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

Pan, Guoqing; Zhu, Zhu; Huang, Jian; Yang, Chenggang; Wang, Yingxia; Tuo, Xiaoyu; Su, Guomiao; Zhang, Xiangling; Yang, Zhi; Liu, Tao

doi:10.1007/s10620-013-2666-1

Cited by 27 publications

(18 citation statements)

References 15 publications

(18 reference statements)

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“…In particular, amplification of SEMA5A and SEMA6A loci (found in 20% and 30% of the melanoma, respectively) were consistent with their increased mRNA expression in melanomas compared to nevi ( Supplementary Figure 4 ). These results are in line with the role of SEMA5A in promoting invasion of gastric cancer cells [ 21 ] and of SEMA6A in controlling cell growth of BRAF V600E mutant melanomas [ 22 ]. Semaphorins signal through Plexin and Neuropilin receptors to elicit their effects inside the cells [ 23 ].…”

Section: Resultssupporting

confidence: 84%

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

et al. 2016

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Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

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Section: Resultssupporting

confidence: 84%

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

et al. 2016

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“…For example Sema5a transfection to pancreatic cancer cell lines resulted in higher cell invasion in vitro , and injection of such cells to nude mice enhanced tumorgenicity and tumor growth in vivo 19. Similarly, SEMA5A has been shown to promote in vitro migration and invasion of gastric cancer cell lines 20. On the other hand, SEMA5A has been reported to impede glioma cell motility 21, and has been associated with better prognosis in women with non-small cell lung cancer 22.…”

Section: Discussionmentioning

confidence: 99%

A Combined ULBP2 and SEMA5A Expression Signature as a Prognostic and Predictive Biomarker for Colon Cancer

Demirkol¹,

Gömceli²,

Isbilen³

et al. 2017

J. Cancer

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Background: Prognostic biomarkers for cancer have the power to change the course of disease if they add value beyond known prognostic factors, if they can help shape treatment protocols, and if they are reliable. The aim of this study was to identify such biomarkers for colon cancer and to understand the molecular mechanisms leading to prognostic stratifications based on these biomarkers.Methods and Findings: We used an in house R based script (SSAT) for the in silico discovery of stage-independent prognostic biomarkers using two cohorts, GSE17536 and GSE17537, that include 177 and 55 colon cancer patients, respectively. This identified 2 genes, ULBP2 and SEMA5A, which when used jointly, could distinguish patients with distinct prognosis. We validated our findings using a third cohort of 48 patients ex vivo. We find that in all cohorts, a combined ULBP2/SEMA5A classification (SU-GIB) can stratify distinct prognostic sub-groups with hazard ratios that range from 2.4 to 4.5 (p≤0.01) when overall- or cancer-specific survival is used as an end-measure, independent of confounding prognostic parameters. In addition, our preliminary analyses suggest SU-GIB is comparable to Oncotype DX colon(®) in predicting recurrence in two different cohorts (HR: 1.5-2; p≤0.02). SU-GIB has potential as a companion diagnostic for several drugs including the PI3K/mTOR inhibitor BEZ235, which are suitable for the treatment of patients within the bad prognosis group. We show that tumors from patients with worse prognosis have low EGFR autophosphorylation rates, but high caspase 7 activity, and show upregulation of pro-inflammatory cytokines that relate to a relatively mesenchymal phenotype.Conclusions: We describe two novel genes that can be used to prognosticate colon cancer and suggest approaches by which such tumors can be treated. We also describe molecular characteristics of tumors stratified by the SU-GIB signature.

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“…6A). Application of Wortmannin (0.5 µM) or LY294002 (10 µM) (24) induced increased apoptosis in Slit2-knockdown cells treated with oxaliplatin (Fig. 6B).…”

Section: Knockdown Of Slit2 Activates Akt-mediated Survival Signalingmentioning

confidence: 95%

Knockdown of Slit2 promotes growth and motility in gastric cancer cells via activation of AKT/β-catenin

et al. 2013

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We previously showed that Slit2 was highly expressed in gastric cancer tissues that exhibit less advanced clinicopathological features, suggesting a tumor suppressor role for Slit2. In the present study, we investigated the effects of Slit2 knockdown on gastric cancer cells. Slit2-specific shRNAs were used to generate Slit2-knockdown SGC-7901 gastric cancer cells. Cell proliferation assay, Annexin V/PI double staining and cell cycle analysis were used to investigate the role of Slit2 knockdown in cell growth. Wound-healing and in vitro migration/invasion assays were performed. Subcutaneous tumor formation and peritoneal spreading in nude mice were employed to examine the in vivo effects of Slit2 knockdown. Cell signaling changes induced by Slit2 knockdown were analyzed by immunoblotting. Slit2 knockdown increased gastric cancer cell growth in monolayer and soft agar/Matrigel 3D culture. Slit2 knockdown inhibited apoptosis but did not alter cell cycle progression. Slit2-knockdown cells formed larger tumors and produced more peritoneal metastatic nodules in nude mice. Slit2 knockdown increased AKT phosphorylation, activated anti-apoptotic signaling, suppressed GSK3β activity and induced β-catenin activation. Blocking the effects of PI3K/AKT using pharmacological inhibitors abolished the ability of Slit2 knockdown to induce apoptosis resistance and cell migration/invasion. These results indicate that Slit2 knockdown promotes gastric cancer growth and metastasis through activation of the AKT/β‑catenin-mediated signaling pathway.

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

Cited by 27 publications

References 15 publications

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

A Combined ULBP2 and SEMA5A Expression Signature as a Prognostic and Predictive Biomarker for Colon Cancer

Knockdown of Slit2 promotes growth and motility in gastric cancer cells via activation of AKT/β-catenin

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