The axon guidance molecule semaphorin 3F is a negative regulator of tumor progression and proliferation in ileal neuroendocrine tumors

Abstract

Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs.SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways.This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy.

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

“…Many studies have found that semaphorin proteins have certain modulatory effects on tumorous occurrence and development (57–59), for example, the axon guidance molecule semaphorin 3F was found in normal neuroendocrine cells, while it was lost in most human primary tumors and all metastases. 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).…”

Role of the tumor microenvironment in digestive neuroendocrine tumors

“…More specifically, NRP-1 and NRP-2 are co-receptors for class-3 semaphorins (SEMA3), a potent angiogenesis inhibitor (Neufeld et al 2005). A recent study showed that expression of semaphorin 3F (SEMA3F) is almost indetectable in a series of human SI-NETs (primitive site and metastasis), while conserved in the normal neuroendocrine tissue (Bollard et al 2015). The authors further showed that upregulation of SEMA3F in the enteroendocrine cell lines STC-1 and GluTag led to a reduced ability of the cell line to form tumors and liver metastasis in a xenograft model of SI-NET liver metastasis (Bollard et al 2015).…”

The protective value of miR-204-5p for prognosis and its potential gene network in various malignancies: a comprehensive exploration based on RNA-seq high-throughput data and bioinformatics

“…Next, the bioinformatics studies of the functional pathway category and integrated network were performed, including GO, KEGG, Panther enrichment analysis and PPI. Interestingly, the top three terms in KEGG analysis were all closely related to tumorigenesis and tumor progression, including “Axon guidance” [ 46 , 47 ], “Neurotrophin signaling pathway” [ 48 , 49 ] and “MAPK signaling pathway” [ 50 ]. Among all the potential targets, PPI revealed that several hub genes were strongly associated with different process of malignancies, including CDC42 [ 51 ], SOS1 [ 52 ], PIK3R1 [ 53 ], MAPK1 [ 54 ], PLCG1 [ 55 ], ESR1 [ 56 ], MAPK11 [ 57 ] and AR [ 58 ].…”