Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell adhesion molecule expression has been linked to disease outcome in prostatic adenocarcinomas (PACs). We evaluated the coordinated expression of catenin-related proteins, E-cadherin, N-cadherin, and CD44s in PACs. Archival sections from 112 PACs were immunostained by an automated method (Ventana Medical Systems, Tucson, AZ) using monoclonal antibodies to alpha- and beta-catenins, p120CTN, E-cadherin, N-cadherin, and CD44s proteins. Immunoreactivity was semiquantitatively scored, and results were evaluated for association between these markers. Staining results were also correlated with tumor grade, stage, ploidy, preoperative serum PSA, and postoperative biochemical disease recurrence. Decreased expression of alpha- and beta- catenins, p120CTN, E-cadherin, and CD44s proteins (range, 5% to 49%) was noted in PACs, and downregulation of each of these proteins correlated with high tumor grade (P =.02 to.0001). Although loss of E-cadherin and p120CTN each correlated with stage (E-cadherin, P =.02; p120CTN, P =.02) and ploidy (E-cadherin, P =.0001; p120CTN, P =.004), downregulation of CD44s correlated with ploidy (P =.002), serum PSA (P =.005), and postoperative disease recurrence (P =.02). N-cadherin was positive in only 5% of PACs and did not correlate with any prognostic parameters. alpha-Catenin downregulation correlated with decreased expression of E-cadherin (P =.0001). Additionally, decreased expression of each of these 2 proteins respectively correlated with loss of beta-catenin (P =.0001 and.004), p120CTN (P =.005 and.001), and CD44s (P =.008 and.01). beta-Catenin expression levels correlated with p120CTN (P =.01). A trend for co-downregulation of CD44s and p120CTN and of CD44s and beta-catenin was observed. In conclusion, the significant association between decreased expression of various members of the CAM family of proteins supports their collective role in mediating cell-cell adhesion. Altered expression of these proteins may be of prognostic value in patients with prostate cancer.
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PMID:Co-downregulation of cell adhesion proteins alpha- and beta-catenins, p120CTN, E-cadherin, and CD44 in prostatic adenocarcinomas. 1152 Dec 30

WNT2 is one of proto-oncogenes with the potential to activate the WNT - beta-catenin - TCF signaling pathway, which is most homologous to WNT2B among members of the human WNT gene family. Here, expression of WNT2 mRNA was comprehensively investigated. WNT2 mRNAs were highly expressed in fetal lung, and weakly expressed in placenta. Among 2.0-, 2.9-, 4.1-, and 6.0-kb WNT2 mRNAs, the 2.0-kb WNT2 mRNA was the major transcript in fetal lung. In 3 cases of prostate cancer and 1 case each of lung cancer and cervical cancer, WNT2 was over-expressed in non-cancerous portion as well as in primary tumor. WNT2 was up-regulated in 14 out of 18 cases of primary colorectal cancer, 4 out of 7 cases of uterus tumor, 2 out of 9 cases of breast cancer, and in 2 out of 14 cases of kidney tumor. Up-regulation of WNT2 was also detected in 4 out of 8 cases of primary gastric cancer by using expression array filter hybridization, and in 10 out of another 10 cases of primary gastric cancer by using cDNA-PCR. Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer might play a key role in carcinogenesis through activation of the WNT - beta-catenin - TCF signaling pathway.
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PMID:Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. 1160 1

The androgen-signaling pathway is important for the growth and progression of prostate cancer cells. The growth-promoting effects of androgen on prostate cells are mediated mostly through the androgen receptor (AR). There is increasing evidence that transcription activation by AR is mediated through interaction with other cofactors. beta-Catenin plays a critical role in embryonic development and tumorigenesis through its effects on E-cadherin-mediated cell adhesion and Wnt-dependent signal transduction. Here, we demonstrate that a specific protein-protein interaction occurs between beta-catenin and AR. Unlike the steroid hormone receptor coactivator 1 (SRC1), beta-catenin showed a strong interaction with AR but not with other steroid hormone receptors such as estrogen receptor alpha, progesterone receptor beta, and glucocorticoid receptor. The ligand binding domain of AR and the NH(2) terminus combined with the first six armadillo repeats of beta-catenin were shown to be necessary for the interaction. Through this specific interaction, beta-catenin augments the ligand-dependent activity of AR in prostate cancer cells. Moreover, expression of E-cadherin in E-cadherin-negative prostate cancer cells results in redistribution of the cytoplasmic beta-catenin to the cell membrane and reduction of AR-mediated transcription. These data suggest that loss of E-cadherin can elevate the cellular levels of beta-catenin in prostate cancer cells, which may directly contribute to invasiveness and a more malignant tumor phenotype by augmenting AR activity during prostate cancer progression.
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PMID:Linking beta-catenin to androgen-signaling pathway. 1179 9

