Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

Lalmanach, Gilles; Kasabova-Arjomand, Mariana; Lecaille, Fabien; Saidi, Ahlame

doi:10.3390/cancers13081877

Cited by 15 publications

(13 citation statements)

References 119 publications

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“…Our study further validated these characteristics of APOD demonstrating a positive correlation with infiltration of macrophages (CD68) and WNT signaling pathway (WNT2B). Cystatin E/M (CST6), a representative cysteine protease inhibitor, has been well appreciated as a tumor-promoting and tumor-suppressing agent and is pursued as an epigenetically therapeutic target in special cancer types ( 106 ). Loss of expression in 70% of gastric cancer was reported due to promoter hypermethylation which was associated with shorter survival ( 107 ).…”

Section: Discussionmentioning

confidence: 99%

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma

Khan

Lin²,

Wang³

et al. 2022

Front. Immunol.

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BackgroundGastric cancer (GC) represents a major global clinical problem with very limited therapeutic options and poor prognosis. Necroptosis, a recently discovered inflammatory form of cell death, has been implicated in carcinogenesis and inducing necroptosis has also been considered as a therapeutic strategy.ObjectiveWe aim to evaluate the role of this pathway in gastric cancer development, prognosis and immune aspects of its tumor microenvironment.Methods and resultsIn this study, we evaluated the gene expression of 55 necroptosis-related genes (NRGs) that were identified via carrying out a comprehensive review of the medical literature. Necroptosis pathway was deregulated in gastric cancer samples (n=375) as compared to adjacent normal tissues (n=32) obtained from the “The Cancer Genome Atlas (TCGA)”. Based on the expression of these NRGs, two molecular subtypes were obtained through consensus clustering that also showed significant prognostic difference. Differentially expressed genes between these two clusters were retrieved and subjected to prognostic evaluation via univariate cox regression analysis and LASSO cox regression analysis. A 13-gene risk signature, termed as necroptosis-related genes prognostic index (NRGPI), was constructed that comprehensively differentiated the gastric cancer patients into high- and low-risk subgroups. The prognostic significance of NRGPI was validated in the GEO cohort (GSE84437: n=408). The NRGPI-high subgroup was characterized by upregulation of 10 genes (CYTL1, PLCL1, CGB5, CNTN1, GRP, APOD, CST6, GPX3, FCN1, SERPINE1) and downregulation of 3 genes (EFNA3, E2F2, SOX14). Further dissection of these two risk groups by differential gene expression analysis indicated involvement of signaling pathways associated with cancer cell progression and immune suppression such as WNT and TGF-β signaling pathway. Para-inflammation and type-II interferon pathways were activated in NRGPI-high patients with an increased infiltration of Tregs and M2 macrophage indicating an exhausted immune phenotype of the tumor microenvironment. These molecular characteristics were mainly driven by the eight NRGPI oncogenes (CYTL1, PLCL1, CNTN1, GRP, APOD, GPX3, FCN1, SERPINE1) as validated in the gastric cancer cell lines and clinical samples. NRGPI-high patients showed sensitivity to a number of targeted agents, in particular, the tyrosine kinase inhibitors.ConclusionsNecroptosis appears to play a critical role in the development of gastric cancer, prognosis and shaping of its tumor immune microenvironment. NRGPI can be used as a promising prognostic biomarker to identify gastric cancer patients with a cold tumor immune microenvironment and poor prognosis who may response to selected molecular targeted therapy.

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Section: Discussionmentioning

confidence: 99%

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma

Khan

Lin²,

Wang³

et al. 2022

Front. Immunol.

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“…The dual function of CST6 as both tumor suppressing and tumor promoting has been well appreciated (Lalmanach et al, 2021), but its global function and expression pattern in the development of cancer remain largely unknown. Here, we comprehensively characterized the expression pattern of CST6 in cancer from TCGA, and the result was verified from another large sample dataset.…”

Section: Discussionmentioning

confidence: 99%

“…CST6 could serve as a biomarker for tumor diagnosis and play a dual functional effect across cancer types (Lalmanach et al, 2021). Previous studies of CST6 expression in cancer were limited to sample sizes and focused on a single cancer type.…”

Section: Gene Expression Analysis Of Cystatin E/m In the The Cancer Genome Atlas Datasetsmentioning

confidence: 99%

“…The dysfunction of CST6 contributed to the alterations in proteolysis of tissue architecture, which might accelerate the spread of cancer cells (Shridhar et al, 2004;Keppler, 2006). Increasing evidence has demonstrated the dual functional effects of CST6 in cancer progress (Lalmanach et al, 2021). For instance, the overexpression of CST6 could rescue mice from bone metastasis by suppressing proliferation, migration, and invasion (Jin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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A Pan-Cancer Analysis of Cystatin E/M Reveals Its Dual Functional Effects and Positive Regulation of Epithelial Cell in Human Tumors

Ding

Cao

et al. 2021

Front. Genet.

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Cystatin E/M (CST6), a representative cysteine protease inhibitor, plays both tumor-promoting and tumor-suppressing functions and is pursued as an epigenetically therapeutic target in special cancer types. However, a comprehensive and systematic analysis for CST6 in pan-cancer level is still lacking. In the present study, we explored the expression pattern of CST6 in multiple cancer types across ∼10,000 samples from TCGA (The Cancer Genome Atlas) and ∼8,000 samples from MMDs (Merged Microarray-acquired Datasets). We found that the dynamic expression alteration of CST6 was consistent with dual function in different types of cancer. In addition, we observed that the expression of CST6 was globally regulated by the DNA methylation in its promoter region. CST6 expression was positively correlated with the epithelial cell infiltration involved in epithelial-to-mesenchymal transition (EMT) and proliferation. The relationship between CST6 and tumor microenvironment was also explored. In particular, we found that CST6 serves a protective function in the process of melanoma metastasis. Finally, the clinical association analysis further revealed the dual function of CST6 in cancer, and a combination of the epithelial cell infiltration and CST6 expression could predict the prognosis for SKCM patients. In summary, this first CST6 pan-cancer study improves the understanding of the dual functional effects on CST6 in different types of human cancer.

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“…More specifically, BRCA1 and MGMT are both DNA repair genes [ 37 , 38 ]; RASSF10 and USP44 are involved in cell cycle regulation [ 39 , 40 ]. SLFN11 is an inhibitor of DNA replication that promotes cell death in response to DNA damage [ 41 ], and CST6 directly inhibits the activity of cysteine-type endopeptidases [ 42 ]. The DNA methylation of BRCA1 [ 43 ] and MGMT [ 44 ] has been previously reported in ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer

Tserpeli

Stergiopoulou

Londra

et al. 2021

Cancers

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Background: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. Methods: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. Results: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Conclusions: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.

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Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

Cited by 15 publications

References 119 publications

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma

A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma

A Pan-Cancer Analysis of Cystatin E/M Reveals Its Dual Functional Effects and Positive Regulation of Epithelial Cell in Human Tumors

Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer

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