Synergistic ferroptosis-starvation therapy for bladder cancer based on hyaluronic acid modified metal-organic frameworks.

Bladder cancer (BCa) is one of the most common malignancies of the urinary tract. Metastasis and recurrence of BCa are the leading causes of poor prognosis, and only a few patients can benefit from current first-line treatments such as chemotherapy and immunotherapy. It is urgent to develop more effective therapeutic method with low side effects. Here, a cascade nanoreactor, ZIF-8/PdCuAu/GOx@HA (ZPG@H), is proposed for starvation therapy and ferroptosis of BCa. The ZPG@H nanoreactor was constructed by co-encapsulation of PdCuAu nanoparticles and glucose oxidase into zeolitic imidazolate framework-8 (ZIF-8) modified by hyaluronic acid. The vitro results indicated that ZPG@H enhanced intracellular reactive oxygen species levels and reduced mitochondrial depolarization in the tumor microenvironment. Therefore, the integrated advantages of starvation therapy and chemodynamic therapy endow ZPG@H with a perfect ferroptosis inducing ability. This effectiveness, combined with its excellent biocompatibility and biosafety, means that ZPG@H could make a critical contribution to the development of novel BCa treatments.

Regulation of cisplatin resistance in bladder cancer by epigenetic mechanisms.

Bladder cancer is one of the most common malignancies in the world. Cisplatin is one of the most potent and widely used anticancer drugs and has been employed in several malignancies. Cisplatin-based combination chemotherapies have become important adjuvant therapies for bladder cancer patients. Cisplatin-based treatment often results in the development of chemoresistance, leading to therapeutic failure and limiting its application and effectiveness in bladder cancer. To develop improved and more effective cancer therapy, research has been conducted to elucidate the underlying mechanism of cisplatin resistance. Epigenetic modifications have been demonstrated involved in drug resistance to chemotherapy, and epigenetic biomarkers, such as urine tumor DNA methylation assay, have been applied in patients screening or monitoring. Here, we provide a systematic description of epigenetic mechanisms, including DNA methylation, noncoding RNA regulation, m6A modification and posttranslational modifications, related to cisplatin resistance in bladder cancer.

FGFBP1 as a potential biomarker predicting bacillus Calmette-Guérin response in bladder cancer.

Accurate prediction of Bacillus Calmette-Guérin (BCG) response is essential to identify bladder cancer (BCa) patients most likely to respond sustainably, but no molecular marker predicting BCG response is available in clinical routine. Therefore, we first identified that fibroblast growth factor binding protein 1 (FGFBP1) was upregulated in failures of BCG therapy, and the increased FGFBP1 had a poor outcome for BCa patients in the E-MTAB-4321 and GSE19423 datasets. These different expression genes associated with FGFBP1 expression are mainly involved in neutrophil activation, neutrophil-mediated immunity, and tumor necrosis factor-mediated signal pathways in biological processes. A significant positive correlation was observed between FGFBP1 expression and regulatory T-cell (Treg) infiltration by the Spearman correlation test in the BCG cohort (r = 0.177) and The Cancer Genome Atlas (TCGA) cohort (r = 0.176), suggesting that FGFBP1 may influence the response of BCa patients to BCG immunotherapy through immune escape. Though FGFBP1 expression was positively correlated with the expressions of PD-L1, CTLA4, and PDCD1 in TCGA cohort, a strong association between FGFBP1 and PD-L1 expression was only detected in the BCG cohort (r = 0.750). Furthermore, elevated FGFBP1 was observed in BCa cell lines and tissues in comparison to corresponding normal controls by RT-qPCR, Western blotting, and immunohistochemical staining. Increased FGFBP1 was further detected in the failures than in the responders by immunohistochemical staining. Notably, FGFBP1 is positively associated with PD-L1 expression in BCa patients with BCG treatment. To sum up, FGFBP1 in BCa tissue could be identified as a promising biomarker for the accurate prediction of BCG response in BCa.

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis.

Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1ß, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.