We provide evidence that the androgen receptor (AR) can promote nuclear translocation of beta-catenin in LNCaP and PC3 prostate cancer cells. Using AR-expressing cells (LNCaP) and non-AR-expressing cells (PC3) we showed by time course cell fractionation that the AR can shuttle beta-catenin into the nucleus when exposed to exogenous androgen. Cells exposed to the synthetic androgen, R1881, show distinct, punctate, nuclear co-localization of the AR and beta-catenin. We further showed that the AR does not interact with adenomatous polyposis coli or glycogen synthase kinase-3beta and, therefore, conclude that androgen-mediated transport of beta-catenin occurs through a distinct pathway. The minimal necessary components of the AR and beta-catenin required for binding nuclear accumulation of beta-catenin nuclear import appears to be the DNA/ligand binding regions and the Armadillo repeats of beta-catenin. We also employed a novel DNA binding assay to illustrate that beta-catenin has the capacity to bind to the probasin promoter in an AR-dependent manner. The physiological relevance of AR-mediated transport of beta-catenin and binding to an AR promoter appeared to be a substantial increase in AR transcriptional reporter activity. AR-mediated import represents a novel mode of nuclear accumulation of beta-catenin.
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PMID:The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. 1185 48

SOX transcription factors with high-mobility-group DNA-binding domain (HMG box) play key roles in embryogenesis. Some members of the SOX family are negative regulators of the WNT-beta-catenin-TCF signaling pathway. We have previously cloned and characterized human SOX17, constituting a subfamily with SOX7 and SOX18. Another group mapped SOX7 gene to human chromosome 8p22, and reported almost ubiquitous expression of 5.0-kb SOX7 mRNA in human normal tissues. Here, expression of SOX7 mRNA was investigated by using SOX7 specific probe, which hybridized to 3.8-kb human SOX7 mRNA, but not to 5.0-kb mRNA. SOX7 mRNA was relatively highly expressed in adult lung, trachea, lymph node, placenta, fetal lung, and heart. In adult heart, SOX7 mRNA was more highly expressed in ventricules, inter-ventricular septum and apex than in atriums. SOX7 mRNA was significantly up-regulated in pancreatic cancer cell lines BxPC-3, PSN-1, Hs766T, and in 4 cases out of 8 cases of primary gastric cancer. SOX7 mRNA was relatively highly expressed in a gastric cancer cell line MKN45, esophageal cancer cell lines TE2, TE3, TE4, TE5, TE7, TE8, TE11, TE12, and TE13. On the other hand, SOX7 mRNA was significantly down-regulated in 7 out of 18 cases of primary colorectal tumors, in 4 out of 9 cases of primary breast cancer, in 4 out of 14 cases of primary kidney tumors, and also in some cases of primary lung and prostate cancer. SOX7 gene might be one of cancer-associated genes on human chromosome 8p22.
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PMID:Expression of human SOX7 in normal tissues and tumors. 1189 28

