Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for non-small cell lung cancer

Terlizzi, Michela; Colarusso, Chiara; Rosa, Ilaria De; Rosa, N.; Somma, Pasquale; Curcio, Carlo; Sanduzzi, Alessandro; Micheli, Pietro; Molino, Antonio; Saccomanno, Antonello; Salvi, Rosario; Aquino, Rita Patrizia; Pinto, Aldo; Sorrentino, Rosalinda

doi:10.18632/oncotarget.25049

Cited by 21 publications

(42 citation statements)

References 23 publications

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“…Recently, we demonstrated higher circulating levels of caspase-4 in NSCLC patients than healthy subjects (12). In this study we found that caspase-4 is expressed in tumor masses than non-cancerous tissues (Fig.…”

Section: Resultssupporting

confidence: 62%

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Terlizzi

Colarusso

Rosa³

et al. 2020

Preprint

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Background. Therapy/prognosis of Non-small cell lung cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression. However, more than 50% of NSCLC patients are negative to key drugable biomarkers. Methods: We used human samples of NSCLC and mouse models of lung adenocarcinoma. Key Results. We found that caspase-4 was highly expressed in human lung tumor masses and was correlated to lower survival rate, especially of NSCLC patients positive to K-Ras and/or c-MyC gene alteration. In support, the involvement of caspase-4 in lung carcinogenesis was proved by means of animal models in that K-RasLA1 and K-RasLA1/p53R172HΔ transgenic mice had higher levels of caspase-11, responsible for lung carcinogenesis. Indeed, carcinogen-exposed caspase-11 knockout mice had lower tumor lesions and importantly bone marrow transplantation and adoptive transfer experiments demonstrated the carcinogenic relevance of caspase-11 in structural lung cells. In humans, caspase-4 was correlated to the TNM stage in that it induced cell proliferation in a K-Ras, c-MyC and IL-1α dependent manner. Caspase-4 positive (+) adenocarcinoma (79,3%) and squamous carcinoma (88.2%) patients had lower median survival than patients who had lower levels of caspase-4.Conclusions. We identified a group of NSCLC patients as caspase-4 positive and a subgroup of double and triple positive caspase-4, k-Ras and/or c-MyC patients. Because K-Ras and c-MyC are still undruggable, the identification of caspase-4 as a novel oncoprotein could introduce novelty in the clinical yet unmet needs for NSCLC patients.

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Section: Resultssupporting

confidence: 62%

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Terlizzi

Colarusso

Rosa³

et al. 2020

Preprint

Self Cite

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“…Wang reported that in patients with gastric cancer, higher expression of CASP4 was associated with better OS [17]. However, Terlizzi et al found that CASP4 overexpression is associated with poor prognosis in patients with nonsmall cell lung cancer [18]. The prognostic signi cance of CASP4 in ccRCC has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Caspase 4 Overexpression in Clear Cell Renal Cell Carcinoma and Its Prognostic Role

Meng¹,

Tian²,

Long³

et al. 2020

Preprint

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Background: Caspase 4 (CASP4) dysregulation is related to the occurrence, development, and outcome of many malignant tumors, but its role in clear cell renal cell carcinoma (ccRCC) is unclear. This study was conducted to investigate the expression level of CASP4 in tumor tissues and its relationship with clinical prognosis of patients with ccRCC. Methods: First, the Oncomine and The Cancer Genome Atlas databases were used to determine CASP4 mRNA expression in ccRCC and its association with ccRCC prognosis. We then performed immunohistochemical staining and evaluation of 30 paired ccRCC and adjacent normal tissues to confirm these results. The correlation between CASP4 expression and ccRCC prognosis was evaluated using Kaplan-Meier analysis, and related genes and pathways were obtained from The Cancer Genome Atlas database by gene set enrichment analysis and gene set variation analysis. Finally, we explored the co-expression of genes with CASP4 in ccRCC. Results: CASP4 mRNA expression in ccRCC was significantly higher than that in normal tissues (p < 0.001). Kaplan-Meier analysis showed that the overall survival of patients with ccRCC showing high CASP4 expression was significantly reduced (p < 0.001). We then used external datasets (Gene Expression Omnibus database and patients from our center) to verify the level of CASP4 expression and survival differences (all p < 0.05). We also found that differential expression levels of CASP4 were correlated with pathological grade and clinical TNM stage (all p < 0.05). Conclusions: Overall, our study shows that CASP4 is highly expressed in ccRCC and is an important factor affecting prognosis. Thus, CASP4 may be a potential prognostic biomarker of ccRCC.

