Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients
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(2020) 39:242
RESEARCH
Open Access
Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients Michela Terlizzi1,2, Chiara Colarusso1,2, Ilaria De Rosa3, Pasquale Somma3, Carlo Curcio4, Rita P. Aquino1,2, Luigi Panico3, Rosario Salvi4, Federica Zito Marino5, Gerardo Botti6, Aldo Pinto1,2 and Rosalinda Sorrentino1,2*
Abstract 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 caspase11 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. Keywords: Lung cancer, Caspase-4, K-Ras, cMyc, Survival rate, Oncoprotein, Cell proliferation, Tumor progression
Background Lung cancer is one of the leading causes of cancerrelated death worldwide [1, 2]. Epidemiological studies report that lung chronic inflammation initiate/promote the development of lung cancer, possibly in conjunction * Correspondence: [email protected] 1 Department of Pharmacy (DIFARMA), University of Salerno, Italy and ImmunePharma s.r.l., Via Giovanni Paolo II 132, Fisciano, 84084 Salerno, Italy 2 ImmunePharma srl, Department of Pharmacy, University of Salerno, 84084 Fisciano, SA, Italy Full list of author information is available at the end of the article
with tobacco use and/or other environmental pollutants (i.e. asbestos, silica, diesel exhaust). Epithelial cells, alveolar macrophages (MФ) and resident dendritic cells (DCs) are the first line of defense for the respiratory tract. Their prolonged contact with insulting exogenous molecules can initiate and sustain inflammat
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