Mitochondria are the convergence point of multiple pathways that trigger programmed cell death (PCD). Mitochondrial-associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the role of mtPCD in the prognostic prediction of cancers including non-small-cell lung cancer (NSCLC) remains to be investigated. Here, 12 mtPCD patterns were analyzed in transcriptomics, genomics, and clinical data collected from 4 datasets containing 977 patients. A risk-score assessment system containing 18 genes was established. We found that NSCLC patients with a high-risk score had a poorer prognosis. A nomogram was constructed by incorporating the risk score with clinical features. The risk score was further associated with clinicopathological information, tumor-mutation frequency, and immunotherapy responses. NSCLC patients with a high risk score had more Treg cells infiltration. However, these patients had higher tumor-mutation burden scores and may be more sensitive to immunotherapy. Moreover, receptor-interacting serine/threonine protein kinase 2 (RIPK2) was selected from mtPCD gene model for validation. We found that RIPK2 exhibited oncogenic function, and its expression level was inversely associated with the overall survival of NSCLC. Taken together, our results indicated the accuracy and practicability of the mtPCD gene model and RIPK2 in predicting the prognosis of NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Prognosis ; Male ; Female ; Nomograms ; Middle Aged ; Mitochondria/metabolism* ; Apoptosis/genetics* ; Mutation ; Biomarkers, Tumor/genetics* ; Aged

The p60 subunit of the chromatin assembly factor-1 complex, that is, chromatin assembly factor-1 subunit B (CHAF1B), is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self-renewal. CHAF1B is overexpressed in several cancers and may represent a potential target for cancer therapy. However, its expression and clinical significance in lung squamous-cell carcinoma (LUSC) remain unclear. In this study, we performed weighted gene correlation network analysis to analyze the Gene Expression Omnibus GSE68793 LUSC dataset and identified CHAF1B as one of the most important driver gene candidates. Immunohistochemical analysis of 126 LUSC tumor samples and 80 adjacent normal lung tissues showed the marked upregulation of CHAF1B in tumor tissues and the negative association of its expression level with patient survival outcomes. Silencing of CHAF1B suppressed LUSC proliferation in vitro and LUSC tumor growth in vivo. Furthermore, bulk RNA sequencing of CHAF1B knockdown cells indicated SET domain containing 7 (SETD7) as a significant CHAF1B target gene. In addition, CHAF1B competitively binds to the SETD7 promoter region and represses its transcription. Altogether, these results imply that CHAF1B plays a vital role in LUSC tumorigenesis and may represent a potential molecular target for this deadly disease.
Humans ; Lung Neoplasms/metabolism* ; Histone-Lysine N-Methyltransferase/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Gene Expression Regulation, Neoplastic ; Disease Progression ; Cell Proliferation/genetics* ; Cell Line, Tumor ; Chromatin Assembly Factor-1/metabolism* ; Animals ; Mice ; Male ; Female

The characteristic genetic abnormality of neuroendocrine neoplasms (NENs), a heterogeneous group of tumors found in various organs, remains to be identified. Here, based on the analysis of the splicing variants of an oncogene Focal Adhesion Kinase (FAK) in The Cancer Genome Atlas datasets that contain 9193 patients of 33 cancer subtypes, we found that Box 6/Box 7-containing FAK variants (FAK^6/7) were observed in 7 (87.5%) of 8 pancreatic neuroendocrine carcinomas and 20 (11.76%) of 170 pancreatic ductal adenocarcinomas (PDACs). We tested FAK variants in 157 tumor samples collected from Chinese patients with pancreatic tumors, and found that FAK^6/7 was positive in 34 (75.6%) of 45 pancreatic NENs, 19 (47.5%) of 40 pancreatic solid pseudopapillary neoplasms, and 2 (2.9%) of 69 PDACs. We further tested FAK splicing variants in breast neuroendocrine carcinoma (BrNECs), and found that FAK^6/7 was positive in 14 (93.3%) of 15 BrNECs but 0 in 23 non-NEC breast cancers. We explored the underlying mechanisms and found that a splicing factor serine/arginine repetitive matrix protein 4 (SRRM4) was overexpressed in FAK^6/7-positive pancreatic tumors and breast tumors, which promoted the formation of FAK^6/7 in cells. These results suggested that FAK^6/7 could be a biomarker of NENs and represent a potential therapeutic target for these orphan diseases.
Female ; Humans ; Alternative Splicing ; Breast Neoplasms/metabolism* ; Carcinoma, Pancreatic Ductal/pathology* ; Focal Adhesion Protein-Tyrosine Kinases/therapeutic use* ; Nerve Tissue Proteins/genetics* ; Neuroendocrine Tumors/genetics* ; Oncogenes ; Pancreatic Neoplasms/metabolism*

