Abstract
Background
Vascular endothelial growth factor-C (VEGF-C) plays an important role during cancer progression and metastasis through activation of VEGF receptors. However, the role of VEGF-C in esophageal squamous cell carcinoma (ESCC) remains unclear.
Methods
The expression of VEGF-C in advanced stages of esophageal cancer was examined by immunohistochemistry and its expression was correlated with the protein level of cortactin (CTTN) by Western blot. Knockdown and overexpression of the CTTN protein were respectively performed to investigate the effects on VEGF-C-enhanced ESCC migration/invasion by in vitro transwell assay, cell tracing assay, and tumor growth/experimental metastasis in animal models.
Results
The expression of VEGF-C was positively correlated with tumor status and poor clinical prognosis in patient with esophageal cancer. VEGF-C-upregulated CTTN expression contributed the migration/invasive abilities of ESCC cell lines through Src-mediated downregulation of miR-326. Moreover, knockdown of CTTN expression significantly abolished VEGF-C-induced tumor growth and experimental lung metastasis in vivo.
Conclusions
Upregulation of CTTN is critical for VEGF-C-mediated tumor growth and metastasis of ESCC. These finding suggest that VEGF-C upregulated CTTN expression through Src-mediated downregulation of miR-326. CTTN may be a crucial mediator of VEGF-C-involved ESCC metastasis, which provides a potential target for diagnosis and individualized treatment in clinical practice.
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Acknowledgment
This work was supported by grants from the National Science Council, Taiwan (NSC 102-2314-B-039-200, NSC 102-2314-B-038-028-MY3, NSC 101-2320-B-400-016-MY3); from National Health Research Institutes, Taiwan (CA-102-PP-41, CA-103-PP-35); from China Medical University Hospital (DMR-101-014); from China Medical University (CMU99-TC-22, CMU100-S-22) and from the Chi-Mei Medical Center (CMNCKU 10116). We thank Dr. Mien-Chie Hung kindly provided human ESCC cell lines. We thank National RNAi Core Facility (Academia Sinica, Taiwan) for providing specific shRNAs. We thank Ms. Fang-Yu Tsai, Dr. I-Shou Chang and Dr. Shih-Sheng Jiang of Taiwan Bioinformatics Institute Core Facility for assistances on using Oncomine (National Core Facility Program for Biotechnology, NSC-100-2319-B-400-001).
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Chih-Ming Su and Yen-Hao Su have contributed equally to this work.
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Su, CM., Su, YH., Chiu, CF. et al. Vascular Endothelial Growth Factor-C Upregulates Cortactin and Promotes Metastasis of Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 21 (Suppl 4), 767–775 (2014). https://doi.org/10.1245/s10434-014-4009-7
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DOI: https://doi.org/10.1245/s10434-014-4009-7