Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients
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 aden...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-11-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-020-01754-0 |
| _version_ | 1818211873986707456 |
|---|---|
| author | Michela Terlizzi Chiara Colarusso Ilaria De Rosa Pasquale Somma Carlo Curcio Rita P. Aquino Luigi Panico Rosario Salvi Federica Zito Marino Gerardo Botti Aldo Pinto Rosalinda Sorrentino |
| author_facet | Michela Terlizzi Chiara Colarusso Ilaria De Rosa Pasquale Somma Carlo Curcio Rita P. Aquino Luigi Panico Rosario Salvi Federica Zito Marino Gerardo Botti Aldo Pinto Rosalinda Sorrentino |
| author_sort | Michela Terlizzi |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-12-12T05:39:25Z |
| format | Article |
| id | doaj.art-cb4538c17dda47399a2472c39472d744 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-12T05:39:25Z |
| publishDate | 2020-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-cb4538c17dda47399a2472c39472d7442022-12-22T00:35:58ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-11-0139111710.1186/s13046-020-01754-0Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patientsMichela Terlizzi0Chiara Colarusso1Ilaria De Rosa2Pasquale Somma3Carlo Curcio4Rita P. Aquino5Luigi Panico6Rosario Salvi7Federica Zito Marino8Gerardo Botti9Aldo Pinto10Rosalinda Sorrentino11Department of Pharmacy (DIFARMA), University of SalernoDepartment of Pharmacy (DIFARMA), University of SalernoAnatomy and Pathology Unit, Ospedale dei Colli, AORN, “Monaldi”Anatomy and Pathology Unit, Ospedale dei Colli, AORN, “Monaldi”Thoracic Surgery Unit, Ospedale dei Colli, AORN, “Monaldi”Department of Pharmacy (DIFARMA), University of SalernoAnatomy and Pathology Unit, Ospedale dei Colli, AORN, “Monaldi”Thoracic Surgery Unit, Ospedale dei Colli, AORN, “Monaldi”Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”Scientific Direction IRCCS National Cancer Institute “G. Pascale”Department of Pharmacy (DIFARMA), University of SalernoDepartment of Pharmacy (DIFARMA), University of SalernoAbstract 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.http://link.springer.com/article/10.1186/s13046-020-01754-0Lung cancerCaspase-4K-RascMycSurvival rateOncoprotein |
| spellingShingle | Michela Terlizzi Chiara Colarusso Ilaria De Rosa Pasquale Somma Carlo Curcio Rita P. Aquino Luigi Panico Rosario Salvi Federica Zito Marino Gerardo Botti Aldo Pinto Rosalinda Sorrentino Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients Journal of Experimental & Clinical Cancer Research Lung cancer Caspase-4 K-Ras cMyc Survival rate Oncoprotein |
| title | Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients |
| title_full | Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients |
| title_fullStr | Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients |
| title_full_unstemmed | Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients |
| title_short | Identification of a novel subpopulation of Caspase-4 positive non-small cell lung Cancer patients |
| title_sort | identification of a novel subpopulation of caspase 4 positive non small cell lung cancer patients |
| topic | Lung cancer Caspase-4 K-Ras cMyc Survival rate Oncoprotein |
| url | http://link.springer.com/article/10.1186/s13046-020-01754-0 |
| work_keys_str_mv | AT michelaterlizzi identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT chiaracolarusso identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT ilariaderosa identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT pasqualesomma identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT carlocurcio identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT ritapaquino identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT luigipanico identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT rosariosalvi identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT federicazitomarino identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT gerardobotti identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT aldopinto identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients AT rosalindasorrentino identificationofanovelsubpopulationofcaspase4positivenonsmallcelllungcancerpatients |