Semaphorin 5A, an Axon Guidance Molecule, Enhances the Invasion and Metastasis of Human Gastric Cancer through Activation of MMP9

Abstract

Semaphorin 5A, a member of semaphorin family, was originally identified as axonal guidance factor functioning during neuronal development. Previously, we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer. However, its functional roles and mechanism(s) in invasion and metastasis of gastric cancer remain unclear. By using human gastric caner cell lines Parental SGC7901, SGC7901-siScrambled and SGC7901-siSema 5A, we found that semaphorin 5A significantly promoted the invasive and metastatic abilities of gastric cancer cell in vitro. Semaphorin 5A increased the expression of MMP9 by activating phosphorylated ErK1/2 in gastric cancer cell. Furthermore, MEK inhibitor PD98059 and MMP9 antibody (Ab) significantly inhibited in vitro invasive and metastatic abilities induced by semaphorin 5A. Taken together, the present work revealed a novel function of semaphorin 5A that the existence of semaphorin 5A could promote invasion and metastasis of gastric cancer by regulating MMP9 expression, at least partially, via the MEK/ERKs signal transduction pathway. Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy.

Semaphorin 5A mediated cellular navigation: Connecting nervous system and cancer

“…This data supports their earlier observation of higher SEMA5A expression in the lymph node metastasis than the primary tumor and the normal tissues [55]. This increased invasiveness was found to be mediated by the activation of the MEK/ERK pathway leading to the up regulation of MMP9 [56]. These initial reports are suggestive of important roles of SEMA5A in gastric carcinogenesis; however, more work deciphering the molecular pathways is needed.…”

“…The reason for this discrepancy can be derived from the difference in the signaling pathways triggered by the interaction of Sema5A with plexin-B3. As observed the invasive growth via plexin-B3 receptor involves signaling through the Met receptor tyrosine kinase or the MEK/ERK pathway [56]. However, whether or not there is any cross talk between these two pathways still remains unexplained.…”

Semaphorin 5A Promotes Gastric Cancer Invasion/Metastasis via Urokinase-Type Plasminogen Activator/Phosphoinositide 3-Kinase/Protein Kinase B

“…Our previous data have demonstrated that semaphorin 5A was overexpressed in gastric cancer tissues, indicating a possible role for semaphorin 5A in occurrence and development of gastric cancer [7, 8]. In a recent study, we also found that semaphorin 5A enhances the invasion and metastasis of human gastric cancer through activation of MMP9 [9]. However, further analysis of the semaphorin 5A-induced signaling pathway was expected to provide us with a better understanding of the activity of semaphorin 5A, and also on the mechanisms underlying the invasion and subsequent metastasis of gastric cancer cells.…”

The role of the semaphorins in cancer

“…249 However, there is also evidence suggesting that it promotes the progression of prostate cancer 250,251 and it was reported to contribute the progression of neurofibromatosis type 1 (NF1). 249 Class-5 semaphorins: Sema5A was recently found to promote tumor metastasis in gastric cancer 252 and in pancreatic cancer 107 but inhibited the motility of glioma cells. 253 Sema5B may play a role in renal cell carcinoma since down-regulation of sema5B expression in renal cell carcinoma cells significantly compromises their viability.…”