Frequent inactivation of SLIT2 and ROBO1 signaling in head and neck lesions: clinical and prognostic implications

Maiti, Guru Prasad; Ghosh, Amlan; Mondal, Prasenjit; Ghosh, Susmita; Chakraborty, Jayanta; Roy, Anup; Roychowdhury, Sukla; Panda, Chinmay Kumar

doi:10.1016/j.oooo.2014.09.029

Cited by 14 publications

(12 citation statements)

References 29 publications

(36 reference statements)

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“…Among these 27 genes enrolled in IRGS, six genes (ULBP1, CCR6, CCL22, ROBO1, DKK1 and PDGFA) have previously shown to correlate with the tumorigenesis of HNSCC [20][21][22][23][24][25]. As reported, CCR6 Fig.…”

Section: Discussionmentioning

confidence: 79%

“…Reliable prognostic biomarkers are needed to identify patients with the highest risk of unfavorable survival outcomes. Numerous studies have highlighted the biomarkers associated with the pathogenesis and biology of HNSCC [14,[20][21][22][23][24][25]. Unfortunately, the accuracy of their survival evaluations remains limited and they have not yet been applied in routine clinical practice.…”

Section: Discussionmentioning

confidence: 99%

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Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

She

Kong

et al. 2020

Cancer Cell Int

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Background: Immune-related genes (IRGs) were linked to the prognosis of head and neck squamous cell carcinoma (HNSCC). This study aimed to identify the effects of an immune-related gene signature (IRGS) that can predict the of HNSCC prognosis. Methods: The expression data of 770 HNSCC patients from the TCGA database and the GEO database were used. To explore a predictive model, the Cox proportional hazards model was applied. The Kaplan-Meier survival analysis, as well as univariate and multivariate analyses were performed to evaluate the independent predictive value of IRGS. To explore biological functions of IRGS, enrichment analyses and pathway annotation for differentially expressed genes (DEGs) in different immune groups were applied, as well as the immune infiltration. Results: A prognostic signature comprising 27 IRGs was generated. IRGS significantly stratified HNSCC patients into high and low immune risk groups in regard to overall survival in the training cohort (HR = 3.69, 95% CI 2.73-4.98, P < 0.001). Likewise, IRGS could be linked to the prognosis of HNSCC in patients of the validation cohort (HR = 1.84, 95% CI 1.21-2.81, P < 0.01). Even after adjusting for TNM stage, IRGS was maintained as an independent predictor in the multivariate analysis (HR = 3.62, 95% CI 2.58-5.09, P < 0.001), and in the validation cohort (HR = 1.73, 95% CI 1.12-2.67, P = 0.014). The IFN-α response, the IFN-γ response, IL-2/STAT5 signaling, and IL-6/JAK/STAT3 signaling were all negatively correlated with the immune risk (P < 0.01). Immune infiltration of the high-risk group was significantly lower than that of the low-risk group (P < 0.01). Most notably, the infiltration of CD8 T cells, memory-activated CD4 T cells, and regulatory T cells was strongly upregulated in the low immune risk groups, while memory resting CD4 T cell infiltration was downregulated (P < 0.01). Conclusion: Our analysis provides a comprehensive prognosis of the immune microenvironments and outcomes for different individuals. Further studies are needed to evaluate the clinical application of this signature.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

She

Kong

et al. 2020

Cancer Cell Int

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“…Reduced Slit2 expression has been reported in a great variety of cancers, and is predominantly due to the hypermethylation of the Slit2 promoter (34)(35)(36)(37)(38)(39). Although Slit2 downregulation has also been reported in HCC tissues (21), large-scale mining of microarray data from the Oncomine database revealed a heterogeneous expression pattern for Slit2 in HCC clinical samples (Fig.…”

Section: Discussionmentioning

confidence: 99%

Slit2 and Robo1 induce opposing effects on metastasis of hepatocellular carcinoma Sk-hep-1 cells