Understanding the molecular etiology of prostate cancer (CaP) progression is paramount for broadening current diagnostic and therapeutic modalities. Current interest in the role of wnt pathway signaling in prostate tumorigenesis was generated with the finding of beta-catenin mutation and corresponding nuclear localization in primary lesions. The recent finding of beta-catenin-induced enhancement of androgen receptor (AR) function potentially ties beta-catenin to key regulatory steps of prostate cell growth, differentiation, and transformation. By immunohistological analysis of metastatic tumors, we detected nuclear beta-catenin in 20% of lethal CaP cases, suggesting a more common role for beta-catenin in advanced disease than would be predicted by its mutation rate. Interestingly, beta-catenin nuclear localization was found to occur concomitantly with androgen-induced regrowth of normal rat prostate. These in vivo observations likely implicate beta-catenin involvement in both normal and neoplastic prostate physiology, thus prompting our interest in further characterizing modes of beta-catenin signaling in prostate cells. Extending our previous findings, we demonstrate that transient beta-catenin over-expression stimulates T cell factor (TCF) signaling in most CaP cell lines. Further, this activity is not subject to cross-regulation by phosphoinositide-3-kinase (PI3-K)/Akt signaling, a stimulatory pathway often upregulated in CaP upon PTEN inactivation. Consistent with a previous report, we observed that transient beta-catenin over-expression enhances AR-mediated transcription off two natural target gene promoters. However, we were unable to recapitulate beta-catenin-induced stimulation of ectopically expressed AR in AR-negative cells, suggesting that other AR-associated factors are required for this activity. Although LNCaP cells are capable of this mode of AR co-stimulation, stable expression of mutant beta-catenin did not alter their proliferative response to androgen. In total, our characterization of beta-catenin signaling in CaP reveals the complex nature of its activity in prostate tissue, indicating that beta-catenin potentially contributes to multiple stimulatory inputs required for disease progression.
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PMID:In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. 1196 41

The present study documents that stabilization of beta-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized beta-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of beta-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating beta-catenin expressing basal cells. Our observations indicate that beta-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate.
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PMID:Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia. 1203 66

PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin. Given the recent evidence that beta-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces beta-catenin-mediated augmentation of AR transactivation. Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta-regulated degradation of beta-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways and provide fresh insights into the mechanisms of prostate tumor development and progression.
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PMID:Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. 1206 52

D-RNAi (Messenger RNA-antisense DNA interference), a novel posttranscriptional phenomenon of silencing gene expression by transfection of mRNA-aDNA hybrids, was originally observed in the effects of bcl-2 on phorbol ester-induced apoptosis in human prostate cancer LNCaP cells. This phenomenon was also demonstrated in chicken embryos and a human CD4(+) T cell line, H9. The in vivo transduction of beta-catenin D-RNAi was shown to knock out more than 99% endogenous beta-catenin gene expression, while the in cell transfection of HIV-1 D-RNAi homolog rejected viral gene replication completely. D-RNAi was found to have long-term gene knockout effects resulting from a posttranscriptional gene silencing mechanism that may involve the homologous recombination between intracellular mRNA and the mRNA components of a D-RNAi construct. These findings provide a potential intracellular defense system against cancer and viral infections.
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PMID:D-RNAi (messenger RNA-antisense DNA interference) as a novel defense system against cancer and viral infections. 1218 82

The E-cadherin protein mediates Ca(2+)-dependent interepithelial adhesion. Association of E-cadherin with the catenin family of proteins is critical for the maintenance of a functional adhesive complex. We have identified a novel truncated E-cadherin species of 100-kDa (E-cad(100)) in prostate and mammary epithelial cells. E-cad(100) was generated by treatment of cells with ionomycin or TPA. Cell-permeable calpain inhibitors prevented E-cad(100) induction by ionomycin. Immunoblotting for spectrin and mu-calpain confirmed calpain activation in response to ionomycin treatment. Both the mu- and m-isoforms of calpain efficiently generated E-cad(100) in vitro. The E-cad(100) fragment was unable to bind to beta-catenin, gamma-catenin, and p120, suggesting that this cleavage event would disrupt the E-cadherin adhesion complex. Mutational analysis localized the calpain cleavage site to the cytosolic domain upstream of the beta- and gamma-catenin binding motifs of E-cadherin. Because E-cadherin is inactivated in many adenocarcinomas we hypothesized that calpain may play a role in prostate tumorigenesis. A prostate cDNA microarray data base was analyzed for calpain expression in which it was found that m-calpain was up-regulated in localized prostate cancer, and to an even higher degree in metastatic prostate cancer compared with normal prostate tissue. Furthermore, we examined the cleavage of E-cadherin in prostate cancer specimens and found that E-cad(100) accumulated in both localized and metastatic prostate tumors, supporting the cDNA microarray data. These findings demonstrate a novel mechanism by which E-cadherin is functionally inactivated through calpain-mediated proteolysis and suggests that E-cadherin is targeted by calpain during the tumorigenic progression of prostate cancer.
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PMID:The role of calpain in the proteolytic cleavage of E-cadherin in prostate and mammary epithelial cells. 1239 69


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