title: Lipopolysaccharide increases the release of VEGF-C that enhances cell motility and promotes lymphangiogenesis and lymphatic metastasis through the TLR4- NF-κB/JNK pathways in colorectal cancer.
abstract: Lipopolysaccharide (LPS) exists in the outer membrane of Gram-negative bacteria. Colorectal normal epithelium and colorectal cancer cells in situ are continuously exposed to LPS from intestinal bacteria, while little is known about the influence of LPS on colorectal cancer progression and metastasis. In this study, we investigated the potential role of LPS on colorectal cancer progression and metastasis as well as the underlying mechanisms. We measured higher LPS concentration in colorectal cancer tissues and even higher LPS concentration in colorectal cancer tissues with lymph node metastasis. LPS significantly enhanced cancer cell motility and promoted human dermal lymphatic endothelial cells' (HDLECs') capacity of tube-like formation in vitro, as well as accelerates lymphangiogenesis and lymph node metastasis in nude mice. Furthermore, we demonstrated LPS notably increased the expression of VEGF-C in a time-dependent and concentration-dependent manner. VEGF-C is a key regulator for lymphangiogenesis and lymph node metastasis. By constructing lentivirus-mediated shVEGF-C cells, VEGF-C down-regulation suppressed LPS' promotive effect on cancer cell motility and HDLEC tube-like formation capacity. In addition, we found TLR4- NF-κB/JNK signal pathways were important for LPS to increase VEGF-C expression. All these result suggested a critical role for LPS in migration, invasion, lymphangiogenesis and lymph node metastasis of colorectal cancer, providing evidence that LPS increased VEGF-C secretion to promote cell motility and lymphangiogenesis via TLR4- NF-κB/JNK signaling.
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Hua
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Shugang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Jinzhou
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery 2 Section, The First Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian, China.|Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Ye
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D042583:Lymphangiogenesis / Q000187:drug effects*; D008207:Lymphatic Metastasis; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D042582:Vascular Endothelial Growth Factor C; D048031:JNK Mitogen-Activated Protein Kinases
keywords: VEGF-C; cell motility; colorectal cancer; lipopolysaccharide; lymphatic metastasis