title: Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, for which the development of new biomarkers and therapeutic targets has become critical. The main cause of poor prognosis in PDAC patients is the high invasive and metastatic potential of the cancer. In the present study, we report a new signaling pathway that was found to mediate the enhanced tumor cell motility in pancreatic cancer. Semaphorin 4D (Sema4D) is a ligand known to be expressed on different cell types, and has been reported to be involved in the regulation of immune functions, epithelial morphogenesis, and tumor growth and metastasis. In this study, we revealed for the first time that the cancer tissue cells expressing Sema4D in PDAC are tumor-infiltrating lymphocytes. The overexpression of Sema4D and of its receptor, plexinB1, was found to be significantly correlated with clinical factors, such as lymph node metastasis, distant metastasis, and poor prognosis in patients with PDAC. Through in vitro analysis, we demonstrated that Sema4D can potentiate the invasiveness of pancreatic cancer cells and we identified the downstream molecules. The binding of Sema4D to plexinB1 induced small GTPase Ras homolog gene family, member A activation and resulted in the phosphorylation of MAPK and Akt. In addition, in terms of potential therapeutic application, we clearly demonstrated that the enhanced-cell invasiveness induced by Sema4D could be inhibited by knockdown of plexinB1, suggesting that blockade of plexinB1 might diminish the invasive potential of pancreatic cancer cells. Our findings provide new insight into possible prognostic biomarkers and therapeutic targets in PDAC patients.
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kato
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kubota
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Shinohara
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Seitaro
authors.initials: S
authors.lastname: Watanabe
authors.forename: Masato
authors.initials: M
authors.lastname: Yoneda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Inamori
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Noboru
authors.initials: N
authors.lastname: Nakaigawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Masataka
authors.initials: M
authors.lastname: Taguri
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kubota
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D016895:Culture Media, Serum-Free; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010183:Pancreatic Ducts / Q000166:cytology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039961:Semaphorins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D016895:Culture Media, Serum-Free; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D039961:Semaphorins