High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma
High mobility group box-1-inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma
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DOI：
10.1111/j.1349-7006.2008.00894.x
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发表时间：
2008-09-01
期刊：
影响因子：
5.7
通讯作者：
Kuniyasu, Hiroki
中科院分区：
文献类型：
--
作者：
Sasahira, Tomonori;Kirita, Tadaaki;Kuniyasu, Hiroki
黑色素瘤抑制活性（MIA）是从恶性黑色素瘤细胞中分离的11-kDa分泌蛋白，其与多种人类恶性肿瘤中的侵袭和转移相关。我们用免疫组化方法检测了62例口腔鳞状细胞癌（OSCC）中MIA的表达。MIA表达与淋巴结转移显著相关（P = 0.00018）。MIA表达与高迁移率族蛋白B1（HMGB 1）表达（P < 0.0001）和淋巴管密度（P < 0.0001）相关。转移性人OSCC细胞系（HSC 3）中MIA、HMGB 1、核因子kB（NFkB）p65和HMGB 1-NFkB p65结合的表达水平显著高于非转移性OSCC细胞系（HSC 4）中的那些。用晚期糖基化终产物受体（receptor for advanced glycation end products，HMGB 1）反义或小干扰RNA和人重组HMGB 1（hrHMGB 1）处理HSC 3细胞不影响MIA表达，而HMGB 1反义或siRNA处理降低了MIA表达。然后HMGB 1作为NFkB辅因子而不是作为NFkB配体增强MIA表达。MIA抗体中和MIA增加了细胞外信号相关激酶1/2磷酸化，但降低了p38磷酸化和血管上皮生长因子（VEGF）-C和-D的表达。用p38抑制剂处理降低HSC 3细胞中VEGF-C和-D的表达。这些结果表明，MIA的表达通过细胞内HMGB 1和NF κ Bp 65的相互作用而增强，并且MIA通过VEGF-C和VEGF-D的增加而与OSCC中的肿瘤进展和淋巴结转移密切相关。
Melanoma inhibitory activity (MIA) is an 11-kDa secretory protein isolated from malignant melanoma cells that is correlated with invasion and metastasis in various human malignancies. We examined MIA expression in 62 oral squamous cell carcinomas (OSCC) by immunohistochemistry. MIA expression was significantly associated with nodal metastasis (P = 0.00018). MIA expression was also associated with expression of high mobility group box-1 (HMGB1) (P < 0.0001) and lymph vessel density (P < 0.0001). Expression levels of MIA, HMGB1, nuclear factor kB (NFkB) p65 and HMGB1-NFkB p65 binding were significantly higher in a metastatic human OSCC cell line (HSC3) than those in a non-metastatic OSCC cell line (HSC4). Treatment with receptor for advanced glycation end products (RAGE) antisense or small interfering RNA and human recombinant HMGB1 (hrHMGB1) did not affect MIA expression, whereas HMGB1 antisense or siRNA treatment decreased MIA expression in HSC3 cells. Then HMGB1 enhanced MIA expression as an NFkB cofactor but not as a RAGE ligand. MIA neutralization by MIA antibodies increased extracellular signal-related kinase 1/2 phosphorylation, but decreased p38 phosphorylation and the expression of vascular epithelial growth factor (VEGF)-C and -D. Treatment with p38 inihibitor decreased VEGF-C and -D expression in HSC3 cells. These results suggest that MIA expression is enhanced by the interaction of intracellular HMGB1 and NFkBp65 and MIA is closely involved in tumor progression and nodal metastasis by the increments of VEGF-C and VEGF-D in OSCC.