Distinct prognostic value of mRNA expression of guanylate-binding protein genes in skin cutaneous melanoma

Wang, Qiao-Qi; Wang, Xiangkun; Liang, Qian; Wang, Shijun; Liao, Xiwen; Pan, Fuqiang; Chen, Hongyang; Dong, Lei

doi:10.3892/ol.2018.8306

Cited by 44 publications

(49 citation statements)

References 35 publications

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“…Consistent with our RNA-seq data, the most heavily down-regulated gene in B16-F1 that was identified by our IFN pathway-focused qRT-PCR array was Oas1a, whose human homolog is also down-regulated in aggressive breast and prostate cancers (36). Among other IFNstimulated genes differentially expressed between B16-F1 and B16-F1ΔFOXC2, we also observed down-regulation in B16-F1 of several guanylate-binding protein-encoding genes, many of which correlate positively with survival when expressed at high levels in melanoma patients (37). Therefore, FOXC2-associated down-regulation of these and other IFN pathway genes in B16-F1 is likely to contribute to the rapid progression of this tumor as compared to its FOXC2-deficient counterpart.…”

Section: Discussionmentioning

confidence: 65%

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Hargadon

Győrffy

Strong

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. Materials and Methods: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. Results: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. Conclusion: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies. Melanoma, a highly aggressive form of cancer arising from pigment-producing melanocytes, is responsible for the majority of skin cancer-related mortality, accounting for~6 0,000 annual deaths worldwide (1). Importantly, the incidence of melanoma has risen substantially over the last 40 years (2), a trend that is expected to continue to at least 2031 (3). Although surgical removal of primary lesions is typically successful in the treatment of early-stage disease, many melanoma patients are not diagnosed until later stages of metastatic disease in which surgery is either not possible or largely ineffective. Unfortunately, malignant melanoma is highly resistant to radiation and chemotherapy, and the only FDA-approved chemotherapeutic for the treatment of melanoma, dacarbazine (DTIC), has a minimal impact on patient survival (4). While advances in targeted therapy and immunotherapy have improved the prognosis for melanoma in recent years, there are still patients who do not respond to these regimens, and relapse of therapy-resistant tumors remains an ongoing challenge in many patients who do achieve clinical benefit (5, 6). Therefore, in order to improve the clinical outcome of melanoma patients going forward, it is necessary to gain additional insight into factors that promote melanoma progression and resistance to these therapeutic modalities. FOXC2 is a member of the forkhead box family of transcription factors that control a variety of cellular processes in embryonic and adult tissues. In addition to its normal regulation of development, growth, and metabolism in various tissue types, FOXC2 has recently emerged as a driver of several hallmarks of cancer progression as well. Within vascular endothelial cells, FOXC2 promotes expression of multiple genes that enhance angiogenesis (7-9). FOXC2 can also become overexpressed or dysregulated in tumor cells themselves, where it is asso...

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Section: Discussionmentioning

confidence: 65%

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Hargadon

Győrffy

Strong

et al. 2019

Cancer Genomics Proteomics

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“…To date, the role of mouse Gbp10, one of eleven members of the Gbp family, in tumor biology is unclear. However, in human cutaneous melanoma, several Gbp mRNAs are associated with favorable prognosis (Wang et al, ). Hence, the higher expression of Gbp10 in WT versus Mcpt6 −/− mice may represent a protective function in melanoma development.…”

Section: Discussionmentioning

confidence: 99%

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Grujić

Hellman

Gustafson

et al. 2020

Pigment Cell Melanoma Res

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Tryptase‐positive mast cells populate melanomas, but it is not known whether tryptase impacts on melanoma progression. Here we addressed this and show that melanoma growth is significantly higher in tryptase‐deficient (Mcpt6−/−) versus wild‐type mice. Histochemical analysis showed that mast cells were frequent in the tumor stroma of both wild‐type and Mcpt6−/− mice, and also revealed their presence within the tumor parenchyma. Confocal microscopy analysis revealed that tryptase was taken up by the tumor cells. Further, tryptase‐positive granules were released from mast cells and were widely distributed within the tumor tissue, suggesting that tryptase could impact on the tumor microenvironment. Indeed, gene expression analysis showed that the absence of Mcpt6 caused decreased expression of numerous genes, including Cxcl9, Tgtp2, and Gbp10, while the expression of 5p‐miR3098 was enhanced. The levels of CXCL9 were lower in serum from Mcpt6−/− versus wild‐type mice. In further support of a functional impact of tryptase on melanoma, recombinant tryptase (Mcpt6) was taken up by cultured melanoma cells and caused reduced proliferation. Altogether, our results indicate a protective role of mast cell tryptase in melanoma growth.

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“…Future experiments will reveal whether PAR‐1‐ or GBP‐mediated inhibition of furin activity may also prevent the development or proliferation of certain cancers. Remarkably, increased GBP2/5 expression is associated with favorable outcome in patients suffering from melanoma or breast cancer . Thus, a better understanding of cellular mechanisms regulating furin activity will help to understand the pathogenesis of infectious diseases and cancer and may uncover novel targets for therapeutic intervention.…”

Section: Suppression Of Furin‐mediated Processing Of Viral Glycoprotementioning

confidence: 99%

Furin‐mediated protein processing in infectious diseases and cancer

2019

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Proteolytic cleavage regulates numerous processes in health and disease. One key player is the ubiquitously expressed serine protease furin, which cleaves a plethora of proteins at polybasic recognition motifs. Mammalian substrates of furin include cytokines, hormones, growth factors and receptors. Thus, it is not surprising that aberrant furin activity is associated with a variety of disorders including cancer. Furthermore, the enzymatic activity of furin is exploited by numerous viral and bacterial pathogens, thereby enhancing their virulence and spread. In this review, we describe the physiological and pathophysiological substrates of furin and discuss how dysregulation of a simple proteolytic cleavage event may promote infectious diseases and cancer. One major focus is the role of furin in viral glycoprotein maturation and pathogenicity. We also outline cellular mechanisms regulating the expression and activation of furin and summarise current approaches that target this protease for therapeutic intervention.

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Distinct prognostic value of mRNA expression of guanylate-binding protein genes in skin cutaneous melanoma

Cited by 44 publications

References 35 publications

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

The FOXC2 Transcription Factor Promotes Melanoma Outgrowth and Regulates Expression of Genes Associated With Drug Resistance and Interferon Responsiveness

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

Furin‐mediated protein processing in infectious diseases and cancer

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