Abstract:Purpose
The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC.
Experimental design
The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to … Show more
“…Therefore, it cannot be excluded that the inconsistency between studies may be attributed to discrepancies in the methods used. On the other hand, higher levels of mRNA HNRNPU were observed in tumoral vs. adjacent tissue in breast [ 11 ], hepatocellular [ 12 ], and bladder cancers [ 13 ]. Although there were no significant associations between the investigated clinicopathological features and HNRNPU protein expression levels, the survival analyses showed an adverse correlation between a high HNRNPU protein level and clinical outcomes of NSCLC patients.…”
The present study aimed to investigate expression levels and prognostic significance of RUVBL1 and HNRNPU in stage I and II non–small-cell lung cancer (NSCLC) patients. Therefore, we evaluated immunohistochemical staining of RUVBL1 and HNRNPU, as well as RNA-seq data from public sources, and the results were evaluated concerning overall survival (OS) and clinicopathological features. We found that RUVBL1 and HNRNPU proteins and mRNA levels were higher in tumor tissues as compared to adjacent/normal tissues. RUVBL1 (p = 0.013) and HNRNPU (p = 0.021) high protein levels were independent prognostic factors for poor OS. Also, the multivariate analysis in the TCGA dataset revealed that high RUVBL1 (p = 0.064) and HNRNPU (p = 0.181) mRNA levels were not significantly associated with prognosis. However, the co-expression status of these markers (R + H +) was independently associated with poor OS both in the TCGA dataset (p = 0.027) and in our cohort (p = 0.001). In conclusion, combined and individual expression of RUVBL1 and HNRNPU proteins, as well as R + H + mRNA status, may serve as potential prognostic biomarkers for NSCLC. This study adds to the previous observations that RUVBL1 and HNRNPU might be novel and promising therapeutic targets and markers for prognostic evaluation.
“…Therefore, it cannot be excluded that the inconsistency between studies may be attributed to discrepancies in the methods used. On the other hand, higher levels of mRNA HNRNPU were observed in tumoral vs. adjacent tissue in breast [ 11 ], hepatocellular [ 12 ], and bladder cancers [ 13 ]. Although there were no significant associations between the investigated clinicopathological features and HNRNPU protein expression levels, the survival analyses showed an adverse correlation between a high HNRNPU protein level and clinical outcomes of NSCLC patients.…”
The present study aimed to investigate expression levels and prognostic significance of RUVBL1 and HNRNPU in stage I and II non–small-cell lung cancer (NSCLC) patients. Therefore, we evaluated immunohistochemical staining of RUVBL1 and HNRNPU, as well as RNA-seq data from public sources, and the results were evaluated concerning overall survival (OS) and clinicopathological features. We found that RUVBL1 and HNRNPU proteins and mRNA levels were higher in tumor tissues as compared to adjacent/normal tissues. RUVBL1 (p = 0.013) and HNRNPU (p = 0.021) high protein levels were independent prognostic factors for poor OS. Also, the multivariate analysis in the TCGA dataset revealed that high RUVBL1 (p = 0.064) and HNRNPU (p = 0.181) mRNA levels were not significantly associated with prognosis. However, the co-expression status of these markers (R + H +) was independently associated with poor OS both in the TCGA dataset (p = 0.027) and in our cohort (p = 0.001). In conclusion, combined and individual expression of RUVBL1 and HNRNPU proteins, as well as R + H + mRNA status, may serve as potential prognostic biomarkers for NSCLC. This study adds to the previous observations that RUVBL1 and HNRNPU might be novel and promising therapeutic targets and markers for prognostic evaluation.
“…As previously described, hnRNPU plays a critical role in regulating chromatin dynamics through functional interaction with cohesion complex and chromatin loop formation [ 32 , 33 ]. Dysregulation of hnRNPU results in carcinogenesis and drug resistance [ 34 , 35 , 42 ]. Co-immunoprecipitation assays performed in MDA-MB-468 cells confirmed the interaction between endogenous CDC20 and hnRNPU ( Figure 3 f).…”
Section: Resultsmentioning
confidence: 99%
“…The impact of hnRNPU in carcinogenesis has been documented previously in different types of tumors [ 34 , 42 ]. To determine the role of hnRNPU in breast cancers, we measured the expression of hnRNPU in normal breast epithelial, DCIS, and different breast cancer cell lines, including TNBC, HER2+, and Luminal subtypes.…”
Section: Resultsmentioning
confidence: 99%
“…In NB cells, hnRNPU interacts with CTCF resulting in transcriptional alteration of genes associated with tumor progression [ 34 ]. Moreover, hnRNPU expression was associated with cisplatin sensitivity in bladder cancer [ 42 ]. Additionally, hnRNPU has been shown to promote breast cancer cell proliferation, migration, and invasion [ 35 ].…”
Cell division cycle 20 (CDC20) functions as a critical cell cycle regulator. It plays an important role in cancer development and drug resistance. However, the molecular mechanisms by which CDC20 regulates cellular drug response remain poorly understood. Chromatin-associated CDC20 interactome in breast cancer cells was analyzed by using affinity purification coupled with mass spectrometry. hnRNPU as a CDC20 binding partner was validated by co-immunoprecipitation and immunostaining. The molecular domain, comprising amino acid residues 461–653, on hnRNPU required for its interaction with CDC20 was identified by mapping of interactions. Co-immunoprecipitation showed that CDC20-mediated hnRNPU ubiquitination promotes its interaction with the CTCF and cohesin complex. The effects of CDC20–hnRNPU on nuclear size and chromatin condensation were investigated by analyzing DAPI and H2B-mCherry staining, respectively. The role of CDC20–hnRNPU in tumor progression and drug resistance was examined by CCK-8 cell survival and clonogenic assays. Our study indicates that CDC20-mediated ubiquitination of hnRNPU modulates chromatin condensation by regulating the interaction between hnRNPU and the CTCF–cohesin complex. Dysregulation of the CDC20–hnRNPU axis contributes to tumor progression and drug resistance.
“…The following supporting information can be downloaded at: , Table S1: CRISPR/Cas gene targets for the treatment of malignant disorders, and the experimental setup (in vivo/ex vivo and in vivo) used for gene editing (knockout, knockdown, knock-in) with the outcome of the experiment. References [ 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ] are cited in Supplementary Materials File.…”
The increasing burden on human malignant diseases became a major concern for healthcare practitioners, that must deal with tumor relapse and the inability to efficiently treat metastasis, in addition to side effects. Throughout the decades, many therapeutic strategies have been employed to improve the clinical outcomes of cancer patients and great efforts have been made to develop more efficient and targeted medicines. The malignant cell is characterized by genetic and epigenetic modifications, therefore targeting those specific drivers of carcinogenesis is highly desirable. Among the genome editing technologies, CRISPR/Cas9 stood as a promising candidate for cancer treatment alternatives, due to its low complexity design. First described as a defense mechanism of bacteria against invading foreign DNA, later it was shown that CRISPR components can be engineered to target specific DNA sequences in a test tube, a discovery that was awarded later with the Nobel Prize in chemistry for its rapid expansion as a reliable genome editing tool in many fields of research, including medicine. The present paper aims of describing CRISPR/Cas9 potential targets for malignant disorders, and the approaches used for achieving this goal. Aside from preclinical studies, we also present the clinical trials that use CRISPR-based technology for therapeutic purposes of cancer. Finally, a summary of the presented studies adds a more focused view of the therapeutic value CRISPR/Cas9 holds and the associated shortcomings.
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