Expression of semaphorin 6D and its receptor plexin-A1 in gastric cancer and their association with tumor angiogenesis

Abstract

Abstract. The semaphorin and plexin family of ligands and receptor proteins provides important axon growth and guidance cues required for development. In recent years, studies have expanded their role in the regulation of cardiac morphogenesis and tumorigenesis. However, the mechanism responsible for their role in regulating cancer development and progression has not been clarified. In the present study, semaphorin 6D (Sema6D) and its receptor plexin-A1 were identified to be expressed at high levels in vascular epithelial cells within gastric cancer, and were positively correlated with vascular endothelial growth factor receptor 2 (VEGFR2). These findings verify our hypothesis that Sema6D and plexin-A1 may be closely associated with tumor angiogenesis. Combined with experimental observations in the MGC803 gastric cancer cell line, it was observed that knocking down plexin-A1 signaling led to a decreased expression of VEGFR2 at the messenger RNA and protein levels. Sema6D recognized and activated plexin-A1, which subsequently activated its downstream target, VEGFR2. The activation of VEGFR2 functioned as a positive regulator of tumor angiogenesis. Our data provided an understanding of the complex signaling cascades involved in the angiogenesis-related pathway in tumor cells. In light of our observations, pharmacological interventions targeting Sema6D/plexin-A1/VEGFR2 signaling may potentially be used as a target for the development of novel anti-angiogenic drugs in gastric cancer. IntroductionThe semaphor in fam ily is a la rge super-protei n fa m ily cont a in ing secreted, t ra nsmembra ne a nd glycosylphosphatidylinositol-linked proteins, and it has been divided into eight hypotypes based on their structures and amino acid sequence similarity: Invertebrate semaphorins consist of classes 1 and 2, while classes 3-7 are vertebrate semaphorins (with the exception of class 5C semaphorins, which are encoded by viral genomes) (1). The semaphorin family was initially identified to be involved in mediating axonal guidance in the developing nervous system (2). Certain members of the semaphorin family have been also shown to exert diverse and important functions in other physiological processes, including heart morphogenesis (3,4), vascular growth (5), immune cell regulation (6) and tumor progression (7,8). Important regulatory functions of certain members of the semaphorin family within tumor angiogenesis have been reported. For example, semaphorin 3A (Sema3A) inhibits angiogenesis through competition for vascular endothelial growth factor (VEGF) (9), and Sema3B has also been indicated as a putative tumor suppressor that inhibits tumor growth and angiogenesis (10). By contrast, Sema3C presumably may promote angiogenesis by stimulating integrin phosphorylation and VEGF120 secretion (11), and Sema4D has been demonstrated to serve a role in tumor-induced angiogenesis (12).Sema6D, mapped on chromosome 2, is the best characterized factor of the class 6 semaphorins, which are single-pass membrane-bound semaphorins (13). It wa...

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“…SEMA6D has been reported to be highly expressed in vascular epithelial cells in gastric cancer; it was also positively correlated with the expression of vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, SEMA6D may be associated with tumor angiogenesis [ 49 , 50 ]. The HADHB gene encodes the beta subunit of a mitochondrial trifunctional protein that catalyzes the last three steps of mitochondrial beta-oxidation of long-chain fatty acids.…”

Screening and identification of biomarkers associated with the diagnosis and prognosis of lung adenocarcinoma

“…In addition, bio‐signal analysis has revealed that the SEMA6D gene may play an important role in promoting the OS of patients with breast cancer 28 . Studies have shown that the SEMA6D gene is directly related to the presence of VEGFR2 in the angiogenesis of gastric cancer, which plays an important pathogenic role 29 . Studies on esophageal cancer have identified that SEMA6D is a target gene that is upregulated by hsa‐miR‐1 30 .…”

Semaphorins in Angiogenesis and Autoimmune Diseases: Therapeutic Targets?

“…In models of gastric cancer, signaling due to Sema6D and Plexin-A1/VEGFR2 interaction results in effects similar to VEGF binding alone. In addition, Sema6D/Plexin-A1 expression is positively correlated with the expression of VEGFR2, therefore contributing to its angiogenic and tumorigenic properties (59). Poor prognosis of gastric cancer has been correlated with Sema6D expression and increased angiogenesis (59) ( Table 1).…”