Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma.
Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma.
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DOI：
10.3389/fimmu.2018.00412
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发表时间：
2018
影响因子：
7.3
通讯作者：
Tang CH
中科院分区：
文献类型：
--
作者：
Lien MY;Tsai HC;Chang AC;Tsai MH;Hua CH;Wang SW;Tang CH
炎性趋化因子(C-C基序)配体4(CCL4)在肿瘤的发生发展中起重要作用。特别是，口腔鳞状细胞癌(OSCC)患者血清CCl4水平较高与疾病的晚期相关。口腔鳞状细胞癌约占台湾口腔癌的95%，由于侵袭性的局部侵袭和转移，导致复发，预后差。口腔鳞状细胞癌优先通过淋巴管扩散，即使在疾病的早期也有转移到颈部淋巴结的倾向。血管内皮生长因子C(VEGF-C)是淋巴管生成的重要调节因子。尤其是，血管内皮生长因子-C是淋巴管发育的特异性因子，其表达水平与口腔鳞癌的淋巴转移密切相关。然而，CCl_4是否与口腔鳞癌中血管内皮生长因子-C的表达和淋巴管生成有关尚不清楚。我们在体内外实验中发现，CCl_4可促进口腔癌细胞中血管内皮生长因子-C的表达，促进淋巴管生成。MIR-195-3p可逆转CCl_4诱导的血管内皮生长因子-C的表达。CCl_4刺激口腔癌细胞可增强JAK2和STAT3的磷酸化。因此，CCl4可能成为抑制口腔鳞癌淋巴管生成和转移的新的分子治疗靶点。
The inflammatory chemokine (C–C motif) ligand 4 (CCL4) plays an important role in the pathogenesis and progression of cancer. In particular, higher serum CCL4 levels in patients with oral squamous cell carcinoma (OSCC) are associated with a more advanced stage of disease. OSCC accounts for approximately 95% of oral cancer in Taiwan and has a poor prognosis, due to aggressive local invasion and metastasis, leading to recurrence. OSCC spreads preferentially through lymphatic vessels and has the propensity to metastasize to the cervical lymph nodes even in the early stage of disease. Vascular endothelial growth factor C (VEGF-C) is an essential regulator of lymphangiogenesis. In particular, VEGF-C is specific to lymphatic vessel development, and VEGF-C expression levels have been found to directly correlate with lymph node metastasis in OSCC. However, it is unclear as to whether CCL4 correlates with VEGF-C expression and lymphangiogenesis in OSCC. We found that CCL4 increased VEGF-C expression and promoted lymphangiogenesis in oral cancer cells in vitro and in vivo. miR-195-3p mimic reversed CCL4-enhanced VEGF-C expression. CCL4 stimulation of oral cancer cells augmented JAK2 and STAT3 phosphorylation. Thus, CCL4 may be a new molecular therapeutic target for inhibition of lymphangiogenesis and metastasis in OSCC.