Bladder cancer is one of the most frequently occurring malignant tumors in the urinary system. Sodium butyrate (NaB) is a histone deacetylase inhibitor and exerts remarkable antitumor effects in various cancer cells. MicroRNAs (miRNAs) and autophagy play crucial roles in cancer occurrence and development. In the present study, we evaluated the anticancer effects, including cell migration inhibition and the apoptotic effects of NaB in human bladder cancer cells. Furthermore, we found that NaB inhibited migration and induced AMPK/mTOR pathway‐activated autophagy and reactive oxygen species (ROS) overproduction via the miR‐139‐5p/Bmi‐1 axis. In addition, we found that ROS overproduction contributed to NaB‐induced caspase‐dependent apoptosis and autophagy. The interplay between autophagy and apoptosis in NaB treatment was clarified. Our findings provide a further understanding of EMT reversion, apoptosis and autophagy induced by antitumor drugs and a novel perspective and alternative strategy for bladder cancer chemotherapy.
Circular RNAs (circRNAs), a subclass of noncoding RNAs, are reportedly involved in the progression of various diseases. However, the exact role of circRIMS1, also termed hsa_circ_0132246, in human bladder cancer remains unknown. By performing RNA sequencing comparing bladder cell lines and normal uroepithelial cells, circRIMS1 was selected as a research object. We further verified by qRT-PCR that circRIMS1 is upregulated in both bladder cancer tissue and cell lines. Proliferation, colony-formation, Transwell migration, invasion, apoptosis, western blotting, and
in vivo
experiments were utilized to clarify the roles of circRIMS1, microRNA (miR)-433-3p, and cell cycle and apoptosis regulator 1 (CCAR1). For mechanistic investigation, RNA pulldown, fluorescence
in situ
hybridization (FISH), and luciferase reporter assay confirmed the binding of circRIMS1 with miR-433-3p. Inhibition of circRIMS1 suppressed the proliferation, migration, and invasion of bladder cancer cells both
in vitro
and
in vivo
. Moreover, the circRIMS1/miR-433-3p/CCAR1 regulatory axis was confirmed to be responsible for the biological functions of circRIMS1. Taken together, our research demonstrated that circRIMS1 promotes tumor growth, migration, and invasion through the miR-433-3p/CCAR1 regulatory axis, representing a potential therapeutic target and biomarker in bladder cancer.
10-hydroxycamptothecin (HCPT), a natural plant extract, exerts anticancer capacity.HCPT has been reported to induce apoptosis and autophagy in human cancer cells.The interaction between autophagy and apoptosis induced by HCPT and the molecular mechanism in bladder cancer cells were investigated in this study. Our results confirmed that HCPT suppressed cell viability and migration and caused cellcycle arrest in T24 and 5637. Then, we used Z-VAD(OMe)-FMK to clarify that apoptosis induced by HCPT was mediated by caspase. Moreover, HCPT boosted autophagy through activating the AMPK/mTOR/ULK1 pathway. Blocking autophagy by 3-methyladenine, the adenosine monophosphate-activated protein kinase (AMPK) inhibitor dorsomorphin and siATG7 reversed HCPT-induced cytotoxicity. Conversely, rapamycin and the AMPK activator AICAR enhanced growth inhibition and cell apoptosis, suggesting that autophagy played a proapoptosis role. Taken together, our findings showed that HCPT-induced autophagy mediated by the AMPK pathway in T24 and 5637 cell lines, which reinforced the apoptosis, indicating that HCPT together with autophagy activator would be a novel strategy for clinical treatment in bladder cancer.
K E Y W O R D SAMPK pathway, apoptosis, autophagy, bladder cancer, hydroxycamptothecin
Background
Transcriptional coactivator with PDZ-binding motif (TAZ) has been reported to be involved in tumor progression, angiogenesis, epithelial-mesenchymal transition (EMT), glycometabolic modulation and reactive oxygen species (ROS) buildup. Herein, the underlying molecular mechanisms of the TAZ-induced biological effects in bladder cancer were discovered.
