Pyroptosis, a lytic pro-inflammatory type of programmed cell death, has been widely studied in diverse inflammatory disease models. Membrane perforation and cell swelling induced by cleaved gasdermin family members is the main characteristic of pyroptosis. Emerging evidence has revealed a complicated relationship between pyroptosis and cancer. On the one hand, as inflammatory cell death, pyroptosis provides a comfortable environment for tumor proliferation. On the other hand, excessive activation of pyroptosis can inhibit the development of tumor cells. In this review, we first summarized the latest progress about the molecular mechanism of pyroptosis. Then, members from gasdermin family, the central molecules of pyroptosis which formed pores on the cell membrane, were highlighted. In the second part of this review, we summarized drugs that induced pyroptosis in different tumors and their concrete mechanisms based on recent literature reports. In the final section, we discussed several hotspots in pyroptosis and cancer therapy, which will point out the direction of sequent research. In brief, inducing pyroptosis in cancer cells is a promising strategy for cancer therapy.
Melanoma is the deadliest form of skin cancer and one of the most aggressive cancers. ZFAS1 is a newly identified lncRNA, playing an oncogenic role in several types of cancer. The present study aimed to investigate the function and mechanism of ZFAS1-induced regulation of melanoma. ZFAS1 expression was increased in melanoma tissues and cells compared with normal controls. ZFAS1 expression in metastatic tissues was higher than that in nonmetastatic subjects. Higher expression of ZFAS1 predicted lower survival rates. Knockdown of ZFAS1 decreased proliferation, increased apoptosis, decreased migration and invasion, and reduced epithelial–mesenchymal transition potential in melanoma cells. Moreover, ZFAS1 knockdown inhibited tumor growth in nude mice. There was a direct binding between ZFAS1 and miR-150-5p. ZFAS1 negatively regulated miR-150-5p expression and upregulation of miR-150-5p was involved in ZFAS1 knockdown-induced effect on proliferation, apoptosis, migration, and invasion. Using bioinformatics, we predicted the binding between RAB9A and miR-150-5p, and the direct interaction between RAB9A and miR-150-5p was confirmed by luciferase reporter and RNA immunoprecipitation assays. We also showed that RAB9A expression was regulated negatively by miR-150-5p, but was regulated positively by ZFAS1. Downregulation of RAB9A significantly inhibited the increase in proliferation, decrease in apoptosis, and increase in migration and invasion induced by miR-150-5p inhibitors. Moreover, RAB9A knockdown decreased proliferation, increased apoptosis, and decreased migration and invasion in melanoma cells. In summary, we confirmed the tumor-promoting role of ZFAS1 in melanoma and provide evidence for the role and mechanism of the ZFAS1/miR-150-5p/RAB9A axis. These findings may lead to novel therapeutic strategies for melanoma.
Malignant melanoma is an aggressive form of cancer which is highly resistant to chemotherapy. We have previously found that gambogic acid (GA), a kind of polyprenylated xanthone, exhibits an antitumour role in melanoma. The study was designed to investigate novel mechanisms of the antitumour effect of GA in melanoma cells and implanted nude mice. Gambogic acid significantly decreased cell viability, increased apoptosis and reduced migration and invasion in A375 cells. In addition, cisplatin-induced cytotoxicity in both A375 and A375/CDDP cells was increased by GA. The expression of miR-199a-3p was increased by GA in A375 cells and implanted tumours, and inhibition of miR-199a-3p significantly prevented GA-induced effect on cell viability, apoptosis, migration, invasion and cisplatin sensitivity in A375 cells. miR-199a-3p mimics reduced tumour weight and volume in vivo and decreased cell viability, increased apoptosis and reduced migration and invasion in vitro. miR-199a-3p expression was decreased in melanoma tissues and cells, as compared with their controls. miR-199a-3p possessed a potential binding site in the 3'-UTR of zinc finger E-box binding homeobox (ZEB1). ZEB1 expression was increased in melanoma tissues and cells, as compared with their controls. ZEB1 and miR-199a-3p expression was negatively correlated in melanoma tissues. The expression of ZEB1 was decreased by GA in A375 cells and implanted tumours, and up-regulation of ZEB1 significantly prevented GA-induced effect on cell viability, apoptosis, migration, invasion and cisplatin sensitivity. Down-regulation of ZEB1 reduced tumour weight and volume in vivo and decreased cell viability, increased apoptosis and reduced migration and invasion in vitro. We identified the important roles of miR-199a-3p and ZEB1 in melanoma and elucidated the tumour suppressor function of miR-199a-3p through inhibition of ZEB1. The results highlight the importance of miR-199a-3p-ZEB1 signalling in antitumour effect of GA in malignant melanoma and provide novel targets for the chemotherapy of melanoma.
Inconsistent findings on the association between urine albumin‐to‐creatinine ratio (UACR) and risk of hypertension have been reported. This meta‐analysis sought to evaluate the association between the elevated level of UACR within the normal range and incident hypertension in the general population. We comprehensively searched PubMed and Embase databases until July 31, 2020. All longitudinal observational studies that assessed the association of elevated baseline level of UACR within the normal range with incident hypertension in the general population were included. The predictive value was estimated by pooling risk ratio (RR) with 95% confidence intervals (CI) for the highest versus the lowest category of UACR level. Nine articles (10 studies) involving 27 771 individuals were identified and analyzed. When compared with the lowest category of UACR, individuals with the highest UACR had a 1.75‐fold (RR 1.75; 95% CI 1.47–2.09; p < .001) higher risk of hypertension in a random effect model. Gender‐specific analysis indicated that the impact of UACR on the development of hypertension seemed to be stronger in women (RR 2.47; 95% CI 1.10–5.55; p = .029) than in men (RR 1.88; 95% CI 1.35–2.61; p < .001). An increased UACR within the normal range is independently associated with a higher risk of hypertension in the general population. Baseline UACR can be served as a predictor of incident hypertension in the general population.
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