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“…In our previous study we found circulating and tumor-associated caspase-4 as a novel diagnostic, predictive and prognostic biomarker for non-small cell lung cancer (NSCLC) patients [8]. Therefore, according to the altered metabotype of lung cancer patients, the main goal of the actual study was to understand any correlation between caspase-4 and the metabolomic profile of NSCLC patients by using both lung tumor tissues and plasma.…”

Section: Research Papermentioning

confidence: 99%

“…High levels of LDH are widely associated to chronic inflammatory diseases as well as to tumor progression/prognosis [9,10]. In our previous study we found that caspase-4 is a novel diagnostic tool for NSCLC patients [8]. Therefore, we first evaluated the levels of circulating (plasma) LDH in NSCLC patients compared to healthy subjects and then correlated them with circulating caspase-4.…”

Section: High Levels Of Plasma Lactate Dehydrogenase (Ldh) Are Associmentioning

confidence: 99%

“…In particular, lactic acid, proline, valine and malonic acid had very high variable importance in projection (VIP) scores in cancerous than non-cancerous tissues ( Figure 2B). We moved on by evaluating the levels of these metabolites according to the levels of caspase-4 in the tumor mass based on a previous identified cut-off (0.307 ng/ml) [8]. Tumor-positive caspase-4 tissues had significantly higher levels of palmitic acid than both healthy (non-cancerous) and tumor-negative caspase-4 tissues ( Figure 3A).…”

Section: Metabolomic Signature In Caspase-4 Positive Nsclc Patientsmentioning

confidence: 99%

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Altered lung tissue lipidomic profile in caspase-4 positive non-small cell lung cancer (NSCLC) patients

et al. 2020

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Lung cancer is by far the leading cause of cancer death. Metabolomic studies have highlighted that both tumor progression and limited curative treatment options are partly due to dysregulated glucose metabolism and its associated signaling pathways. In our previous studies, we identified caspase-4 as a novel diagnostic tool for non-small cell lung cancer (NSCLC). Here, we analyzed the metabolomic profile of both plasma and tumor tissues of NSCLC patients stratified as caspase-4 positive or negative. We found that circulating caspase-4 was correlated to LDH. However, this effect was not observed in caspase-4 positive tumor tissues, where instead, fatty acid biosynthesis was favoured in that the malonic acid and the palmitic acid were higher than in non-cancerous and caspase-4 negative tissues. The glycolytic pathway in caspase-4 positive NSCLC tissues was bypassed by the malonic acid-dependent lipogenesis. On the other hand, the dysregulated glucose metabolism was regulated by a higher presence of succinate dehydrogenase (SDHA) and by the gluconeogenic valine which favoured Krebs' cycle. In conclusion, we found that the recently identified caspase-4 positive subpopulation of NSCLC patients is characterized by a lipidomic profile accompanied by alternative pathways to guarantee glucose metabolism in favour of tumor cell proliferation.

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Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for non-small cell lung cancer

Cited by 21 publications

References 23 publications

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Identification of a novel subpopulation of Caspase-4 positive Non-Small Cell Lung Cancer patients.

Caspase 4 Overexpression in Clear Cell Renal Cell Carcinoma and Its Prognostic Role

Altered lung tissue lipidomic profile in caspase-4 positive non-small cell lung cancer (NSCLC) patients

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