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: Shingo Kato, Kensuke Kubota, Takeshi Shimamura, Yoshiyasu Shinohara, Noritoshi Kobayashi, Seitaro Watanabe, Masato Yoneda, Masahiko Inamori, Fumio Nakamura, Hitoshi Ishiguro, Noboru Nakaigawa, Yoji Nagashima, Masataka Taguri, Yoshinobu Kubota, Yoshio Goshima, Satoshi Morita, Itaru Endo, Shin Maeda, Atsushi Nakajima, Hitoshi Nakagama
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 11 Pg. 2029-37 (Nov 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21812859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Antigens, CD
• CD100 antigen
• Culture Media, Serum-Free
• Neoplasm Proteins
• Nerve Tissue Proteins
• PLXNB1 protein, human
• RNA, Messenger
• RNA, Neoplasm
• RNA, Small Interfering
• Receptors, Cell Surface
• Semaphorins

Topics

• Aged
• Antigens, CD (biosynthesis, genetics, physiology)
• Carcinoma, Pancreatic Ductal (metabolism, pathology)
• Cell Movement (physiology)
• Cells, Cultured (cytology, metabolism)
• Culture Media, Serum-Free
• Epithelial Cells (cytology, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Kaplan-Meier Estimate
• MAP Kinase Signaling System
• Male
• Middle Aged
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Nerve Tissue Proteins (biosynthesis, genetics, physiology)
• Pancreatic Ducts (cytology)
• Pancreatic Neoplasms (metabolism, pathology)
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• RNA, Small Interfering (pharmacology)
• Receptors, Cell Surface (biosynthesis, genetics, physiology)
• Semaphorins (biosynthesis, genetics, physiology)
• Signal Transduction
• Tumor Cells, Cultured (cytology, metabolism)