Semaphorin SEMA3F Affects Multiple Signaling Pathways in Lung Cancer Cells

Abstract

Loss of SEMA3F occurs frequently in lung cancer and correlates with advanced stage of disease. We previously reported that SEMA3F blocked tumor formation by H157 lung cancer cells in a rat orthotopic model. This was associated with loss of activated A V B 3 integrin, impaired cell adhesion to extracellular matrix components, and down-regulation of phospho-extracellular signal-regulated kinase 1/2 (ERK1/2). These results suggested that SEMA3F might interfere with integrin outside-in signaling. In the present report, we found that SEMA3F decreased adhesion to vitronectin, whereas integrin-linked kinase (ILK) kinase activity was down-regulated in SEMA3F-expressing H157 cells. Exposure to SEMA3F-conditioned medium led to diminution of phospho-ERK1/2 in four of eight lung cancer cell lines, and ILK silencing by small interfering RNA led to similar loss of phospho-ERK1/2 in H157 cells. Moreover, SEMA3F expression (with constitutive and inducible systems) also reduced AKT and signal transducer and activator of transcription 3 (STAT3) phosphorylation independently of ILK-ERK1/2. These signaling changes extended downstream to hypoxia-inducible factor-1A (HIF-1A) protein and vascular endothelial growth factor (VEGF) mRNA levels, which were both reduced in three of four SEMA3F-transfected cell lines. Mechanistically, the effects on HIF-1A were consistent with inhibition of its AKT-driven protein translation initiation, with no effect on HIF-1A mRNA level or protein degradation. Furthermore, when H157 cells were injected s.c. in nude mice, tumors derived from SEMA3F-expressing cells showed lower microvessel density and tumor growth. These results show that SEMA3F negatively affects ILK-ERK1/2 and AKT-STAT3 signaling, along with inhibition of HIF-1A and VEGF. These changes would be anticipated to contribute significantly to the observed antitumor activity of SEMA3F. [Cancer Res 2007;67(18):8708-15]

Progesterone and 1,25-Dihydroxyvitamin D3 Inhibit Endometrial Cancer Cell Growth by Upregulating Semaphorin 3B and Semaphorin 3F

“…Our results are in agreement with earlier studies proposing that SEMA3B and SEMA3F act as tumor suppressors (20)(21)(22). Downregulation of SEMA expression in human tumors is attributed to LOH and promoter hypermethylation (46). Consistently, SEMA3B and SEMA3F overexpression in tumor cell lines induced apoptosis, inhibited cell proliferation, and colony formation in soft agar (15,20,22).…”

Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker?

“…4935). In addition, we showed that SEMA3F protein correlated negatively with VEGF in lung cancer (Brambilla et al, 2000), and recently demonstrated that SEMA3F reduced VEGF mRNA level and HIF-1a protein level (Potiron et al, 2007). Lastly, intraperitoneal administration of recombinant extracellular SEMA6A in mouse inhibited both bFGF/VEGF and tumour cell line-induced neovascularisation (Dhanabal et al, 2005).…”

“…However, SEMA3B, like SEMA3F, is described as a tumour suppressor gene (Tomizawa et al, 2001;Tse et al, 2002). SEMA3F acts as a tumour suppressor gene by reducing angiogenesis and metastasis, probably through the inhibition of integrinmediated adhesion and VEGF expression Kessler et al, 2004;Bielenberg et al, 2004;Kusy et al, 2005;Futamura et al, 2007;Potiron et al, 2007). SEMA3B and SEMA3F are also direct p53 targets (Ochi et al, 2002;Futamura et al, 2007).…”

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…Consistently, Sema3F can induce endothelial cell collapse [63], repel endothelial cells and inhibit their survival [59], and this anti-angiogenic effect is synergistically enhanced by the addition of Sema3A [34]. At the molecular level, it has been shown that Sema3F inhibits multiple signaling pathways in cancer cells [63,64]; however, whether these pathways are also affected in endothelial cells remains unclear. While it is clear that Sema3F can function as a potent tumor suppressor in vivo, further studies are required to understand the molecular mechanism behind this function and the role that Sema3F expression plays in cancer development and progression.…”