JWA inhibits melanoma angiogenesis by suppressing ILK signaling and is an independent prognostic biomarker for melanoma
JWA inhibits melanoma angiogenesis by suppressing ILK signaling and is an independent prognostic biomarker for melanoma
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JWA 通过抑制 ILK 信号传导来抑制黑色素瘤血管生成，是黑色素瘤的独立预后生物标志物
DOI：
10.1093/carcin/bgt318
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发表时间：
2013-12-01
期刊：
影响因子：
4.7
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Lu, Jing;Tang, Yun;Li, Gang
黑色素瘤是最致命的皮肤恶性肿瘤，因为它的高转移率。黑色素瘤的生长和转移依赖于持续的血管生成;因此，抑制血管生成是治疗转移性黑色素瘤的有希望的方法。JWA是一种新的微管相关蛋白，我们的前期工作表明JWA抑制黑色素瘤细胞的侵袭和转移。然而，JWA在黑色素瘤血管生成中的作用和预后价值仍然未知。在这里，我们报告说，JWA在黑色素瘤细胞显着抑制管形成的内皮细胞。此外，JWA通过整合素α V β 3调节整合素连接激酶（ILK），这种调节通过转录因子Sp1实现。值得注意的是，体外和体内血管生成测定均显示JWA通过抑制ILK信号传导显著抑制黑素瘤血管生成。此外，我们通过组织微阵列检测了大量黑色素细胞病变（n = 505）中不同阶段JWA蛋白的表达，发现JWA表达与黑色素瘤进展之间呈负相关（P = 5 × 10 - 6）。重要的是，JWA表达降低与患者总体和疾病特异性5年生存率较差相关（分别为P = 0.001和0.007）。多因素考克斯回归分析表明，JWA是黑色素瘤患者的独立预后指标。此外，我们发现黑色素瘤活检组织中JWA和ILK之间存在显著的负相关性，并且它们的伴随表达与黑色素瘤患者的生存密切相关（P = 0.004），进一步表明JWA对ILK表达的调节在黑色素瘤中至关重要。总之，我们的数据突出了JWA在黑色素瘤血管生成中的功能，并揭示了JWA的临床预后价值。
Melanoma is the deadliest cutaneous malignancy because of its high incidence of metastasis. Melanoma growth and metastasis relies on sustained angiogenesis; therefore, inhibiting angiogenesis is a promising approach to treat metastatic melanoma. JWA is a novel microtubule-associated protein and our previous work revealed that JWA inhibited melanoma cell invasion and metastasis. However, the role of JWA in melanoma angiogenesis and the prognostic value are still unknown. Here, we report that JWA in melanoma cells significantly inhibited the tube formation of endothelial cells. In addition, JWA regulated integrin-linked kinase (ILK) through integrin alpha V beta 3 and such regulation was achieved through the transcription factor Sp1. Notably, both in vitro and in vivo angiogenesis assays revealed that JWA dramatically suppressed melanoma angiogenesis by inhibiting ILK signaling. Furthermore, we examined the expression of JWA protein in a large set of melanocytic lesions (n = 505) at different stages by tissue microarray and found an inverse correlation between JWA expression and melanoma progression (P = 5 x 10(-6)). Importantly, reduced JWA expression was correlated with a poorer overall, and disease-specific 5 year survival of patients (P = 0.001 and 0.007, respectively). Multivariate Cox regression analyses indicated that JWA was an independent prognostic marker for melanoma patients. Moreover, we found a significant negative correlation between JWA and ILK in melanoma biopsies, and their concomitant expression was closely correlated with melanoma patient survival (P = 0.004), further indicating the regulation of ILK expression by JWA is critical in melanoma. Taken together, our data highlight the function of JWA in melanoma angiogenesis and reveal the clinical prognostic value of JWA.