Humans ; COVID-19 ; China/epidemiology*

10,11-Dehydrocurvularin (DCV) is a natural-product macrolide that has been shown to exert anti-inflammatory activity. However, the underlying mechanism of its anti-inflammatory activity remains poorly understood. Aberrant activation of the NLRP3 inflammasome is involved in diverse inflammation-related diseases, which should be controlled. The results showed that DCV specifically inhibited the activation of the NLRP3 inflammasome in association with reduced IL-1β secretion and caspase-1 activation, without effect on the NLRC4 and AIM2 inflammasomes. Furthermore, DCV disturbed the interaction between NEK7 and NLRP3, resulting in the inhibition of NLRP3 inflammasome activation. The C=C double bond of DCV was required for the NLRP3 inflammasome inhibition induced by DCV. Importantly, DCV ameliorated inflammation in vivo through inhibiting the NLRP3 inflammasome. Taken together, our study reveals a novel mechanism by which DCV suppresses inflammation, which indicates the potential role of DCV in NLRP3 inflammasome-driven inflammatory disorders.
Animals ; Mice ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Inflammation/drug therapy* ; Anti-Inflammatory Agents/pharmacology* ; Interleukin-1beta/genetics* ; Mice, Inbred C57BL

Sialic acid binding Ig-like lectin 10 (Siglec10) is a member of innate immune checkpoints that inhibits the activation of immune cells through the interaction with its ligand CD24 on tumor cells. Here, by analyzing public databases containing 64 517 patients of 33 cancer types, we found that the expression of Siglec10 was altered in 18 types of cancers and was associated with the clinical outcomes of 11 cancer types. In particular, Siglec10 was upregulated in patients with kidney renal clear cell carcinoma (KIRC) and was inversely associated with the prognosis of the patients. In 131 KIRC patients of our settings, Siglec10 was elevated in the tumor tissues of 83 (63.4%) patients compared with that in their counterpart normal kidney tissues. Moreover, higher level of Siglec10 was associated with advanced disease (stages III and IV) and worse prognosis. Silencing of CD24 in KIRC cells significantly increased the number of Siglec10-expressing macrophages phagocytosing KIRC cells. In addition, luciferase activity assays suggested that Siglec10 was a potential target of the transcription factors c-FOS and GATA1, which were identified by data mining. These results demonstrate that Siglec10 may have important oncogenic functions in KIRC, and represents a novel target for the development of immunotherapies.
Carcinoma, Renal Cell/pathology* ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity, Innate ; Kidney Neoplasms/pathology* ; Lectins/metabolism* ; Prognosis ; Receptors, Cell Surface/metabolism*

