A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer‐associated immunosuppression in BC ...remains undetermined. In this study, we observed a negative correlation between the autophagy‐related markers LC3‐II and programmed death ligand‐1 (PD‐L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf‐A1) increased PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signal‐transduction pathway. Moreover, the treatment of BC cells with CQ and Baf‐A1 inhibited hsa‐microRNA‐34a (miR‐34a) expression and miR‐34a overexpression in BC cells prevented the autophagy blockade–induced PD‐L1 expression; a negative correlation between miR‐34a and PD‐L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR‐34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer‐associated immunosuppression through PD‐L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD‐L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.
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Our model illustrates the pharmacological inhibition of autophagy could induce PD‐L1 expression in BC cells through the ERK–JNK–c‐Jun signaling transduction pathway and miR‐34a downregulation, revealing the effect of genetic and epigenetic regulation of autophagy on PD‐L1. In consequence, BC cells expressing PD‐L1 suppress NK cell cytotoxic activity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Chloroquine (CQ) and hydroxychloroquine (HCQ), two antimalarial drugs, are suggested to have potential anticancer properties. in the present study, we investigated the effects of CQ and HCQ ...on cell growth of bladder cancer with emphasis on autophagy inhibition and apoptosis induction in vitro . The results showed that CQ and HCQ inhibited the proliferation of multiple human bladder cell lines (including RT4, 5637, and T24) in a time- and dose-dependent fashion, especially in advanced bladder cancer cell lines (5637 and T24) compared to immortalized uroepithelial cells (SV-Huc-1) or other reference cancer cell lines (PC3 and MCF-7). We found that 24-hour treatment of CQ or HCQ significantly decreased the clonogenic formation in 5637 and T24 cells compared to SV-Huc-1. As human bladder cancer tumor exhibits high basal level of autophagic activities, we detected the autophagic flux in cells treated with CQ and HCQ, showing an alternation in LC3 flux in CQ- or HCQ-treated cells. Moreover, bladder cancer cells treated with CQ and HCQ underwent apoptosis, resulting in increased caspase 3/7 activities, increased level of cleaved poly(ADP-ribose) polymerase (PARP), caspase 3, and DNA fragmentation. Given these results, targeting autophagy with CQ and HCQ represents an effective cancer therapeutic strategy against human bladder cancer.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bladder cancer (BC) is the second most common urological tumour in Western countries. Approximately, 80% of patients with BC will present with non-muscle invasive bladder cancer (NMIBC), whereas a ...quarter will have muscle invasive disease (MIBC) at the time of BC diagnosis. However, patients with NMIBC are at risk of BC recurrence or progression into MIBC, and an MIBC prognosis is determined by the presence of progression and metastasis. Matrix metalloproteinase 2 (MMP2), a type of matrix metalloproteinase (MMP), plays a major role in tumour invasion and is well-characterized in BC prognosis. In BC, the mechanisms regulating MMP2 expression, and, in turn, promote cancer invasion, have hardly been explored. Thrombospondin-4 (THBS4/TSP4) is a matricellular glycoprotein that regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion and extracellular matrix modelling. Based on the results of a meta-analysis in the Gene Expression Profiling Interactive Analysis 2 database, we observed that TSP4 expression levels were consistent with overall survival (OS) rate and BC progression, with the highest expression levels observed in the advanced stages of BC and associated with poor OS rate. In our pilot experiments, incubation with recombinant TSP4 promoted the migration and invasion in BC cells. Furthermore, MMP2 expression levels increased after recombinant TSP4 incubation. TSP4-induced-MMP2 expression and cell motility were regulated via the AKT signalling pathway. Our findings facilitate further investigation into TSP4 silencing-based therapeutic strategies for BC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Earth dams or embankments are susceptible to instability due to internal seepage, piping, and erosion, which can lead to catastrophic failure. Therefore, monitoring the seepage water level before the ...dam collapses is an important task for early warning of dam failure. Currently, there are hardly any monitoring methods that use wireless underground transmission to monitor the water content inside earth dams. Real-time monitoring of changes in the soil moisture content can more directly determine the water level of seepage. Wireless transmission of sensors buried underground requires signal transmission through the soil medium, which is more complex than traditional air transmission. Henceforth, this study establishes a wireless underground transmission sensor that overcomes the distance limitation of underground transmission through a hop network. A series of feasibility tests were conducted on the wireless underground transmission sensor, including peer-to-peer transmission tests, multi-hop underground transmission tests, power management tests, and soil moisture measurement tests. Finally, field seepage tests were conducted to apply wireless underground transmission sensors to monitor the internal seepage water level before an earth dam failure. The findings show that wireless underground transmission sensors can achieve the monitoring of seepage water levels inside earth dams. In addition, the results supersede those of a conventional water level gauge. This could be crucial in early warning systems during the era of climate change, which has caused unprecedented flooding events.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Bladder cancer (BC), one of the most common urological neoplastic disorders in men, has an extremely low survival rate because of its tendency to metastasize. The anticancer drugs chloroquine (CQ) ...and hydroxy CQ (HCQ) might inhibit tumor progression and invasiveness. However, the mechanism by which CQ and HCQ influence BC is undetermined. In this study, CQ and HCQ treatments inhibited the migration and invasion of two BC cell types (5637 and T24) through expression modulation of matrix metalloproteinase‐2 (MMP‐2), which belongs to the matrix MMP family and is a key mediator of cancer progression. Moreover, additional data revealed that the migrative and invasive effects of BC cells treated with CQ or HCQ were abolished after treatment with rapamycin, which induces autophagy, demonstrating that CQ and HCQ functions in BC are based on autophagy inhibition. In conclusion, our research demonstrated that CQ and HCQ regulated cell motility in BC through MMP‐2 downregulation by targeting autophagy functions, providing a novel therapeutic strategy for BC treatment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Bladder cancer (BC) is the second most common urologic malignancy and the ninth most common malignancy worldwide. Surgical resection is the mainstay of treatment for patients with early-stage ...disease, whereas therapeutic options are limited for patients with advanced-stage or residual BC. Programmed cell death ligand-1 (PD-L1) is an important target for immunotherapy. It is known that PD-L1 is overexpressed in BC; a clinical trial involving PD-L1 immune checkpoint inhibitors in advanced BC is ongoing. In the present study, we used Western blot and quantitative real-time PCR (qPCR) to define the expression level of PD-L1 after cisplatin treatment in BC-derived cell lines. The signal activation was also evaluated by Western blot in BC-derived cell lines. We found that chemotherapeutic drug cisplatin can induce PD-L1 but not PD-L2 expression in BC-derived cell lines. Furthermore, the expression level of PD-L1 was increased in a dose- and time-dependent manner after cisplatin treatment. The cisplatin-induced PD-L1 expression is mainly mediated by ERK1/2 but not Akt/mTOR signal pathway. Moreover, we found that cisplatin activates transcription factor activator protein-1 (AP-1) to regulate PD-L1 expression. The chemotherapy drug such as cisplatin may trigger resistance of BC through PD-L1 up-regulation. The present study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic BC.
Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration‐approved ...antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B‐light chain 3 (LC3)‐II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate‐activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy‐promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3‐II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy‐promoting function. Finally, miconazole and autophagy inhibitor 3‐methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Benzyl isothiocyanate (BITC), a bioactive natural product present in cruciferous vegetables, has been proved to prevent cancer progression through various mechanisms. In our previous report, we ...proved that BITC exhibits antitumor effects in bladder cancer by suppressing IGF1R, FGFR3, and mTOR, which is mediated by miR‐99a expression. In this study, we identified the signal pathway involved in regulating miR‐99a expression after BITC exposure in bladder cancer. Treatment with different BITC concentrations resulted in induction of miR‐99a expression in bladder cancer cell lines. Activation of extracellular signal‐regulated protein kinase (ERK) and c‐jun N‐terminal kinase was observed in bladder cancer after BITC treatment for 24 hours. Interestingly, by using a chemical inhibitor of candidate pathways, we found that only the ERK signal pathway is required for miR‐99a expression. Furthermore, we evaluated the transcription factor that may contribute to miR‐99a expression in response to BITC treatment. The results indicated that c‐Jun/AP‐1 was activated after BITC treatment. Moreover, we confirmed c‐Jun/AP‐1 activation through immunofluorescence and the luciferase reporter assay. The results showed that BITC treatment markedly improved nuclear translocation of c‐Jun/AP‐1 and luciferase activity dose dependently. Finally, pretreatment with the ERK inhibitor U0126 diminished c‐Jun phosphorylation and transcriptional activation, suggesting that BITC elicits ERK/c‐Jun signal transduction, which is responsible for miR‐99a expression in bladder cancer. The present work identifies the mechanism involved in upregulation miR‐99a after BITC treatment, which provides an explanation for BITC biological function in our previous work.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Bladder cancer (BC), a common urologic cancer, is the fifth most frequently diagnosed tumor worldwide. hsa‑miR‑34a displays antitumor activity in several types of cancer. However, the functional ...mechanisms underlying hsa‑miR‑34a in BC remains largely unknown. We observed that hsa‑mir‑34a levels were significantly and negatively associated with clinical disease stage as well as regional lymph node metastasis in human BC. In a series of in vitro investigations, overexpression of hsa‑miR‑34a inhibited cell migration and invasion in BC cell lines 5637 and UMUC3 as detected by Transwell assays. We further found that hsa‑miR‑34a inhibited cell migration and invasion by silencing matrix metalloproteinase‑2 (MMP‑2) expression and thus interrupting MMP‑2‑mediated cell motility. Our analysis of BC datasets from The Cancer Genome Atlas database revealed a negative correlation between hsa‑miR‑34a and MMP‑2. Moreover, higher MMP‑2 protein expression was observed in the BC tissues when compared with that noted in the normal tissue. MMP‑2 levels were also significantly associated with clinical disease stage and poor survival rate in human BC. These findings indicate that MMP‑2 plays a critical role in regulating BC progression. Therefore, hsa‑miR‑34a is a promising treatment to target MMP‑2 for the prevention and inhibition of cell migration and invasion in BC.
Flood defense strategies have evolved from hard-engineered systems to nature-based solutions that advocate for sustainability to meet today’s environmental, social, and economic goals. This paper ...aims to analyze the historical progression and evolutionary trends in flood control strategies that have led to nature-based solutions. An evaluative literature review was conducted to narrate the evolution of nature-based flood management approaches for different flood types, river floods, coastal floods, and stormwater run-offs. The analysis reflected three evolutionary trends: the transformation of hard measures to soft measures; secondly, the increase in society’s attention to ecosystems and their services; and, finally, divergence from single-function solutions to multi-function solutions. However, continuous monitoring and evaluation of the previous projects and adapting to the lessons learned are the key to progress towards sustainable flood management strategies and their societal acceptance.
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