Association between metal mixture exposure and abnormal glucose metabolism in multiple mixture exposure models: Evidence from NHANES 2015-2016.

Previous studies primarily focused on the single metal exposure and one-sided glucose metabolism disordered states, leading to conflicting results. Herein, we combined diabetes and prediabetes as abnormal glucose metabolism (AGM) to describe the effect of metal mixture exposure on it. Eligible data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2015-2016. In the generalized linear model (GLM), Cd (OR: 1.060, 95 %CI: 1.032-1.089, P value < 0.001) and Tl (OR: 1.039, 95 %CI: 1.004-1.075, P value = 0.031) exposure were positively associated with AGM. In the weighted quantile sum (WQS) regression model, the positive index was obviously associated with AGM (OR: 1.358, 95 %CI: 1.007-1.832, P value = 0.045). In the least absolute shrinkage and selection operator (LASSO) regression model, Cd and Tl were selected as the most contributors. In the Bayesian kernel machine regression (BKMR) model, the effect of co-exposure to metal mixture was associated with AGM, and Cd exposure showed a significantly positive trend. In conclusion, Cd and Tl exposure exhibited independent positive effects on AGM among metal mixture exposure, consistent with their effects on prediabetes.

Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. METHODS: The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. RESULTS: High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. CONCLUSION: WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract.

Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis.

p62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies.

Cancer immunotherapy especially immune checkpoint inhibition has achieved unprecedented successes in cancer treatment. However, there are many patients who failed to benefit from these therapies, highlighting the need for new combinations to increase the clinical efficacy of immune checkpoint inhibitors. In this review, we summarized the latest discoveries on the combination of nucleic acid-sensing immunity and immune checkpoint inhibitors in cancer immunotherapy. Given the critical role of nuclear acid-mediated immunity in maintaining the activation of T cell function, it seems that harnessing the nuclear acid-mediated immunity opens up new strategies to enhance the effect of immune checkpoint inhibitors for tumor control.

EGFR TKIs impair lysosome-dependent degradation of SQSTM1 to compromise the effectiveness in lung cancer.

Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.