MKP‑1 overexpression is associated with chemoresistance in bladder cancer via the MAPK pathway

Lei, Siyu; Xu, Hao; Chen, Naiwen; Pan, Huaizhong; Xie, Weiqing; He, Yi; Jin, Jing

doi:10.3892/ol.2020.11741

Cited by 12 publications

(5 citation statements)

References 45 publications

(54 reference statements)

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“…Therefore, overexpression of TNFAIP8L3, caused by hypomethylation, may contribute to BLCA progression or resistance to therapies. MAPK signaling and JAK-STAT signaling pathways have been shown to have vital roles in BLCA progression and might be connected with TNFAIP8L3 activation ( Huang et al, 2020 ; Lei et al, 2020 ), but the mechanisms connecting TNFAIP8L3 and these two pathways remain unclear. Further studies are required.…”

Section: Discussionmentioning

confidence: 99%

A Novel CpG Methylation Risk Indicator for Predicting Prognosis in Bladder Cancer

Guo

Yin

Dai

et al. 2021

Front. Cell Dev. Biol.

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PurposeBladder cancer (BLCA) is one of the most common cancers worldwide. In a large proportion of BLCA patients, disease recurs and/or progress after resection, which remains a major clinical issue in BLCA management. Therefore, it is vital to identify prognostic biomarkers for treatment stratification. We investigated the efficiency of CpG methylation for the potential to be a prognostic biomarker for patients with BLCA.Patients and MethodsOverall, 357 BLCA patients from The Cancer Genome Atlas (TCGA) were randomly separated into the training and internal validation cohorts. Least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) were used to select candidate CpGs and build the methylation risk score model, which was validated for its prognostic value in the validation cohort by Kaplan–Meier analysis. Hazard curves were generated to reveal the risk nodes throughout the follow-up. Gene Set Enrichment Analysis (GSEA) was used to reveal the potential biological pathways associated with the methylation model. Quantitative real-time polymerase chain reaction (PCR) and western blotting were performed to verify the expression level of the methylated genes.ResultsAfter incorporating the CpGs obtained by the two algorithms, CpG methylation of eight genes corresponding to TNFAIP8L3, KRTDAP, APC, ZC3H3, COL9A2, SLCO4A1, POU3F3, and ADARB2 were prominent candidate predictors in establishing a methylation risk score for BLCA (MRSB), which was used to divide the patients into high- and low-risk progression groups (p < 0.001). The effectiveness of the MRSB was validated in the internal cohort (p < 0.001). In the MRSB high-risk group, the hazard curve exhibited an initial wide, high peak within 10 months after treatment, whereas some gentle peaks around 2 years were noted. Furthermore, a nomogram comprising MRSB, age, sex, and tumor clinical stage was developed to predict the individual progression risk, and it performed well. Survival analysis implicated the effectiveness of MRSB, which remains significant in all the subgroup analysis based on the clinical features. A functional analysis of MRSB and the corresponding genes revealed potential pathways affecting tumor progression. Validation of quantitative real-time PCR and western blotting revealed that TNFAIP8L3 was upregulated in the BLCA tissues.ConclusionWe developed the MRSB, an eight-gene-based methylation signature, which has great potential to be used to predict the post-surgery progression risk of BLCA.

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Section: Discussionmentioning

confidence: 99%

A Novel CpG Methylation Risk Indicator for Predicting Prognosis in Bladder Cancer

Guo

Yin

Dai

et al. 2021

Front. Cell Dev. Biol.

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“…Therefore, MMP7 can be used as a related effector of invasion and metastasis. Similarly, MKP-1 is overexpressed in several cancer types, associated with cancer progression, and may be a potential prognostic marker 35 . In T-ALL cell lines, cells with MKP-1 deficiency exhibited compromised tumorigenicity, which was regulated by Notch3 36 .…”

Section: Discussionmentioning

confidence: 99%

Targeting the ZMIZ1-Notch1 signaling axis for the treatment of tongue squamous cell carcinoma

