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1.
Adv Sci (Weinh) ; 11(7): e2305922, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38084438

ABSTRACT

Immune checkpoint inhibitors (ICIs) show promise as second-line treatment for advanced bladder cancer (BLCA); however, their responsiveness is limited by the immune evasion mechanisms in tumor cells. This study conduct a Cox regression analysis to screen mRNA-binding proteins and reveals an association between Ras GTPase-activating protein-binding protein 1 (G3BP1) and diminished effectiveness of ICI therapy in patients with advanced BLCA. Subsequent investigation demonstrates that G3BP1 enhances immune evasion in BLCA cells by downregulating major histocompatibility complex class I (MHC-I) through phosphoinositide 3-kinase (PI3K)/Akt signaling activation. Mechanistically, G3BP1 interacts with splicing factor synergistic lethal with U5 snRNA 7 (SLU7) to form a complex with poly(A)-binding protein cytoplasmic 1 and eukaryotic translation initiation factor 4 gamma 1. This complex stabilizes the closed-loop structure of the mRNAs of class IA PI3Ks and consequently facilitates their translation and stabilization, thereby activating PI3K/Akt signaling to downregulate MHC-I. Consistently, targeting G3BP1 with epigallocatechin gallate (EGCG) impedes immune evasion and sensitizes BLCA cells to anti-programmed cell death (PD)-1 antibodies in mice. Thus, G3BP1 and SLU7 collaboratively contribute to immune evasion in BLCA, indicating that EGCG is a precision therapeutic agent to enhance the effectiveness of anti-PD-1 therapy.


Subject(s)
DNA Helicases , Urinary Bladder Neoplasms , Humans , Animals , Mice , DNA Helicases/genetics , DNA Helicases/metabolism , RNA Helicases/genetics , RNA Helicases/metabolism , Phosphatidylinositol 3-Kinases , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Immune Evasion , RNA Recognition Motif Proteins/genetics , RNA Recognition Motif Proteins/metabolism , Carrier Proteins/genetics , Urinary Bladder Neoplasms/drug therapy , RNA Splicing Factors
2.
Front Oncol ; 13: 1198723, 2023.
Article in English | MEDLINE | ID: mdl-37916163

ABSTRACT

Background: Since the application of Immune checkpoint inhibitors (ICI), the clinical outcome for metastatic cancer has been greatly improved. Nevertheless, treatment response varies in patients, making it urgent to identify patients who will receive clinical benefits after ICI therapy. Adipose body composition has proved to be associated with tumor response. In this systematic review, we aimed to summarize the current evidence on imaging adipose biomarkers that predict clinical outcomes in patients treated with ICI in various cancer types. Methods: Embase and PubMed were searched from database inception to 1st February 2023. Articles included investigated the association between imaging-based adipose biomarkers and the clinical outcomes of patients treated with ICI. The methodological quality of included studies was evaluated through Newcastle- Ottawa Quality Assessment Scale and Radiomics Quality Score tools. Results: Totally, 22 studies including 2256 patients were selected. Non-small cell lung cancer (NSCLC) had the most articles (6 studies), followed by melanoma (5 studies), renal cell carcinoma (RCC) (3 studies), urothelial carcinoma (UC) (2 studies), head and neck squamous cell carcinoma (HNSCC) (1 study), gastric cancer (1 study) and liver cancer (1 study). The remaining 3 studies investigated metastatic solid tumors including various types of cancers. Adipose biomarkers can be summarized into 5 categories, including total fat, visceral fat, subcutaneous fat, intramuscular fat and others, which exerted diverse correlations with patients' prognosis after being treated with ICI in different cancers. Most biomarkers of body fat were positively associated with survival benefits. Nevertheless, more total fat was predictable of worse outcomes in NSCLC, while inter-muscular fat was associated with poor clinical benefits in UC. Conclusion: There is relatively well-supported evidence for imaging-based adipose biomarkers to predict the clinical outcome of ICI. In general, most of the studies show that adipose tissue is positively correlated with clinical outcomes. This review summarizes the significant biomarkers proven by researches for each cancer type. Further validation and large independent prospective cohorts are needed in the future. The protocol of this systematic review has been registered at the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO, registration no: CRD42023401986).

