scholarly journals The SARS-CoV-2 Host Cell Membrane Fusion Protein TMPRSS2 is A Tumor Suppressor and its Downregulation Promotes Antitumor Immunity and Immunotherapy Response in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Zhixian Liu ◽  
Zhilan Zhang ◽  
Qiushi Feng ◽  
Xiao-Sheng Wang
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Antitumor Immunity ◽  
Host Cells ◽  
Host Cell Membrane ◽  
Clinical Prognosis ◽  
In Vivo Experiments

Abstract TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains unexplored. In five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. We found that TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD dataset we collected. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. In conclusion, TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a link between lung cancer and pneumonia caused by SARS-CoV-2 infection.

scholarly journals The SARS-CoV-2 host cell membrane fusion protein TMPRSS2 is a tumor suppressor and its downregulation promotes antitumor immunity and immunotherapy response in lung adenocarcinoma

2021 ◽  
Author(s):  
Zhixian Liu ◽  
Zhilan Zhang ◽  
Qiushi Feng ◽  
Xiaosheng Wang
Keyword(s):  
Lung Cancer ◽  
Cell Membrane ◽  
Fusion Protein ◽  
Membrane Fusion ◽  
Antitumor Immunity ◽  
Host Cell Membrane ◽  
Membrane Fusion Protein ◽  
In Vivo Experiments

Abstract Background Cancer patients are susceptible to SARS-CoV-2 infection. An investigation into the association between the SARS-CoV-2 host cell membrane fusion protein TMPRSS2 and lung cancer is significant, considering that lung cancer is the leading cause of cancer death and that the lungs are the primary organ SARS-CoV-2 attacks. Methods Using five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, cancer-associated pathways, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. We validated the findings from the bioinformatics analysis through in vitro and in vivo experiments and clinical samples we collected. Results TMPRSS2 expression levels were negatively correlated with the enrichment levels of both antitumor immune signatures and immunosuppressive signatures in LUAD. However, TMPRSS2 expression levels showed a significant positive correlation with the ratios of immune-stimulatory/immune-inhibitory signatures (CD8 + T cells/PD-L1) in LUAD. TMPRSS2 downregulation correlated with elevated activities of many oncogenic pathways in LUAD, including cell cycle, mismatch repair, p53, and extracellular matrix signaling. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor advancement, and worse survival in LUAD. In vitro and in vivo experiments validated the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. Conclusion TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a connection between lung cancer and pneumonia caused by SARS-CoV-2 infection.

scholarly journals The SARS-CoV-2 host cell membrane fusion protein TMPRSS2 is a tumor suppressor and its downregulation correlates with increased antitumor immunity and immunotherapy response in lung adenocarcinoma

2021 ◽  
Author(s):  
Zhixian Liu ◽  
Zhilan Zhang ◽  
Qiushi Feng ◽  
Xiaosheng Wang
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Membrane ◽  
Antitumor Immunity ◽  
Host Cell Membrane ◽  
Expression Levels ◽  
Membrane Fusion Protein ◽  
In Vivo Experiments

Background TMPRSS2 is a host cell membrane fusion protein for SARS-CoV-2 invading human host cells. It also has an association with cancer, particularly prostate cancer. However, its association with lung cancer remains insufficiently explored. Thus, an in-depth investigation into the association between TMPRSS2 and lung cancer is significant, considering that lung cancer is the leading cause of cancer death and that the lungs are the primary organ SARS-CoV-2 attacks. Methods Using five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, cancer-associated pathways, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we validated the findings from the bioinformatics analysis by performing in vitro experiments with the human LUAD cell line A549 and in vivo experiments with mouse tumor models. We also validated our findings in LUAD patients from Jiangsu Cancer Hospital, China. Results TMPRSS2 expression levels were negatively correlated with the enrichment levels of CD8+ T and NK cells and immune cytolytic activity in LUAD, which represent antitumor immune signatures. Meanwhile, TMPRSS2 expression levels were negatively correlated with the enrichment levels of CD4+ regulatory T cells and myeloid-derived suppressor cells and PD-L1 expression levels in LUAD, which represent antitumor immunosuppressive signatures. However, TMPRSS2 expression levels showed a significant positive correlation with the ratios of immune-stimulatory/immune-inhibitory signatures (CD8+ T cells/PD-L1) in LUAD. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory signatures than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with elevated activities of many oncogenic pathways in LUAD, including cell cycle, mismatch repair, p53, and extracellular matrix (ECM) signaling. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor advancement, and worse survival in LUAD. In vitro and in vivo experiments validated the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. Conclusions TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a connection between lung cancer and pneumonia caused by SARS-CoV-2 infection.

scholarly journals The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Long Gao ◽  
Yuan Liu ◽  
Xiaohong Du ◽  
Sai Ma ◽  
Minmin Ge ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Enzymatic Activity ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
In Vitro Assays ◽  
Knock Out

