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.
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.
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.
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