3.
Cell Rep ; 42(8): 112963, 2023 08 29.
Article in English | MEDLINE | ID: mdl-37561631

ABSTRACT

Dysregulation of transcription is a hallmark of cancer, including bladder cancer (BLCA). CRISPR-Cas9 screening using a lentivirus library with single guide RNAs (sgRNAs) targeting human transcription factors and chromatin modifiers is used to reveal genes critical for the proliferation and survival of BLCA cells. As a result, the nuclear transcription factor Y subunit gamma (NFYC)-37, but not NFYC-50, is observed to promote cell proliferation and tumor growth in BLCA. Mechanistically, NFYC-37 interacts with CBP and SREBP2 to activate mevalonate pathway transcription, promoting cholesterol biosynthesis. However, NFYC-50 recruits more of the arginine methyltransferase CARM1 than NFYC-37 to methylate CBP, which prevents the CBP-SREBP2 interaction and subsequently inhibits the mevalonate pathway. Importantly, statins targeting the mevalonate pathway can suppress NFYC-37-induced cell proliferation and tumor growth, indicating the need for conducting a clinical trial with statins for treating patients with BLCA and high NFYC-37 levels, as most patients with BLCA have high NFYC-37 levels.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Urinary Bladder Neoplasms , Humans , Mevalonic Acid/metabolism , RNA, Guide, CRISPR-Cas Systems , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Transcription Factors/metabolism
4.
Cell Prolif ; 55(12): e13325, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36054300

ABSTRACT

INTRODUCTION: Bladder cancer (BC) is one of the most common malignant cancers, with poor prognosis and high incidence. Cisplatin is the standard chemotherapy for muscle invasive bladder cancer; however, chemotherapy resistance remains a major challenge. Moreover, oncogenic signalling and the specific mechanisms underlying cisplatin resistance in BC remain largely unclear METHODS: In this study, RT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure gene and protein expression. Colony formation assay and flow cytometry were performed to evaluate the proliferation of BC cells. Gene set enrichment analysis was performed to identify the function in which ZBTB11 was involved. Luciferase and chromatin immunoprecipitation experiments were performed to determine the transcriptional regulation mechanism of ZBTB11. The effects of ZBTB11 on the malignant phenotypes of BC cells were examined in vitro and in vivo RESULTS: The results showed that ZBTB11 was remarkably upregulated in BC tissues, which was associated with poor prognosis in patients with BC. Furthermore, we found that knockdown of ZBTB11 remarkably inhibited the proliferation and tumorigenesis of BC cells by inducing apoptosis. Mechanistically, the knockdown of ZBTB11 transcriptionally inhibited DDX1 to suppress R-loop clearance, resulting in DNA damage in BC cells. Importantly, the ZBTB11/DDX1 axis is required for the chemotherapy resistance of BC cells to cisplatin CONCLUSION: Our findings not only reveal an underlying mechanism by which the ZBTB11/DDX1 axis promotes the tumorigenesis of BC but also provide a potential target for a combination strategy of cisplatin-based chemotherapy for BC.


Subject(s)
MicroRNAs , Urinary Bladder Neoplasms , Humans , Cisplatin/pharmacology , Cisplatin/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , R-Loop Structures , Cell Line, Tumor , Carcinogenesis/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Cell Proliferation/genetics , DEAD-box RNA Helicases/metabolism
6.
Cancer Sci ; 113(9): 3071-3084, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35701858

ABSTRACT

Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue-based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC.


Subject(s)
Urinary Bladder Neoplasms , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , RNA, Small Interfering/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Tripartite Motif Proteins/genetics , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Urinary Bladder Neoplasms/genetics
7.
Cancer Med ; 11(2): 539-552, 2022 01.
Article in English | MEDLINE | ID: mdl-34816620

ABSTRACT

BACKGROUND: Reliable molecular markers are much needed for early prediction of recurrence in muscle-invasive bladder cancer (MIBC) patients. We aimed to build a long-noncoding RNA (lncRNA) signature to improve recurrence prediction and lncRNA-based molecular classification of MIBC. METHODS: LncRNAs of 320 MIBC patients from the Cancer Genome Atlas (TCGA) database were analyzed, and a nomogram was established. A molecular classification system was created, and immunotherapy and chemotherapy response predictions, immune score analysis, immune infiltration analysis, and mutational data analysis were conducted. Survival analysis validation was also performed. RESULTS: An eight-lncRNA signature classifed the patients into high- and low-risk subgroups, and these groups had significantly different (disease-free survival) DFS. The ability of the eight-lncRNA signature to make an accurate prognosis was tested using a validation dataset from our samples. The nomogram achieved a C-index of 0.719 (95% CI, 0.674-0.764). Time-dependent receiver operating characteristic curve (ROC) analysis indicated the superior prognostic accuracy of nomograms for DFS prediction (0.76, 95% CI, 0.697-0.807). Further, the four clusters (median DFS = 11.8, 15.3, 17.9, and 18.9 months, respectively) showed a high frequency of TTN (cluster 1), fibroblast growth factor receptor-3 (cluster 2), TP53 (cluster 3), and TP53 mutations (cluster 4), respectively. They were enriched with M2 macrophages (cluster 1), CD8+ T cells (cluster 2), M0 macrophages (cluster 3), and M0 macrophages (cluster 4), respectively. Clusters 2 and 3 demonstrated potential sensitivity to immunotherapy and insensitivity to chemotherapy, whereas cluster 4 showed potential insensitivity to immunotherapy and sensitivity to chemotherapy. CONCLUSIONS: The eight-lncRNA signature risk model may be a reliable prognostic signature for MIBC, which provides new insights into prediction of recurrence of MIBC. The model may help clinical decision and eventually benefit patients.


