Pathological and functional significance of Semaphorin-5A in pancreatic cancer progression and metastasis
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Sugandha Saxena1,2, Yuri Hayashi1, Lingyun Wu1, Mohammad Awaji1, Pranita Atri2, Michelle L. Varney3, Abhilasha Purohit1,4, Satyanarayana Rachagani2, Surinder K. Batra2 and Rakesh K. Singh1
1Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
3Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
4The Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA
Rakesh K. Singh, email: [email protected]
Keywords: Semaphorin-5A; pancreatic cancer; metastasis; pancreatic neuroendocrine tumors; Plexin-B3
Abbreviations: PC: Pancreatic cancer; SEMA5A: Human Semaphorin-5A; Sema5A: Mouse Semaphorin-5A; PanNET: Pancreatic Neuroendocrine Tumors; cMET: Hepatocyte growth factor receptor
Received: October 30, 2017 Accepted: December 11, 2017 Published: December 23, 2017
Semaphorin-5A (SEMA5A) has differential cell surface expression between normal and cancer cells and represents an attractive target for therapeutic intervention in pancreatic cancer (PC). In this study, we delineated the pathological expression and significance of SEMA5A during PC progression and metastasis. We utilized human tissue microarrays and different PC mouse models (Pdx1-cre; LSL- Kras(G12D), Pdx1-Cre; LSL-Kras(G12D); LSL-p53(R172H) and RIP1-Tag2) to analyze SEMA5A expression during PC progression. Using human patients and different mouse models, we demonstrated that SEMA5A expression was highest in liver metastases, followed by primary pancreatic tumors, and the lowest expression was found in the normal pancreas. SEMA5A expression was localized on tumor cells with no staining in the surrounding stroma. To understand the functional significance of SEMA5A, we treated PC cell lines with recombinant SEMA5A. We observed an increase in migration, chemotaxis, and scattering of PC cells. To delineate the signaling axis of SEMA5A, we generated SEMA5A receptor-Plexin-B3 knockdown in T3M-4 and CD18/HPAF PC cell lines and observed that the effect of SEMA5A treatment was absent in the Plexin-B3 knockdown counterparts of T3M-4 and CD18/HPAF cells. SEMA5A treatment leads to phosphorylation of cMET in Plexin-B3 dependent manner. Our data demonstrate that there is an increase in SEMA5A expression during PC progression and the elevation of this expression takes place at metastatic sites especially the liver in both exocrine and endocrine tumors. SEMA5A can elicit a migratory response in cells by activating cMET through the Plexin-B3 receptor. In conclusion, SEMA5A signaling represents a potential molecule for targeting metastasis in pancreatic cancer.
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