Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients

• Published in: Journal of experimental & clinical cancer research Vol. 39; no. 1; pp. 1 - 17
• Main Authors: Terlizzi, Michela, Colarusso, Chiara, De Rosa, Ilaria, Somma, Pasquale, Curcio, Carlo, Aquino, Rita P., Panico, Luigi, Salvi, Rosario, Zito Marino, Federica, Botti, Gerardo, Pinto, Aldo, Sorrentino, Rosalinda
• Format: Journal Article
• Language: English
• Published: London BioMed Central 13.11.2020; BioMed Central Ltd; BMC
• Subjects: Animal experimentation; Antibodies; Apoptosis; Biomedical and Life Sciences; Biomedicine; Bone marrow transplantation; Cancer Research; Caspase-4; cMyc; Comparative analysis; Cytokines; Development and progression; EDTA; Experiments; Gene mutation; Immunology; K-Ras; Laboratory animals; Lung cancer; Mutation; Non-small cell lung cancer; Oncology; Oncoprotein; Pathogens; Pharmacy; Polymerase chain reaction; Small cell lung cancer; Survival rate; Thermal cycling; Transplants & implants; United Kingdom > UK; United States > US; Italy; Cell proliferation; K-Ras; Lung cancer; Oncoprotein; Tumor progression; cMyc; Survival rate; Caspase-4
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-020-01754-0

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. Results We showed that caspase-4 was highly present in the tumor mass compared to non-cancerous human tissues. Interestingly, the orthologue murine caspase-11 promoted lung carcinogenesis in mice. Carcinogen-exposed caspase-11 knockout mice had lower tumor lesions than wild type mice, due to the relevance of caspase-11 in the structural lung cell as demonstrated by bone marrow transplantation and adoptive transfer experiments. Similarly to what observed in mice, caspase-4 was correlated to the stage of lung cancer in humans 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. Moreover, PD-L1 expression and gene mutation (i.e. EGFR) were not correlated to caspase-4 expression. Instead, NSCLC patients who had K-Ras or c-MyC gene alteration were positively correlated to higher levels of caspase-4 and lower survival rate. Conclusions We identified a subgroup of NSCLC patients as caspase-4 positive among which double and triple positive caspase-4, K-Ras and/or c-MyC patients which prognosis was poor. Because K-Ras and c-MyC are still undrugable, the identification of caspase-4 as a novel oncoprotein could introduce novelty in the clinical yet unmet needs for NSCLC patients.