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

2020 ◽  
Author(s):  
Michela Terlizzi ◽  
Chiara Colarusso ◽  
Ilaria De Rosa ◽  
Pasquale Somma ◽  
Carlo Curcio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Dependent Manner ◽  
Lung Carcinogenesis ◽  
Small Cell Lung ◽  
Lower Survival Rate ◽  
Gene Alteration ◽  
Nsclc 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 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.

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

2020 ◽  
Author(s):  
Michela Terlizzi ◽  
Chiara Colarusso ◽  
Ilaria De Rosa ◽  
Pasquale Somma ◽  
Carlo Curcio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Dependent Manner ◽  
Lung Carcinogenesis ◽  
Small Cell Lung ◽  
Lower Survival Rate ◽  
Gene Alteration ◽  
Nsclc 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 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.

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

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Michela Terlizzi ◽  
Chiara Colarusso ◽  
Ilaria De Rosa ◽  
Pasquale Somma ◽  
Carlo Curcio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Dependent Manner ◽  
Lung Carcinogenesis ◽  
Small Cell Lung ◽  
Lower Survival Rate ◽  
Gene Alteration ◽  
Nsclc 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 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.

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

2020 ◽  
Author(s):  
Michela Terlizzi ◽  
Chiara Colarusso ◽  
Ilaria De Rosa ◽  
Pasquale Somma ◽  
Carlo Curcio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Lung Tumor ◽  
Small Cell ◽  
Dependent Manner ◽  
Lung Carcinogenesis ◽  
Small Cell Lung ◽  
Gene Alteration ◽  
Nsclc 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 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.

scholarly journals MicroRNA-154 Expression is Associated With The Prognosis in Non-Small Cell Lung Cancer.

2020 ◽  
Author(s):  
Yue Zhao ◽  
Xiangjun Kong ◽  
Hongbing Wang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Prognostic Indicator ◽  
Small Cell ◽  
Rank Test ◽  
Small Cell Lung ◽  
Lower Survival Rate ◽  
Nsclc Patients ◽  
Low Expression

Abstract Background: MicroRNAs are noncoding RNAs that regulate cellular processes during the progression of tumors. Among various microRNAs, MicroRNA-154 (miR-154) has been reported to be involved in many critical processes of human malignancies. This study aimed to evaluate the significance and prognostic value of miR-154 in human non-small cell lung cancer (NSCLC).Methods: A total of 144 NSCLC tissues samples and matched non-tumor adjacent tissues specimens were obtained from NSCLC patients and the quantitative real-time PCR (qRT-PCR) was performed to investigate expression levels of miR-154. The correlation between miR-154 expression and survival outcomes of NSCLC patients was performed by Kaplan-Meier analysis, univariate and multivariate analysis.Results: MiR-154 expression was significantly decreased in NSCLC tissues compared with that in matched non-tumor adjacent tissues (P<0.001). In addition, low expression of miR-154 was demonstrated to be associated with tumors size, TNM stages and distant metastasis of NSCLC patients Survival analysis revealed that patients with low expression of miR-154 showed significantly lower survival rate for OS, DFS and RFS, respectively (all, log rank test, P<0.001) and miR-154 could be an independent prognostic indicator for NSCLC patients.Conclusion: The results suggest that miR-154 has the clinical significance in the progression of NSCLC and could be a potential prognostic biomarker for NSCLC patients.

scholarly journals Serum miR-27a is a biomarker for prognosis of non-small cell lung cancer patients receiving chemotherapy

2020 ◽  
Author(s):  
Erfu Xie ◽  
Yazhou Ji ◽  
Mingxin Lin ◽  
Yuexinzi Jin ◽  
Shichang Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Dependent Manner ◽  
Small Cell Lung ◽  
Clinical Value ◽  
Apoptosis Rate ◽  
Nsclc Patients ◽  
Line Chemotherapy

Abstract Background: Lung cancer has a high incidence and a 5-year survival rate of less than 15%. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. Chemotherapy and immunotherapy are the most frequently used alternative treatments for patients with advanced-stage NSCLC in whom surgery failed. Previous studies have suggested that miR-27a is involved in cancer development and progression. The purpose of this study was to investigate the clinical value of miR-27a in the prognosis of NSCLC patients after chemotherapy. Methods: Flow cytometry was used to detect the apoptosis rate of SPC-A1 cells treated with optical cisplatin at different times. Simultaneously, the expression of miR-27a in supernatants and cells was detected. Fifty-two newly diagnosed NSCLC patients were recruited. All patients received gemcitabine and cisplatin as first-line chemotherapy and docetaxel as second-line chemotherapy. At the end of every chemotherapy cycle, a therapeutic evaluation was performed according to the RECIST criteria. The expression of serum miR-27a was detected in each cycle. Results: After treatment with 2.5 μg/mL cisplatin, the apoptosis rates of SPC-A1 cells were significantly greater than those of the paired untreated control groups at 12, 24, 48 and 72 h. The expression of miR-27a in supernatants and cells was also consistent with the apoptosis rate and changed a time-dependent manner. The chi-square test showed that an increase in miR-27a after chemotherapy was more common in patients who achieved partial response (PR) than in those who achieved no response (NR) (61.5% vs 30.8%, P =0.026). Kaplan–Meier survival analysis indicated that patients with decreased miR-27a levels had poorer outcomes than those with increased miR-27a levels ( P <0.05). Furthermore, dynamic changes in serum miR-27a with a gradual increasing trend during chemotherapy predicted a good prognosis. Conclusions: Collectively, our results suggest that miR-27a is involved in the apoptosis of lung cancer cells and that serum miR-27a levels are related to the prognosis of NSCLC patients. The expression levels of miR-27a in the serum may be an independent predictor for the prognosis of NSCLC.

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

scholarly journals Silibinin Regulates Tumor Progression and Tumorsphere Formation by Suppressing PD-L1 Expression in Non-Small Cell Lung Cancer (NSCLC) Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1632
Author(s):  
Alexis Rugamba ◽  
Dong Young Kang ◽  
Nipin Sp ◽  
Eun Seong Jo ◽  
Jin-Moo Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Small Cell Lung Cancer ◽  
Anticancer Activity ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Molecular Signaling ◽  
Small Cell Lung

Recently, natural compounds have been used globally for cancer treatment studies. Silibinin is a natural compound extracted from Silybum marianum (milk thistle), which has been suggested as an anticancer drug through various studies. Studies on its activity in various cancers are undergoing. This study demonstrated the molecular signaling behind the anticancer activity of silibinin in non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction and Western blotting analysis were performed for molecular signaling analysis. Wound healing assay, invasion assay, and in vitro angiogenesis were performed for the anticancer activity of silibinin. The results indicated that silibinin inhibited A549, H292, and H460 cell proliferation in a concentration-dependent manner, as confirmed by the induction of G0/G1 cell cycle arrest and apoptosis and the inhibition of tumor angiogenesis, migration, and invasion. This study also assessed the role of silibinin in suppressing tumorsphere formation using the tumorsphere formation assay. By binding to the epidermal growth factor receptor (EGFR), silibinin downregulated phosphorylated EGFR expression, which then inhibited its downstream targets, the JAK2/STAT5 and PI3K/AKT pathways, and thereby reduced matrix metalloproteinase, PD-L1, and vascular endothelial growth factor expression. Binding analysis demonstrated that STAT5 binds to the PD-L1 promoter region in the nucleus and silibinin inhibited the STAT5/PD-L1 complex. Altogether, silibinin could be considered as a candidate for tumor immunotherapy and cancer stem cell-targeted therapy.

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