WNT1 inducible signaling pathway protein 1 (WISP1) plays a key role in many cellular functions in a highly tissue-specific manner; however the role of WISP1 in breast cancer is still poorly understood. Here, we demonstrate that WISP1 acts as an oncogene in human breast cancer. We demonstrated that human breast cancer tissues had higher WISP1 mRNA expression than normal breast tissues and that treatment of recombinant WISP1 enhanced breast cancer cell proliferation. Further, ectopic expression of WISP1 increased the growth of breast cancer cells in vitro and in vivo. WISP1 transfection also induced epithelial-mesenchymal-transition (EMT) in MCF-7 cells, leading to higher migration and invasion. During this EMT-inducing process, E-cadherin was repressed and N-cadherin, snail, and β-catenin were upregulated. Filamentous actin (F-actin) remodeling and polarization were also observed after WISP1 transfection into MCF-7 cells. Moreover, forced overexpression of WISP1 blocked the expression of NDRG1, a breast cancer tumor suppressor gene. Our study provides novel evidence that WISP1-modulated NDRG1 gene expression is dependent on a DNA fragment (−128 to +46) located within the human NDRG1 promoter. Thus, we concluded that WISP1 is a human breast cancer oncogene and is a potential therapeutic target.

These results suggested that the T3 upregulates proliferation of LNCaP cells by downregulating BTG2 gene expression through the consensus TRE pathway.

Epidemiologic data on treatment resistant depression (TRD) in Asia-Pacific countries are limited. We estimated the incidence of TRD in Taiwan using a cohort of 704,265 adults randomly sampled from Taiwan's National Health Insurance Research database for 2005. TRD was defined as a patient having pharmaceutically treated depression (PTD) not adequately responding to 2 antidepressant (AD) regimens, i.e., AD regimens that were followed by other AD regimens. Among 2751 PTD subjects, 576 (20.94%, 95% CI: 19.46, 22.49) developed TRD, a proportion similar to that in North American studies. TRD incidence was 0.82 (95% CI: 0.75, 0.89) cases /1000 population in 2005, increased with age, and was higher in females than in males. SSRI's were the most frequently used ADs. Augmentation with antipsychotics was common. The median time from PTD onset (first AD medication) to TRD onset was 416 days but psychiatrists practicing in Taiwan indicated they would switch within <=3 months if an AD medication was not effective. We therefore repeated the analysis with a 6 months cap on time from onset of PTD to TRD. In this supplemental, post-hoc, analysis, 68 PTD subjects, 2.47%, (95% CI: 1.94, 3.10) developed TRD; i.e., 0.10 (95% CI: 0.08, 0.12) incident cases/1000 population.

The experiments indicate that MT3 is an androgen-upregulated gene, and promotes tumorigenesis of prostate carcinoma cells. The downregulation of Ndrg1 and maspin gene expressions appears to account for the enhancement of proliferative and invasive functions of MT3 in PC-3 cells.

No abstract

Curcumin, a naturally occurring compound, exhibits anticancer chemopreventive effects. We evaluated the effects and mechanisms of curcumin on the gene expression of prostate-specific antigen (PSA) in human androgen-sensitive prostatic carcinoma cells. LNCaP cells were used to determine the effect of curcumin on PSA expression. Quantitative PSA expression was assessed by reverse transcription polymerase chain reaction (RT-PCR), enzymelinked immunosorbent assay (ELISA), and immunoblot assay. The modulation of androgen, interlukin-6 (IL-6), and prostate-derived Ets factor (PDEF) on the PSA gene was identified by transient gene expression assay with the use of a PSA reporter vector. The effect of curcumin on the activity of androgen receptors was evaluated by electrophoretic mobility shift assay (EMSA). Immunoblot assays, RT-PCR, and ELISA indicated that curcumin treatments blocked the stimulation of methyltrienolone (R1881) and IL-6 on PSA gene expression in LNCaP cells. The effects of curcumin appear to be mediated via the androgen response element of PSA gene. Results from immunoblot assay and EMSA revealed the modulation of curcumin on the expression of androgen receptor and androgen receptor binding activity on androgen response element of PSA gene. Although overexpression of PDEF dramatically enhanced PSA gene expression, the results of immunoblot assays and transient reporter assays indicated that curcumin treatments did not affect the gene expression of PDEF. Curcumin inhibits R1881-and IL-6-mediated PSA gene expression in LNCaP cells through downregulation of the expression and activity of androgen receptors.

Luteolin is a polyphenolic flavone and has antitumor activity for many cancers. The prostate-derived Ets factor (PDEF), a novel epithelium-specific Ets transcription factor, acts as an androgen-independent transcriptional activator of the prostate-specific antigen (PSA) promoter. We determined the antitumor function of luteolin via upregulation of PDEF gene expression in human prostate carcinoma LNCaP cells. Results from flow cytometry and Prostate derived Ets transcription factor (PDEF), a novel epithelium-specific Ets transcription factor, not only acts as an androgen-independent transcriptional activator of the prostate-specific antigen (PSA) promoter but also directly interacts with the DNA binding domain of androgen receptors (ARs) and enhances androgen-mediated activation of the PSA promoter.1 Studies indicate that silibinin and tectorigenin treatments decrease PSA secretion in human LNCaP cells through the downregulation of PDEF gene expression.2,3 Furthermore, transient overexpression of PDEF enhances PSA gene expression at the transcriptional and translational levels under androgen-free condition; however, curcumin treatments block PSA gene expression by a mechanism other than inhibition of the PDEF gene expression. 4,5 A recent study using proteomic analysis identified 286 proteins in the PDEF-associated protein complex involved in the cell cycle, DNA repair, cytoskeleton organization, mRNA processing and cell signaling in MDA-MB-231 human breast cancer cells. 6 A global gene expression analysis identified several genes, which are associated with PDEF expression, regulating cell migration during cancer progression. 7 In vitro and xenograft studies revealed that PDEF knock-down in prostate LNCaP and PC-3 cancer cells increased migration and invasiveness suggesting that PDEF is involved in the tumor biology of the human prostate. 8 Expression of B-cell translocation gene 2 (BTG2) in cycling cells induced accumulation of growth-inhibitory forms of pRb and led to G1 cell-cycle arrest.9 BTG2 is more abundantly expressed in prostate tissue with high epithelial

GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor with diverse biological functions. GPR56 expression is variably detected in human melanoma cell lines and correlates inversely with the metastatic potential of melanoma lesions. GPR56 associates with the tetraspanins CD9 and CD81 on the melanoma cell surface. GPR56 activation by immobilized CG4 monoclonal antibody facilitates N-terminal fragment dissociation in a CD9/CD81-dependent manner specifically inducing IL-6 production, which promotes cell migration and invasion. Interestingly, expression of GPR56-C-terminal fragment alone recapitulates the antibody-induced receptor function, implicating a major role for the C-terminal fragment in GPR56 activation and signaling. Analysis of site-directed mutant receptors attests the importance of the conserved N-terminal residues of the C-terminal fragment for its self-activation. Finally, we show that the GPR56-induced signaling in melanoma cells is mediated by the Gα/RhoA pathway. In summary, the expression and activation of GPR56 may modulate melanoma progression in part by inducing IL-6 production after N-terminal fragment dissociation and C-terminal fragment self-activation.