Subject(s)
Biomarkers, Tumor/genetics , RNA, Long Noncoding/genetics , Urinary Bladder Neoplasms/genetics , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/standards , China , Databases, Genetic , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Humans , Nomograms , RNA, Long Noncoding/metabolism , RNA, Long Noncoding/standards , ROC Curve , Survival Analysis , Transcriptome/genetics , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology
8.
Front Genet ; 12: 663982, 2021.
Article in English | MEDLINE | ID: mdl-34234808

ABSTRACT

Circular RNAs (circRNAs) are a panel of non-coding RNAs that mediate the regulation of gene expression, as well as pathological responses. Nonetheless, the function and expression pattern of circRNAs in urinary bladder cancer (UBC) remain unclear. Herein, we examined the function of circCA12 in UBC development. qRT-PCR results demonstrated remarkable circCA12 upregulation in UBC cell lines, as well as tissues. CCK-8, colony formation, and xenograft assays were employed to determine the effect of circCA12 on UBC. Our data illustrated silencing circCA12 repressed the proliferation along with the colony-formation capability of UBC cells. The migration and metastasis potential of UBC cells were remarkably abated in vivo, as well as in vitro after transfection with si-cirCA12 or sh-circCA12. Moreover, luciferase reporter and RIP assays indicated that circCA12 binds to miRNA-1184 through sponging miRNA, thereby up-regulating the expression of RAS family genes (NRAS, KRAS, and HRAS). In conclusion, the circCA12/miRNA-1184/RAS family was identified as a regulatory axis in UBC progression.

9.
Biomed Pharmacother ; 137: 111388, 2021 May.
Article in English | MEDLINE | ID: mdl-33761607

ABSTRACT

This study was the first to investigate the synthesis of near-infrared light-sensitive NO prodrug [Mn(PaPy2Q)(NO)]ClO4, and detection the amount of NO released by the drug in different time and near infrared light (10 mW, 20 mW). It showed that with the increase of light power, the time required for the drug to release NO was shortened, and we selected 20 mW, 10 min as a follow-up study of light power and irradiation time while ensuring the near-infrared light did not affect tumor cells. The cells were irradiated with 20 mW of near-infrared light for 10 min at 6 h after treatment with the drug on PC-3, LNCaP and 22RV1 cells, and NO concentration and cell survival rate were tested at 12 h, 24 h and 48 h. Experiments showed that NO concentration remained stable within 48 h and [Mn(PaPy2Q)(NO)]ClO4 inhibited the proliferation of cells in a concentration and time-dependent manner. Then we also found that [Mn(PaPy2Q)(NO)]ClO4 increased the expression of apoptosis-related proteins (PARP, Bax, Caspase 3/9), inhibited the expression of BCl-2 and increased the activity level of Caspase 3/7, which showed [Mn(PaPy2Q)(NO)]ClO4 promoted prostate cancer cells apoptosis. Next, the results in xenograft mouse model showed that [Mn(PaPy2Q)(NO)]ClO4 also had anti-prostate cancer effects in vivo, and the NO concentration increased in the tumor after near-infrared light irradiation. After [Mn(PaPy2Q)(NO)]ClO4 treatment 6 weeks, tumor volume was significantly reduced, Ki67 and BrdU protein expression was significantly reduced. TUNEL assay results showed that [Mn(PaPy2Q)(NO)]ClO4 could promote the apoptosis of solid tumors in vivo and in a concentration-dependent manner.


Subject(s)
Antineoplastic Agents/pharmacology , Nitric Oxide Donors/pharmacology , Prodrugs/pharmacology , Prostatic Neoplasms/drug therapy , Animals , Antimetabolites/pharmacology , Apoptosis Regulatory Proteins/biosynthesis , Apoptosis Regulatory Proteins/genetics , Bromodeoxyuridine/pharmacology , Cell Line, Tumor , Cell Survival , Humans , Infrared Rays , Ki-67 Antigen/metabolism , Male , Mice , Nitric Oxide/metabolism , Prostatic Neoplasms/metabolism , Xenograft Model Antitumor Assays
10.
Oncol Lett ; 17(5): 4277-4284, 2019 May.
Article in English | MEDLINE | ID: mdl-30944622