BACKGROUND: Immune checkpoint inhibitors (ICIs) such as antibodies against programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have shown remarkable efficacies in many subtypes of cancers. However, ICIs may also cause severe immune-related adverse events in the recipient patients. Recently, ICI-associated myocarditis have been reported in hundreds of patients worldwide, with a mortality rate of approximately 50% in these cases. This study aims to recapitulate the cardiotoxicity and explore the detoxicifying approaches to attenuate mortality caused by PD-1/PD-L1 inhibitors in healthy mice. METHODS: Six to eight-week-old C57BL/6 mice were inoculated with anti-PD-1 antibody (12.5 μg/g every 5 days for 6 injections), anti-PD-L1 antibody (10 μg/g once a week for 6 weeks), anti-PD-L1 antibody (with the same dosage described above) in combination with levothyroxine (0.25 μg/g, intraperitoneally injected half an hour before anti-PD-L1 antibody injection), or isotype control immunoglobulin IgG (10 μg/g once a week for 6 weeks). The ejection function of the hearts was detected by echocardiography, body temperature and blood pressure were detected by Mouse MonitorTM and non-invassive blood pressure minotor, and serum free thyroxine concentration was detected by The enzyme linked immunosorbent assay (ELISA). RESULTS: PD-L1 was expressed at different levels by the cardiomyocytes of the mice. The isotype control immunoglobulin and anti-PD-1 antibody did not cause death of the mice. The 12 mice receiving 3-6 injections of anti-PD-L1 antibody showed a significant increase in the heart-to-tibial ratio and cardiomyoctye degeneration, hyalinization and extravascular inflammatory cell infiltration. In addition, the serum thyroxine was mardedly decreased to 1/3 of that in the control group mice, and the blood pressure and body temperature were abnormally decreased in mice upon treatment with PD-L1 blockade. Eight of the 12 (66.7%) mice died from multiple intravenous injection of anti-PD-L1 antibody.Intraperitoneal injection of levothyroxine 30 min before the injection of anti-PD-L1 antibody significantly attenuated the mortality rate of the anti-PD-L1 antibody-treated mice. CONCLUSIONS The anti-PD-L1 antibody is cardiotoxic and lethal, and levothyroxine is able to rescue the mice from this immune checkpoint inhibitor-caused mortality.

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%-18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.
Adult ; Animals ; COVID-19 ; Epithelial Cells ; Humans ; Lung ; Mice ; Pandemics ; Peptidyl-Dipeptidase A ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Ubiquitin-Protein Ligases/genetics*

Since the outbreak of the COVID-19 pandemic in early December 2019, 81 174 confirmed cases and 3242 deaths have been reported in China as of March 19, 2020. The Chinese people and government have contributed huge efforts to combat this disease, resulting in significant improvement of the situation, with 58 new cases (34 were imported cases) and 11 new deaths reported on March 19, 2020. However, as of March 19, 2020, the COVID-19 pandemic continues to develop in 167 countries/territories outside of China, and 128 665 confirmed cases and 5536 deaths have been reported, with 16 498 new cases and 817 new deaths occurring in last 24 hours. Therefore, the world should work together to fight against this pandemic. Here, we review the recent advances in COVID-19, including the insights in the virus, the responses of the host cells, the cytokine release syndrome, and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm. By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis, we believe that the community can efficiently develop effective vaccines and drugs, and the mankind will eventually win this battle against this pandemic.
Betacoronavirus ; China ; epidemiology ; Coronavirus Infections ; epidemiology ; therapy ; Humans ; Pandemics ; Pneumonia, Viral ; epidemiology ; therapy

In order to unveil ubiquitin pathway genes (UPGs) that are essential for non-small cell lung cancer (NSCLC) cell proliferation, we recently conducted a siRNA screening experiment to knockdown the expression of 696 UPGs found in the human genome in A549 and H1975 NSCLC cells. We found that silencing of one of the candidates, RFWD3 that encodes an E3 ubiquitin ligase essential for the repair of DNA interstrand cross-links in response to DNA damage, led to dramatic inhibition of NSCLC cell proliferation with significant Z-scores. Knockdown of RFWD3 suppressed colony forming activity of NSCLC cells.We further evaluated the significance of RFWD3 in NSCLCs and found that this gene was more elevated in tumor samples than in paired normal lung tissues and was inversely associated with the clinical outcome of patients with NSCLC. Moreover, RFWD3 expression was significantly higher in smokers than in non-smokers. These results show for the first time that RFWD3 is required for NSCLC cell proliferation and may have an important role in lung carcinogenesis.