Sema3A drastically suppresses tumor growth in oral cancer Xenograft model of mice

Abstract

BackgroundMultiple studies suggest anti-angiogenesis to be a promising and rational option in cancer treatment. Interestingly, the axonal sprouting inhibitor semaphorin 3A (Sema3A), a potent suppressor of tumor angiogenesis in various cancer models, is lowly expressed in human oral cancer. Thus, we hypothesized that overexpression of Sema3A in human oral cancer cells may have potential therapeutic effects.MethodsThe LentiSema3A-EGFP was first constructed and transduced to the tongue squamous cell carcinoma cell line SSC-9. Angiogenesis assay was performed with endothelial cell tube formation assay and chorioallantoic membrane (CAM) assay. Tumor xenografts model was used to evaluate the effect of Sema3a on the tumor growth. Finally, western blot was performed to study the mechanisms of inhibiting angiogenesis by Sema3A.ResultsIn vitro and in vivo approaches revealed that Sema3A significantly inhibited tube formation of endothelial cells and reduced angiogenesis in CAM assay. In addition, overexpression of Sema3A in the tongue squamous cell carcinoma cell line SSC-9 resulted in significantly reduced angiogenesis and drastically suppressed tumor growth in mice. Mechanistically, Sema3A inhibited the phosphorylation of VEGFR2, as well as Src and FAK, downstream of the VEGF/VEGFR2 pathway.ConclusionOur results demonstrated that overexpression of Sema3A in oral cancer cells drastically suppressed tumor growth by inhibiting angiogenesis. Our findings provide a basis for the development of novel therapeutics in the management of oral cancer.

Overexpression of Semaphorin 3A Is a Marker Associated with Poor Prognosis in Patients with Nasopharyngeal Carcinoma

“…In contrast, other researchers have shown that Sema3A alters tumor cell behavior directly by influencing migration and growth, or indirectly by interfering with tumor angiogenesis and the immune response [1,24,32,33]. Our findings agree with the results derived from other solid tumors, including pancreatic, lung, and prostate cancers [20,21,23]. Furthermore, one study has shown a positive correlation between Sema3A and the metastatic potential of hepatocellular carcinoma [34].…”

“…Sema3A alters cancer cell behavior directly by affecting cell migration and growth [17,18], and is frequently overexpressed in glioblastoma, pancreatic, lung, and prostate cancer [19][20][21][22]. Its increased expression positively correlates with the grade of malignancy, cell migration, metastatic potential, and poor prognosis [20,23]. Furthermore, Sema3A directly decreases focal adhesions, induces cancer cell invasion in vitro, and modulates tumor-associated macrophages [17,18].…”

“…Moreover, Sema3A can affect cell phenotype indirectly by interfering with tumor angiogenesis and the immune response [12,13]. On the other hand, several reports suggest that Sema3A may be a potent tumor suppressor in oral and lung cancers [23,24]. Whether Sema3A functions as a tumor suppressor or tumor promoter is still unclear and may be cancer specific.…”

The Neuropilin‐1 Ligand, Sema3A, Acts as a Tumor Suppressor in the Pathogenesis of Acute Leukemia

“…For example, Tang et al (2014) detected lower mRNA and protein levels of Sema3A in gastric carcinoma tissues, while overexpression of Sema3A inhibited the proliferation and migration of gastric cancer cells in vitro. Huang et al (2017) further revealed that Sema3A is expressed at lower levels in oral cancer, and overexpression of Sema3A in a xenograft model significantly suppressed oral cancer growth. However, to date, a role for Sema3A in the pathogenesis of acute leukemia as a tumor suppressor protein has not been studied.…”

“…Huang et al . () further revealed that Sema3A is expressed at lower levels in oral cancer, and overexpression of Sema3A in a xenograft model significantly suppressed oral cancer growth. However, to date, a role for Sema3A in the pathogenesis of acute leukemia as a tumor suppressor protein has not been studied.…”