Abstract
BackgroundTherapy/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.MethodsWe used human samples of NSCLC and mouse models of lung adenocarcinoma.ResultsWe 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.ConclusionsWe 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.
Highlights
Therapy/prognosis of Non-Small Cell Lung Cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression
In this study we demonstrated that caspase-4 was highly present in the tumor mass compared to noncancerous tissues of NSCLC patients and was responsible for cell proliferation, suggesting it as a novel oncoprotein that collaborates with c-MyC and K-Ras to promote lung cancer, affecting patients’ survival rate
Caspase-4 is involved in non-small cell lung Cancer Recently, we demonstrated that NSCLC patients had higher circulating levels of caspase-4 than healthy subjects [12]
Summary
Therapy/prognosis of Non-Small Cell Lung Cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression. Human caspase-4, as well as the analogue murine caspase-11, was described as a proinflammatory caspase that can serve as host defense via the induction of pyroptosis to eliminate intracellular pathogens, and via the release of pro-inflammatory IL-1like cytokine (i.e. IL-1α and IL-1β, IL-18) in a canonical inflammasome pathway. In this latter case it was demonstrated that caspase-11 unlikely processes IL-1β and IL-18 in a direct manner [9], rather, it can promote the downstream caspase-1 activation via NLRP3 [9]. IL-1α release can be directly related to caspase-11 [10]
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