AbstractIt has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

scholarly journals CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Jiayu Zhou ◽  
Shizhen Zhang ◽  
Zhoumiao Chen ◽  
Zhengfu He ◽  
Yong Xu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Subcellular Fractionation ◽  
Host Gene ◽  
Circular Rnas ◽  
In Vivo Experiments ◽  
Promising Treatment ◽  
Tumor Growth And Metastasis ◽  
Induced Apoptosis

AbstractLung adenocarcinoma (LUAD) has long been one of the predominant reasons for the global cancer-linked mortality. The tumor progression is shown by several studies to be promoted by increased glycolysis. Enolase 1 (ENO1), as a glycolysis enzyme, performs pivotal role in glucose metabolism and contributes to tumor progression of numerous cancers. Circular RNAs (circRNAs) are catching increasing attentions for their surging roles in regulating gene expression in cancers. Our work is to uncover the regulatory mechanism circ-ENO1 on its host gene ENO1 and its function in glycolysis and tumor progression. Circ-ENO1 and its host gene ENO1 were identified to be upregulated in LUAD cells. Functionally, silencing circ-ENO1 retarded glycolysis, inhibited proliferation, migration and EMT, induced apoptosis. The cytoplasmic localization of circ-ENO1 was determined by FISH and subcellular fractionation. Mechanistically, circ-ENO1 acted as a ceRNA to interact with miR-22-3p and upregulate ENO1 expression. In vivo experiments certified that circ-ENO1 drove tumor growth and metastasis in vivo. In summary, current study elucidated that circ-ENO1 promoted glycolysis and tumor progression in LUAD by miR-22-3p/ENO1 axis, indicating circ-ENO1 as a promising treatment target for LUAD patients.

scholarly journals Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhuochao Liu ◽  
Hongyi Wang ◽  
Chuanzhen Hu ◽  
Chuanlong Wu ◽  
Jun Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Antitumor Immunity ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Specific Monoclonal Antibody ◽  
Osteosarcoma Cells ◽  
Jnk Pathway ◽  
In Vivo Experiments

AbstractIn this study, we identified the multifaceted effects of atezolizumab, a specific monoclonal antibody against PD-L1, in tumor suppression except for restoring antitumor immunity, and investigated the promising ways to improve its efficacy. Atezolizumab could inhibit the proliferation and induce immune-independent apoptosis of osteosarcoma cells. With further exploration, we found that atezolizumab could impair mitochondria of osteosarcoma cells, resulting in increased release of reactive oxygen species and cytochrome-c, eventually leading to mitochondrial-related apoptosis via activating JNK pathway. Nevertheless, the excessive release of reactive oxygen species also activated the protective autophagy of osteosarcoma cells. Therefore, when we combined atezolizumab with autophagy inhibitors, the cytotoxic effect of atezolizumab on osteosarcoma cells was significantly enhanced in vitro. Further in vivo experiments also confirmed that atezolizumab combined with chloroquine achieved the most significant antitumor effect. Taken together, our study indicates that atezolizumab can induce mitochondrial-related apoptosis and protective autophagy independently of the immune system, and targeting autophagy is a promising combinatorial approach to amplify its cytotoxicity.

BAI1 acts as a tumor suppressor in lung cancer A549 cells by inducing metabolic reprogramming via the SCD1/HMGCR module

2020 ◽  
Author(s):  
Lei Liu ◽  
Li Chai ◽  
Jingjing Ran ◽  
Ying Yang ◽  
Li Zhang
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Colony Formation ◽  
Warburg Effect ◽  
Poor Prognosis ◽  
A549 Cells ◽  
Angiogenesis Inhibitor ◽  
Metabolic Reprogramming ◽  
The Warburg Effect

Abstract Brain-specific angiogenesis inhibitor 1 (BAI1) is an important tumor suppressor in multiple cancers. However, the mechanisms behind its anti-tumor activity, particularly the relationship between BAI1 and metabolic aberrant of a tumor, remained unveiled. This study aimed to investigate whether BAI1 could inhibit biological functions in lung cancer A549 cells and the critical regulating molecules that induce metabolic reprogramming. Immunohistochemistry staining was performed to analyze whether variations in the expression of BAI1 in tumor tissues contributes to poor prognosis of lung cancer. Overexpressed BAI1 (BAI1-OE-A549) and control (Vector-NC-A549) were generated by lentiviral transfection. Biological function assays (proliferation, apoptosis, colony formation, invasion and in vivo metastasis), as well as metabolic reprogramming (by the Warburg effect and the glycolytic rate), were performed in both groups. Our results indicated that lower levels of BAI1 contributed to poor prognosis of lung cancer patients. Furthermore, overexpressed of BAI1 dramatically inhibited proliferation, migration, invasion, colony formation and in vivo metastasis of A549 cells. The Warburg effect and the Seahorse assay revealed that BAI1-OE induced metabolism reprogramming by inhibiting the Warburg effect and glycolysis. Further exploration indicated that BAI1 induced metabolic reprogramming by upregulating stearoyl-CoA desaturase 1 (SCD1) and inhibited 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Our study revealed a novel mechanism through which BAI1 acted as tumor suppressor by inducing metabolic reprogramming via the SCD1 and HMGCR module.

