Pathological and functional significance of Semaphorin-5A in pancreatic cancer progression and metastasis

Abstract

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.

High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma

“…However, the role of SEMA5A in cancer has not been elucidated to date. Some researchers have found overexpression of SEMA5A in pancreatic cancer [40-44], gastric carcinoma [45-47], and prostate cancer [48], while this gene was determined to be downregulated in glioma [49, 50] and lung cancer [51]. It has also been reported that SEMA5A was coexpressed with long-chain fatty acyl-Co A synthetase 3, which predicted a better prognosis in ovarian cancer [52].…”

Semaphorin-5A maintains epithelial phenotype of malignant pancreatic cancer cells

“…Compelling evidence suggests that axon guidance molecules such as semaphorins are involved in cancer progression, invasion, and metastasis [3]. Previous reports from our laboratory have identified one such molecule SEMA5A, which demonstrated differential expression in pancreatic tumors in comparison with the normal pancreas [5, 8].…”

“…We plated cells (5 × 10 5 ) on 22 × 22 mm sized coverslips (Fisherbrand ®, Pittsburgh, PA) placed in 6-well plates and the protocol is described previously in detail [8]. We used primary antibodies like, 1:25; E-cad, 1:5; N-cad, 1:5; β-catenin, 1:10; Fascin (Developmental Studies Hybridoma Bank) 1:20; and phalloidin (Texas Red, Molecular Probes) 1:50, and Secondary antibodies conjugated with either mouse or rabbit Cy3 (Jackson Immuno Research).…”

Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb

“…We focused our study on the poorly investigated Sema5A because, to the best of our knowledge, no data have been published yet on its expression and/or function in melanoma, but also because of its controversial role in cancer [ 9 ]. Indeed, Sema5A was found to reduce the motility of glioma cells [ 10 ], while having an opposite effect for the invasion of pancreatic, prostatic and gastric cancer cells [ 14 , 45 , 46 ].…”