Pang,

Sun,

et al. 2024

Sci Rep

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Zinc finger MIZ-type containing 1 (ZMIZ1) is a transcriptional coactivator related to the protein inhibitors of activated STATs (PIAS) family. Mounting evidence suggests that ZMIZ1 plays a crucial role in the occurrence and development of cancers. The function of ZMIZ1 in tongue squamous cell carcinoma (TSCC) and the mechanisms underpinning its role in this disease have not been fully clarified. We performed qualitative ZMIZ1 protein expression analyses using immunohistochemistry in 20 patient-derived, paraffin-embedded TSCC tissue sections. We used RNAi to knock down ZMIZ1 expression in the CAL-27 TSCC cell line and quantified the impact of ZMIZ1 knock down on proliferation, migration and apoptosis via CCK-8, scratch assay and flow cytometry, respectively. We used qRT-PCR and western blotting to investigate the role of ZMIZ1 in this cell line. Finally, we established a model of lung metastasis in nude mice to replicate the in vitro results. ZMIZ1 protein was significantly more abundant in TSCC case tissue samples. ZMIZ1 knockdown reduced the invasion and metastases of TSCC tumor cells and promoted apoptosis. ZMIZ1 knockdown was associated with the down-regulation of Notch signaling pathway related factors Jagged1 and Notch1, and invasion and metastasis related factors MKP-1, SSBP2 and MMP7 in vitro and in vivo, at the mRNA level. In vitro and in vivo data suggest that knock down of ZMIZ1 may inhibit TSCC invasion and metastasis by modulating Notch signaling. ZMIZ1 inhibition may therefore represent a new therapeutic target for TSCC.

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“…The results from KEGG analysis indicated that MAPK, PI3K-Akt, and HIF-1 signaling pathways were markedly identified. MAPK and PI3K-Akt regulate tumor cell survival, proliferation, growth, mobility, and angiogenesis, whose activations were essential for BLCA metastasis and chemotherapy ( Xia et al, 2018 ; Sun et al, 2019 ; Lei et al, 2020 ; Ruan et al, 2020 ; Zhang et al, 2020 ; Xu et al, 2021a ; Kao et al, 2021 ). The HIF-1 signaling pathway was also discovered to be involved in hypoxic BLCA cell proliferation, migration, invasion, metastasis, and EMT, providing a rationale for clinical trials evaluating agents targeting this pathway ( Tickoo et al, 2011 ; Xue et al, 2014 ; Lu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Construction and verification of a novel hypoxia-related lncRNA signature related with survival outcomes and immune microenvironment of bladder urothelial carcinoma by weighted gene co-expression network analysis

Cai

Zhou²,

Wei³

et al. 2022

Front. Genet.

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Background: Bladder urothelial carcinoma (BLCA) is a common malignant tumor with the greatest recurrence rate of any solid tumor. Hypoxia is crucial in the growth and immune escape of malignant tumors. To predict clinical outcomes and immunological microenvironment of patients with BLCA, a hypoxia-related long non-coding RNA (HRlncRNA) signature was established.Methods: The Cancer Genome Atlas (TCGA) provided us with the differentially expressed profile of HRlncRNAs as well as clinical data from patients with BLCA, and we used weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with malignancies.Results: Finally, Cox analysis revealed that HRlncRNAs, which comprised 13 lncRNAs, were implicated in the predictive signature. The training, testing, and overall cohorts of BLCA patients were divided into the low-risk group and high-risk group based on the median of the risk score. The Kaplan–Meier curves revealed that BLCA patients with a high-risk score had a poor prognosis, and the difference between subgroups was statistically significant. The receiver operating characteristic curves revealed that this signature outperformed other strategies in terms of predicting ability. Multivariate analysis revealed that the risk score was an independent prognostic index for overall survival (HR = 1.411; 1.259–1.582; p < 0.001). Then, a nomogram with clinicopathological features and risk score was established. This signature could effectively enhance the capacity to predict survival, according to the calibration plots, stratification, and clinical analysis. The majority of Kyoto Encyclopedia of Genes and Genomes (KEGG) were WNT, MAPK, and ERBB signaling pathways. Two groups had different immune cell subtypes, immune checkpoints, immunotherapy response, and anti-tumor drug sensitivity, which might result in differing survival outcomes. We then validated the differential expression of signature-related genes between tumor and normal tissues using TCGA paired data.Conclusion: This prognostic signature based on 13 HRlncRNAs may become a novel and potential prognostic biomarker, providing more accurate clinical decision-making and effective treatment for BLCA patients.

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MKP‑1 overexpression is associated with chemoresistance in bladder cancer via the MAPK pathway

Cited by 12 publications

References 45 publications

A Novel CpG Methylation Risk Indicator for Predicting Prognosis in Bladder Cancer

A Novel CpG Methylation Risk Indicator for Predicting Prognosis in Bladder Cancer

Targeting the ZMIZ1-Notch1 signaling axis for the treatment of tongue squamous cell carcinoma

Construction and verification of a novel hypoxia-related lncRNA signature related with survival outcomes and immune microenvironment of bladder urothelial carcinoma by weighted gene co-expression network analysis

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