scholarly journals Interferon Consensus Sequence-Binding Protein 8, a Tumor Suppressor, Suppresses Tumor Growth and Invasion of Non-Small Cell Lung Cancer by Interacting with the Wnt/β-Catenin Pathway

2018 ◽  
Vol 51 (2) ◽  
pp. 961-978 ◽  
Author(s):  
Lin Ye ◽  
Tingxiu Xiang ◽  
Jing Zhu ◽  
Dairong Li ◽  
Qin Shao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Consensus Sequence ◽  
Three Dimensional ◽  
Small Cell ◽  
Immunofluorescence Staining ◽  
Small Cell Lung

Background/Aims: Interferon consensus sequence-binding protein 8 (IRF8) belongs to a family of interferon (IFN) regulatory factors that modulates various important physiological processes including carcinogenesis. As reported by others and our group, IRF8 expression is silenced by DNA methylation in both human solid tumors and hematological malignancies. However, the role of IRF8 in lung carcinoma remains elusive. In this study, we determined IRF8 epigenetic regulation, biological functions, and the signaling pathway involved in non-small cell lung cancer (NSCLC). Methods: IRF8 expression were determined by Q- PCR. MSP and A+T determined promotor methylation. MTS, clonogenic, Transwell assay, Flow cytometry, three-dimensional culture and AO/EB stain verified cell function. In vivo tumorigenesis examed the in vivo effects. By Chip-QPCR, RT-PCR, Western blot and Immunofluorescence staining, the mechanisms were studied. Results: IRF8 was significantly downregulated in lung tumor tissues compared with adjacent non-cancerous tissues. Furthermore, methylation-specific PCR analyses revealed that IRF8 methylation in NSCLC was a common event, and demethylation reagent treatment proved that downregulation of IRF8 was due to its promoter CpG hypermethylation. Clinical data showed that the IRF8 methylation was associated with tumor stage, lymph node metastasis status, patient outcome, and tumor histology. Exogenous expression of IRF8 in the silenced or downregulated lung cancer cell lines A549 and H1299 at least partially restored the sensitivity of lung cancer cells to apoptosis, and arrested cells at the G0/G1 phase. Cell viability, clonogenicity, and cell migration and invasive abilities were strongly inhibited by restored expression of IRF8. A three-dimensional culture system demonstrated that IRF8 changed the cells to a more spherical phenotype. Moreover, ectopic expression of IRF8 enhanced NSCLC chemosensitivity to cisplatin. Furthermore, as verified by Chip-qPCR, immunofluorescence staining, and western blotting, IRF8 bound to the T-cell factor/lymphoid enhancer factor (TCF /LEF) promoter, thus repressing β-catenin nuclear translocation and its activation. IRF8 significantly disrupted the effects of Wnt agonist, bml284, further suggesting its involvement in the Wnt/β-catenin pathway. Conclusion: IRF8 acted as a tumor suppressor gene through the transcriptional repression of β-catenin-TCF/LEF in NSCLC. IRF8 methylation may serve as a potential biomarker in NSCLC prognosis.

scholarly journals Requirement for PKC Epsilon in Kras-Driven Lung Tumorigenesis

2020 ◽  
Author(s):  
Rachana Garg ◽  
Mariana Cooke ◽  
Shaofei Wang ◽  
Fernando Benavides ◽  
Martin C. Abba ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cancer Therapeutics ◽  
Rna Seq ◽  
Lung Tumorigenesis ◽  
Mechanistic Analysis ◽  
Oncogenic Driver ◽  
Histological Form

ABSTRACTNon-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCε, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCε expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCε-deficient, conditionally activatable allele of oncogenic Kras (LSL-KrasG12D;PKCε−/− mice) we were able to demonstrate the requirement of PKCε for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCε-deficient KRAS-dependent NSCLC cells. Moreover, PKCε-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCε and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCε in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCε for lung cancer therapeutics.

scholarly journals Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

2020 ◽  
Author(s):  
Giorgia Foggetti ◽  
Chuan Li ◽  
Hongchen Cai ◽  
Jessica A. Hellyer ◽  
Wen-Yang Lin ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Putative Tumor Suppressor ◽  
Lung Adenocarcinomas ◽  
Gene Alterations

AbstractCancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which are the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumor growth. These results are consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduces the sensitivity of EGFR-driven Trp53-deficient tumors to the EGFR inhibitor osimertinib. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.

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