SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C
SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C
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SIX1 通过协调 TGF β 信号增加 VEGF-C 的表达来促进肿瘤淋巴管生成
DOI：
10.1158/0008-5472.can-13-3598
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发表时间：
2014-10-01
期刊：
影响因子：
11.2
通讯作者：
Gao, Qing-Lei
中科院分区：
文献类型：
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作者：
Liu, Dan;Li, Li;Gao, Qing-Lei
淋巴管是癌细胞传播的主要途径之一。恶性肿瘤释放VEGF-C等生长因子诱导淋巴管生成，从而促进淋巴结转移。本文报道了在肿瘤细胞中表达的sine oculis homobox homolog 1 （SIX1）通过与TGF - β协同增加VEGF-C的表达，促进肿瘤淋巴管生成和淋巴结转移。宫颈癌的淋巴管生成和淋巴结转移与SIX1在肿瘤细胞中的高表达密切相关。SIX1通过增强肿瘤细胞中VEGF-C的表达，在体外增强肿瘤细胞对淋巴内皮细胞（lymphatic endothelial cells， LEC）迁移、成管和体内淋巴管生成的促进作用。SIX1增强TGF β诱导的SMAD2/3活化，并协同SMAD通路调节VEGF-C表达。SIX1和TGF β共同诱导肿瘤细胞中VEGF-C的表达比单独使用它们要高得多。TGF β虽然有促进VEGF-C表达的作用，但它可以通过直接抑制LECs成管来抑制淋巴管生成。而VEGF-C生成的增加，不仅直接促进了LECs的迁移和成管，而且抑制了TGF β对LECs的抑制作用。即高水平表达SIX1的肿瘤细胞可以促进淋巴管生成，通过增加VEGF-C的表达来抵消TGF β对淋巴管生成的负面影响。这些发现为肿瘤淋巴管生成和TGF β信号在肿瘤调节中的各种作用提供了新的见解。我们的研究结果也提示SIX1/TGF β可能是预防肿瘤淋巴结转移的潜在治疗靶点。(c) 2014年aacr。
Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGF beta to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGF beta-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGF beta induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGF beta could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGF beta on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGF beta on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGF beta signaling in tumor regulation. Our results also suggest that SIX1/TGF beta might be a potential therapeutic target for preventing lymph node metastasis of tumor. (C) 2014 AACR.