title: The extra domain A of fibronectin increases VEGF-C expression in colorectal carcinoma involving the PI3K/AKT signaling pathway.
abstract: The extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, is predominantly expressed in various malignancies but not in normal tissues. In the present study, we investigated the potential pro-lymphangiogenesis effects of extra domain A (EDA)-mediated vascular endothelial growth factor-C (VEGF-C) secretion in colorectal carcinoma (CRC). We detected the expressions of EDA and VEGF-C in 52 human colorectal tumor tissues and their surrounding mucosae by immunohistochemical analysis, and further tested the correlation between the expressions of these two proteins in aforementioned CRC tissues. Both EDA and VEGF-C were abundantly expressed in the specimens of human CRC tissues. And VEGF-C was associated with increased expression of EDA in human CRC according to linear regression analysis. Besides, EDA expression was significantly correlated with lymph node metastasis, tumor differentiation and clinical stage by clinicopathological analysis of tissue microarrays containing tumor tissues of 115 CRC patients. Then, human CRC cell SW480 was transfected with lentivectors to elicit expression of shRNA against EDA (shRNA-EDA), and SW620 was transfected with a lentiviral vector to overexpress EDA (pGC-FU-EDA), respectively. We confirmed that VEGF-C was upregulated in EDA-overexpressed cells, and downregulated in shRNA-EDA cells. Moreover, a PI3K-dependent signaling pathway was found to be involved in EDA-mediated VEGF-C secretion. The in vivo result demonstrated that EDA could promote tumor growth and tumor-induced lymphangiogenesis in mouse xenograft models. Our findings provide evidence that EDA could play a role in tumor-induced lymphangiogenesis via upregulating autocrine secretion of VEGF-C in colorectal cancer, which is associated with the PI3K/Akt-dependent pathway.
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Xie
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Ou
authors.forename: Xing
authors.initials: X
authors.lastname: Wei
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.forename: Houjie
authors.initials: H
authors.lastname: Liang
mesh_terms: D000368:Aged; D000818:Animals; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D005353:Fibronectins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D042582:Vascular Endothelial Growth Factor C; C467486:VEGFC protein, human; C574442:extra domain A fibronectin, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one