Axon guidance molecule semaphorin3A is a novel tumor suppressor in head and neck squamous cell carcinoma

Abstract

Semaphorin3A (SEMA3A), an axon guidance molecule in the nervous system, plays an inhibitory role in oncogenesis. Here, we investigated the expression pattern and biological roles of SEMA3A in head and neck squamous cell carcinoma (HNSCC) by gain-of-function assays using adenovirus transfection and recombinant human SEMA3A protein. In addition, we explored the therapeutic efficacy of SEMA3A against HNSCC in vivo. We found that lower expression of SEMA3A correlated with shorter overall survival and had independent prognostic importance in patients with HNSCC. Both genetic and recombinant SEMA3A protein inhibited cell proliferation and colony formation and induced apoptosis, accompanied by decreased cyclin E, cyclin D, CDK2, CDK4 and CDK6 and increased P21, P27, activated caspase-5 and caspase-7. Moreover, over-expression of SEMA3A suppressed migration, invasion and epithelial-to-mesenchymal transition due in part to the inhibition of NF-κB and SNAI2 in HNSCC cell lines. Furthermore, intratumoral SEMA3A delivery significantly stagnated tumor growth in a xenograft model. Taken together, our results indicate that SEMA3A serves as a tumor suppressor during HNSCC tumorigenesis and a new target for the treatment of HNSCC.

Adipose MSCs Suppress MCF7 and MDA-MB-231 Breast Cancer Metastasis and EMT Pathways Leading to Dormancy via Exosomal-miRNAs Following Co-Culture Interaction

“…Other signaling pathways that can indirectly contribute to the aforementioned effects include ErbB, a pathway in cancer and neurotrophin signaling, which play a crucial role in the initiation and progression of many cancers [ 45 , 46 ]. Axon guidance, focal adhesion and insulin signaling pathways were reported to affect multiple cell types connected through the tumor microenvironment and act as the major mediator of signal transduction in the metastasis and promotion of tumors [ 47 , 48 , 49 ]. Subsequent activation of Toll-like-receptors (TLRs) in cancer cells and the resulting signaling cascade effect along with chemokine production could play an important role in promoting cancer cell survival and chemoresistance [ 50 ].…”

Identification of prognostic biomarkers in colorectal cancer using a long non‑coding RNA‑mediated competitive endogenous RNA network

“…Axon guidance molecule semaphorin 3F plays a negative regulator role in the development of tumor in ileal neuroendocrine tumors (60). Additionally, the inhibition of migration, invasion and epithelial to mesenchymal transition has been revealed because of the overexpression of SEMA3A by suppressing the expression of NF-κB and SNAI2 in head and neck squamous cell carcinoma (HNSCC); whereas, a shorter overall survival and more important independent prognostic significance could be found in HNSCC patients with lower SEMA3A expression (61). Therefore, axon guidance cues could be promising targets for personalized anticancer therapies.…”

Effect of semaphorin 3A expression on clinicopathological features and prognosis in oropharyngeal carcinoma

“…SEMA3A has been identi ed as a candidate tumor suppressor and it is often found to be downregulated in different types of cancer, such as prostate cancer, breast cancer, and glioma. Increased SEMA3A expression was associated with better prognosis in patients with cancer, including epithelial ovarian carcinoma, gastric cancer, tongue cancer, and HNC [28] [29] [30] [31]. A reduction in SEMA3A expression was observed in our OPC samples compared with normal tonsil tissues.…”

“…Cell proliferation and colony formation were inhibited by SEMA3A and recombinant SEMA3A. Furthermore, intratumoral SEMA3A was believed to restrain tumor growth in a xenograft model [31]. In vitro, SEMA3A suppressed extracellular matrix-mediated adhesion and migration of endothelial cells [20].…”