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Front. Immunol. | doi: 10.3389/fimmu.2018.00412

Chemokine CCL4 induces vascular endothelial growth factor C expression and lymphangiogenesis by miR-195-3p in oral squamous cell carcinoma

Ming-Yu Lien1, Hsiao-Chi Tsai2, Ming-Hsui Tsai3, Chun-Hung Hua3,  Shih-Wei Wang4 and  Chih-Hsin Tang1*
  • 1China Medical University, Taiwan
  • 2Qinghai Red Cross Hospital, China
  • 3China Medical University Hospital, Taiwan
  • 4Mackay Medical College, Taiwan

The inflammatory chemokine (CC 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 (VEGF) 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.

Keywords: CCl4, MiR-195-3p, VEGF-C, Lymphangiogenesis, Human oral squamous carcinoma

Received: 26 Oct 2017; Accepted: 14 Feb 2018.

Edited by:

José Mordoh, Leloir Institute Foundation (FIL), Argentina

Reviewed by:

Veronique Angeli, National University of Singapore, Singapore
Manel Juan, Hospital Clínic de Barcelona, Spain  

Copyright: © 2018 Lien, Tsai, Tsai, Hua, Wang and Tang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Chih-Hsin Tang, China Medical University, Taichung, Taiwan,