ABSTRACT

Previous studies have reported that metformin (MET) has anticancer activity. In combination with chemotherapeutic drugs, MET reduces the dosage of chemotherapeutic drugs required and enhances anticancer efficacy. In the present study, the combination of MET and paclitaxel (PTX) in three human prostate cancer (PCa) cell lines (22RV1, PC-3 and LNCaP) was evaluated to investigate the effects on proliferation and apoptosis of PCa cells. The present study explored whether their effects were associated with reactive oxygen species (ROS). An MTT assay and microscopy were used to study the effect of MET + PTX on cell growth. Half maximal inhibitory concentration (IC50) values were obtained for MET (12.281±1.089 mM for 22RV1, 2.248±0.352 mM for PC-3 cells and 3.610±0.577 mM for LNCaP cells) and PTX (13.170±1.12 nM for PC-3 cells) at 48 h. Since the survival rate of 22RV1 and LNCaP cells did not decrease linearly with increasing PTX concentration, it is difficult to estimate accurate IC50; therefore, only IC50 values for PTX in PC-3 cells were given. When treating the cells with 5 mM MET, the IC50 of PTX decreased to 5.423±0.734 nM for PC-3 cells. Annexin V and propidium iodide staining was used to investigate apoptosis by flow cytometry. The apoptotic mechanisms of MET + PTX in PCa were investigated by detecting the expression of apoptosis-related proteins, activities of caspase-3/7, intracellular ROS accumulation, mitochondrial membrane potential, and intracellular levels of adenosine 5'-triphosphate (ATP). MET + PTX induced PCa apoptosis and ROS accumulation, and decreased mitochondrial membrane potential and intracellular levels of ATP. Taken together, these results indicated that MET + PTX suppressed PCa cell proliferation in a dose- and time-dependent manner. In addition, MET + PTX induced apoptosis by increasing ROS levels, reducing mitochondrial membrane potential, and activating mitochondrial-dependent apoptotic pathways.

11.
Oncol Lett ; 17(1): 757-764, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30655827

ABSTRACT

The aim of the present study was to investigate the influence of the nitric oxide donor prodrug JS-K (C13H16N6O8) on Taxol-induced apoptosis in prostate cancer cells, and to investigate a potential reactive oxygen species (ROS)-associated mechanism. The effect of JS-K on the anticancer activity of Taxol was assessed in prostate cancer cells; cell viability, colony formation, apoptosis, ROS generation and expression levels of apoptosis-associated proteins were investigated. The function of ROS accumulation in the combined effects of JS-K and Taxol was determined using the antioxidant N-acetylcysteine (NAC) and the pro-oxidant oxidized glutathione (GSSG). The results of the present study demonstrated that JS-K was able to increase Taxol-induced suppression of prostate cancer cell proliferation, apoptosis, ROS accumulation and upregulation of apoptosis-associated proteins. Furthermore, NAC reversed the effect of JS-K on Taxol-induced apoptosis and conversely, the pro-oxidant GSSG exacerbated the effect of JS-K on Taxol-induced apoptosis in prostate cancer cells. In conclusion, JS-K enhances the chemosensitivity of prostate cancer cells to Taxol, via the upregulation of intracellular ROS.

12.
Biomed Pharmacother ; 98: 36-44, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29241073

ABSTRACT

Recent studies have shown that resveratrol (RES) inhibits cancer cell growth, migration and invasion. Here, we evaluated RES in two human renal cell carcinoma (RCC) cell lines, ACHN and A498. We investigated the effects of RES on proliferation, cell morphology, colony formation, migration, and invasion. We used a proliferation assay to demonstrate that RES inhibited cell growth with IC50 values 132.9±1.064µM in ACHN, and 112.8±1.191µM in A498, respectively. Using inverted contrast microscopy, we showed that RES reduced cell-to-cell contact and inhibited formation of filopodia. A wound healing assay showed that RES inhibited migration of RCC cells. A Transwell assay showed that RES inhibited RCC migration and invasion. Western blot analysis showed that RES suppresses expression of N-cadherin, Vimentin, Snail, MMP-2, MMP-9, p-Akt and p-ERK1/2, but increased expression of E-cadherin and TIMP-1. In the presence of PD98059, the inhibitor of ERK1/2 pathway, we repeated all of the above experiments, showed that RES acted via the ERK1/2 pathway. Taken together, our results suggested that RES suppressed RCC cell proliferation, migration, and invasion in a concentration- and time-dependent manner. These effects likely resulted from inactivation of the Akt and ERK1/2 signaling pathways.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Cell Movement/drug effects , Cell Proliferation/drug effects , Kidney Neoplasms/drug therapy , MAP Kinase Signaling System/drug effects , Neoplasm Invasiveness/prevention & control , Proto-Oncogene Proteins c-akt/metabolism , Stilbenes/pharmacology , Cadherins/metabolism , Carcinoma, Renal Cell/metabolism , Cell Line , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , Kidney Neoplasms/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Resveratrol , Signal Transduction/drug effects , Vimentin/metabolism
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