Methods
qRT-PCR, western blotting and immunohistochemistry were performed to determine the levels of TAZ in bladder cancer cells and tissues. CCK-8, colony formation, tube formation, wound healing and Transwell assays and flow cytometry were used to evaluate the biological functions of TAZ, miR-942-3p and growth arrest-specific 1 (GAS1). QRT-PCR and western blotting were used to determine the expression levels of related genes. Chromatin immunoprecipitation and a dual-luciferase reporter assay were performed to confirm the interaction between TAZ and miR-942. In vivo tumorigenesis and colorimetric glycolytic assays were also conducted.
Results
We confirmed the upregulation and vital roles of TAZ in bladder cancer. TAZ-induced upregulation of miR-942-3p expression amplified upstream signaling by inhibiting the expression of large tumor suppressor 2 (LATS2, a TAZ inhibitor). MiR-942-3p attenuated the impacts on cell proliferation, angiogenesis, EMT, glycolysis and ROS levels induced by TAZ knockdown. Furthermore, miR-942-3p restrained the expression of GAS1 to modulate biological behaviors.
Conclusion
Our study identified a novel positive feedback loop between TAZ and miR-942-3p that regulates biological functions in bladder cancer cells via GAS1 expression and illustrated that TAZ, miR-942-3p and GAS1 might be potential therapeutic targets for bladder cancer treatment.
Radiation-induced oral mucositis (RIOM) is one of the most common side effects of radiotherapy in cancer patients, especially in almost all head and neck cancer patients. It presents as severe pain and ulceration. The development of RIOM is composed of five stages: initiation, primary damage response, signal amplification, ulceration, and healing. However, the key regulators involved in the RIOM pathogenesis remain largely unknown. In this study, we reveal a novel role of miR-200c, a member of the miR-200 family, in modulating RIOM pathogenesis. Using a mouse model mimicking RIOM, we found that the miR-200 family numbers (miR-141, miR-200a, miR-200b, and miR-200c) except miR-429 were significantly induced during the RIOM formation. Besides, in RIOM mice, miR-200c expression level was also increased dramatically in the normal human keratinocytes (NHKs) after irradiation. Knockdown of miR-200c expression with miR-200c-3p-shRNA significantly reduced senescence phenotype and enhanced cell proliferation in NHKs after irradiation. The generation of reactive oxygen species (ROS) and p47 enzyme involved in ROS production was increased after irradiation but both were markedly reduced in NHKs by miR-200c inhibition. Knockdown of miR-200c expression in NHKs increased DNA double-strand break repair after irradiation compared with control NHKs. Furthermore, miR-200c inhibition repressed the production of proinflammatory cytokines (TGF-β, TNF-α, and IL-1α) via inhibiting NF-κB and Smad2 activation in NHKs exposed to IR. Additionally, miR-200c inhibition promoted NHK migration and increased the expression of molecules that regulate epithelial to mesenchymal transition, including Snail, Vimentin, Zeb1, and Bmi-1. These results not only identify the key role of miR-200c in the pathogenesis of RIOM but also provide a novel therapeutic target to treat RIOM.
Circular RNA (circRNA) is a newly discovered endogenous non-coding RNA (ncRNA), which is characterized with a closed circular structure. A growing body of evidence has verified the vital roles of circRNAs in human cancer. In this research, we selected circPPP1CB as a study object by circRNA sequencing and quantitative real-time PCR (qRT-PCR) validation in human bladder cancer (BC). CircPPP1CB is downregulated in BC and is negatively correlated with clinical stages and histological grades. Functionally, circPPP1CB modulated cell growth, metastasis, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanically, we performed various experiments to verify the circPPP1CB/miR-1307-3p/SMG1 regulatory axis. Taken together, our results demonstrated that circPPP1CB participates in tumor growth, metastasis, and EMT process by interacting with the miR-1307-3p/SMG1 axis, and that circPPP1CB might be a novel therapeutic target and diagnostic biomarker in human BC.
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