Yuan

Guo

et al. 2016

International Journal of Oncology

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The neural guidance molecular, Slit2, and its cognate receptor, Robo1, play critical roles in the development of the nervous system, nevertheless, their functions are not limited to this system. Numerous studies have shown decreased Slit2 expression in a wide variety of cancers, highlighting its potential as a tumor suppressor. However, the Slit2/Robo1 signaling axis was reported to induce either suppressive or stimulatory effects on tumor growth and metastasis, depending on cellular context. There is a paucity of information on the effects of the Slit2/Robo1 signaling axis on the growth and metastasis of human hepatocellular carcinoma (HCC). Large-scale data mining of the Oncomine database has revealed heterogeneous expression of Slit2 in HCC. We screened the Sk-hep-1, a cell line showing a relatively high level of Slit2, and low level of Robo1 expression. After Slit2 knockdown and Robo1 overexpression in these cells, we found Slit2 and Robo1 exerted opposing effects on tumor growth and metastasis both in in vitro and in vivo models. Slit2 knockdown and Robo1 overexpression in Sk-hep-1 cells promoted tumor growth and metastasis, suggesting a negative and positive role for Slit2 and Robo1, respectively, in tumor progression. Robo1 overexpression upregulated matrix metalloproteinase (MMP)2, -9 and membrane-type1 MMP (MT1-MMP) expression, stimulated MMP2, but not MMP9 activation, and downregulated expression of TIMP1 and 2. The PI3K/Akt signaling pathway is of importance in regulating MMP2 expression in Sk-hep-1 cells, since Robo1 overexpression stimulated phosphorylation of Akt while the PI3K inhibitor LY294002, significantly inhibited the upregulation of MMP2 and also the enhanced cell invasion induced by Robo1 overexpression. We postulate that Robo1 promotes tumor invasion partly by the upregulation of MMP2 after activation of PI3K/Akt signaling pathway. Notably, Slit2 knockdown caused the upregulation of Robo1 expression both at the mRNA and protein levels. Thus, the stimulatory effects of Slit2 knockdown on tumor progression can be ascribed, at least in part, to the upregulation of Robo1 and its positive role in tumor progression.

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“…Robo1 and Robo2 are two receptors of the secretory protein Slit2. It was previously reported that Slit2 and Robo1 are expressed in a large number of malignant solid tumors and the binding of the functional region of Slit2 to Robo1 could initiate a cascade of events leading to altered cell proliferation, migration, apoptosis, and angiogenesis [12,23,24]. Up-regulation of Robo1 has been reported to be correlated with poor prognosis of nasopharyngeal cancer (NPC) [20,23].…”

Section: Discussionmentioning

confidence: 99%

Slit2-Robo1 signaling enhances nasopharyngeal carcinoma metastasis via PI3K/AKT/β-catenin pathway

Shi¹,

Zhao²,

Ma³

et al. 2020

Preprint

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Background Distant metastasis remained the major cause of mortality in nasopharyngeal carcinoma (NPC) receiving radiotherapy despite favorable locoregional control in the past decades. Tumor microenvironment plays a critical role in tumor progression by secreting factors that regulate cancer cell metastasis. We explored the role of secreted protein Slit2 in NPC metastasis and the underlying mechanisms. Methods Colony formation assay were determined the opitimal dose. Using real-time PCR, western blotting, and ELISA, we detected the expression of Slit2 in NPC cells and in supernatant. Cell migration assay and cell invasion assay were examined the role of Slit2 in promoting metastasis of NPC cell lines. Western blotting, immunofluorescence staining, transwell and Co-IP assay et al. were performed to explore the detailed molecular mechanism of Slit2 in NPC. Finally, we estimated the effects on Slit2-shRNA NPC cells in vivo tumor metastasis experiment Results We found that irradiated dying NPC cells could secrete Slit2 to enhance the metastatic ability of surviving NPC cells. Mechanistic study showed that Slit2 interacted with its cognate Robo1 receptor, which activated PI3K/Akt pathway and enhanced the nuclear translocation of β-catenin to promote NPC metastasis. Finally, we demonstranted that knockdown of Slit2 in NPC cells significantly suppressed lung and liver metastasis. Conclusion Slit2, a secreted factor released from irradiated dying NPC cells could promote metastasis of living/resistent NPC cells through PI3K/AKT/β-catenin pathway. Tumor microenvironment altered by irradiated dying cancer cells may be promising target to treat cancer metastasis.

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Frequent inactivation of SLIT2 and ROBO1 signaling in head and neck lesions: clinical and prognostic implications

Abstract: Our data suggest that inactivation of SLIT2 and/or ROBO1 is one of the early events in development of dysplastic lesions of head and neck and has prognostic importance.

Cited by 14 publications

References 29 publications

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

Slit2 and Robo1 induce opposing effects on metastasis of hepatocellular carcinoma Sk-hep-1 cells

Slit2-Robo1 signaling enhances nasopharyngeal carcinoma metastasis via PI3K/AKT/β-catenin pathway

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