JWA suppresses tumor angiogenesis via Sp1-activated matrix metalloproteinase-2 and its prognostic significance in human gastric cancer

Abstract

JWA, a multifunctional microtubule-binding protein, plays an important role in regulating tumor metastasis via inhibition of matrix metalloproteinase-2 (MMP-2). Recent investigations suggest that MMP-2 is an angiogenesis-associated molecule. In this study, we provide novel evidence that JWA inhibits tumor angiogenesis in gastric cancer (GC). In two independent retrospective GC cohorts, we found that the expression of JWA was downregulated and that of MMP-2 was upregulated in GC tissues compared with the same in normal gastric mucosa. For patients treated with surgery alone, a strong and independent negative prognostic value was shown for low JWA and high MMP-2 expressions separately, which was even stronger when combined (hazard ratio = 7.75, P < 0.001, in the training cohort; hazard ratio = 2.31, P < 0.001, in the validation cohort). Moreover, we found that loss of JWA expression was strongly correlated with increased GC angiogenesis. In vitro, JWA inhibited MMP-2 at both messenger RNA and protein levels by modulating Sp1 activity. Knockdown of endogenous JWA resulted in enhanced human umbilical vein endothelial cell tube formation and MMP-2 expression. Furthermore, JWA was found to inhibit Sp1 activity via an ubiquitin-proteasome-dependent mechanism and to downregulate the expression of the proangiogenic MMP-2. Our findings imply that JWA and MMP-2 may serve as promising prognostic markers in resectable GC, with JWA as a useful biomarker of angiogenesis in GC and a potential therapeutic target by MMP-2 modulation.

Adhesion Molecule-Mediated Hippo Pathway Modulates Hemangioendothelioma Cell Behavior

“…Regarding our finding of a greater decrease in MMP2 expression following YM155 treatment of EOMA cells than that noted following transfection with survivin siRNA, it is known that, like survivin, the MMP2 and MMP14 promoters also lack a typical TATA or CCAAT box, suggesting that Sp1 may be involved in regulating MMP2 and, possibly, MMP14 promoter activity (59,60), thus being consistent with YM155 also directly affecting MMP2 expression exclusive of its effects on survivin. Indeed, a recent study found that when Sp1 expression was reduced, MMP2 expression was reduced in human umbilical vein endothelial cells (59), consistent with the possibility that YM155 inhibition of at least these two proteins occurs via the same putative mechanism (33,34).…”

“…Indeed, a recent study found that when Sp1 expression was reduced, MMP2 expression was reduced in human umbilical vein endothelial cells (59), consistent with the possibility that YM155 inhibition of at least these two proteins occurs via the same putative mechanism (33,34).…”

JWA deficiency induces malignant transformation of murine embryonic fibroblast cells

“…These results were consistent with the findings of previous numerous researches on JWA gene (19). The present results indicated that the protein expression levels of PARP-1, vimentin and β-catenin were upregulated and E-cadherin was downregulated.…”

Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma

“…Sp1 was identified as a transcription factor by binding to the promoters of its target genes and has been postulated to play important roles in the regulation of multiple critical biological functions, including cell apoptosis [13] and growth [14], cycle progression [15], purine/pyrimidine synthesis [16], metabolism [17], angiogenesis [18],[19] and metastasis [20],[21]. Growing evidence demonstrated Sp1 is abnormally expressed in a variety of epithelial tumors originating from different tissues, including breast [22], thyroid [23], pancreas [24], stomach [25] and lung [26].…”