemoradiation-resistance to apoptosis in advanced colon cancer. The aim of this review is to provide the available evidence of the role of Smac/DIABLO in colon carcinogenesis.
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PMID:Smac/DIABLO and colon cancer. 1763 Sep 21

The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent activities critical to the prevention of cancer in mice and humans. Recent evidence from mouse models suggests that when p53 is absent, further loss of ARF can widen the tumor spectrum, and potentiate invasion and metastasis. A major target of the p53-independent activity of ARF is the COOH-terminal binding protein (CtBP) family of metabolically regulated transcriptional corepressors, which are degraded upon acute exposure to the ARF protein. CtBPs are activated under conditions of metabolic stress, such as hypoxia, to repress epithelial and proapoptotic genes, and can mediate hypoxia-induced migration of cancer cells. The possibility that ARF could suppress tumor cell migration as part of its p53-independent activities was thus explored. Small-interfering RNA (siRNA)-mediated knockdown of ARF in human lung carcinoma cells led to increased cell migration, especially during hypoxia, and this effect was blocked by concomitant treatment with CtBP2 siRNA. Introduction of ARF into p53 and ARF-null human colon cancer cells inhibited hypoxia-induced migration. Furthermore, overexpression of CtBP2 in ARF-expressing cells enhanced cell migration, and an ARF mutant defective in CtBP-family binding was impaired in its ability to inhibit cell migration induced by CtBP2. ARF depletion or CtBP2 overexpression was associated with decreased PTEN expression and activation of the phosphatidylinositol 3-kinase pathway, and a phosphatidylinositol 3-kinase inhibitor blocked CtBP2-mediated cell migration. Thus, ARF can suppress cell migration by antagonizing CtBP2 and the phosphatidylinositol 3-kinase pathway, and these data may explain the increased aggressiveness of ARF-null tumors in mouse models.
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PMID:The alternative reading frame tumor suppressor antagonizes hypoxia-induced cancer cell migration via interaction with the COOH-terminal binding protein corepressor. 1790 40

Metastasis, the major cause of cancer death, is a multistep process that requires interactions between cancer cells and stromal cells and between cancer cells and extracellular matrix. Molecular alterations of the extracellular matrix in the tumor microenvironment have a considerable impact on the metastatic process during tumorigenesis. Here we report that elevated expression of betaig-h3/TGFBI (transforming growth factor, beta-induced), an extracellular matrix protein secreted by colon cancer cells, is associated with high-grade human colon cancers. Ectopic expression of the betaig-h3 protein enhanced the aggressiveness and altered the metastatic properties of colon cancer cells in vivo. Inhibition of betaig-h3 expression dramatically reduced metastasis. Mechanistically, betaig-h3 appears to promote extravasation, a critical step in the metastatic dissemination of cancer cells, by inducing the dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin alphavbeta5-Src signaling pathway. Thus, cancers associated with overexpression of betaig-h3 may have an increased metastatic potential, leading to poor prognosis in cancer patients.
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PMID:Extracellular matrix protein betaig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation. 1824 46

Colon cancer remains a leading cause of mortality worldwide despite the well-characterized molecular events in the adenoma-to-carcinoma sequence. There has been a strong emphasis on early detection of colon cancer, and fecal DNA-based methods have been developed to assist with early screening. Tissue-based assays have been utilized for many years to assess tumor aggressiveness and to determine prognosis and response to chemotherapeutic interventions. The most widely used serum marker for colon cancer (carcinoembryonic antigen) remains a useful modality to assess for occult disease following curative resection. Identification of tumor mutations in circulating tumor cells and microarray analysis holds a great deal of promise in the diagnosis and prognosis of patients with colorectal cancer. The inhibitors of apoptosis may be important markers to determine resistance to radiation cytotoxicity in rectal cancer. This report presents a summary of the current status of the molecular markers of colorectal cancer to establish a diagnosis, determine prognosis and chemoradiotherapeutic interventions, and assess relapse following curative surgery.
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PMID:Recent advances in the molecular diagnosis and prognosis of colorectal cancer. 1859 7

MicroRNAs (miRNA) are a class of small noncoding RNAs with important posttranscriptional regulatory functions. Recent data suggest that miRNAs are aberrantly expressed in many human cancers and that they may play significant roles in carcinogenesis. Here, we used microarrays to profile the expression of 315 human miRNAs in 10 normal mucosa samples and 49 stage II colon cancers differing with regard to microsatellite status and recurrence of disease. Several miRNAs were differentially expressed between normal tissue and tumor microsatellite subtypes, with miR-145 showing the lowest expression in cancer relative to normal tissue. Microsatellite status for the majority of cancers could be correctly predicted based on miRNA expression profiles. Furthermore, a biomarker based on miRNA expression profiles could predict recurrence of disease with an overall performance accuracy of 81%, indicating a potential role of miRNAs in determining tumor aggressiveness. The expression levels of miR-320 and miR-498, both included in the predictive biomarker, correlated with the probability of recurrence-free survival by multivariate analysis. We successfully verified the expression of selected miRNAs using real-time reverse transcription-PCR assays for mature miRNAs, whereas in situ hybridization was used to detect the accumulation of miR-145 and miR-320 in normal epithelial cells and adenocarcinoma cells. Functional studies showed that miR-145 potently suppressed growth of three different colon carcinoma cell lines. In conclusion, our results suggest that perturbed expression of numerous miRNAs in colon cancer may have a functional effect on tumor cell behavior, and, furthermore, that some miRNAs with prognostic potential could be of clinical importance.
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PMID:Diagnostic and prognostic microRNAs in stage II colon cancer. 1916 96

We report a case of endocrine cell carcinoma in the sigmoid colon with inferior mesenteric vein (IMV) tumor embolism. A 79-year-old woman was admitted to our hospital with narrowing of the stools. We performed colonoscopy, computed tomography and positron emission tomography, which disclosed sigmoid colon cancer with IMV tumor embolism. She underwent sigmoidectomy and lymph node dissection. The tumor was diagnosed as endocrine cell carcinoma (type 4, pSS, med, INFalpha, v3, n1, stage IIIb). Immunohistochemically, chromographin A, synaptophysin, cytokeratin 20 and mucicarmine showed partial staining, and CD56 was totally reactive. Three months after operation multiple liver metastases appeared. She was treated with chemotherapy of cisplatin (CDDP) + irinotecan (CPT11). This case highlights the aggressiveness of endocrine cell carcinoma with tumor embolism, and it is essential to establish an accurate diagnosis and effective treatment.
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PMID:A case report of endocrine cell carcinoma in the sigmoid colon with inferior mesenteric vein tumor embolism. 1913 78


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