Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer

Wang, Yiwei; Xu, Liuyue; Shi, Shanshan; Wu, Sha; Meng, Ruijie; Chen, Huifang; Jiang, Zhuhua

doi:10.3390/ijms22084098

Cited by 14 publications

(19 citation statements)

References 41 publications

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“…Elevated neuroendocrine markers and docetaxel resistance are the two notable features of NEPC [ 5 , 48 ]. We then tested whether e2e4 affects these features.…”

Section: Resultsmentioning

confidence: 99%

Profile of chimeric RNAs and TMPRSS2-ERG e2e4 isoform in neuroendocrine prostate cancer

et al. 2022

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Purpose Specific gene fusions and their fusion products (chimeric RNA and protein) have served as ideal diagnostic markers and therapeutic targets for cancer. However, few systematic studies for chimeric RNAs have been conducted in neuroendocrine prostate cancer (NEPC). In this study, we explored the landscape of chimeric RNAs in different types of prostate cancer (PCa) cell lines and aimed to identify chimeric RNAs specifically expressed in NEPC. Methods To do so, we employed the RNA-seq data of eight prostate related cell lines from Cancer Cell Line Encyclopedia (CCLE) for chimeric RNA identification. Multiple filtering criteria were used and the candidate chimeric RNAs were characterized at multiple levels and from various angles. We then performed experimental validation on all 80 candidates, and focused on the ones that are specific to NEPC. Lastly, we studied the clinical relevance and effect of one chimera in neuroendocrine process. Results Out of 80 candidates, 15 were confirmed to be expressed preferentially in NEPC lines. Among them, 13 of the 15 were found to be specifically expressed in NEPC, and four were further validated in another NEPC cell line. Importantly, in silico analysis showed that tumor malignancy may be correlated to the level of these chimeric RNAs. Clinically, the expression of TMPRSS2-ERG (e2e4) was elevated in tumor tissues and indicated poor clinical prognosis, whereas the parental wild type transcripts had no such association. Furthermore, compared to the most frequently detected TMPRSS2-ERG form (e1e4), e2e4 encodes 31 more amino acids and accelerated neuroendocrine process of prostate cancer. Conclusions In summary, these findings painted the landscape of chimeric RNA in NEPC and supported the idea that some chimeric RNAs may represent additional biomarkers and/or treatment targets independent of parental gene transcripts.

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“…Elevated neuroendocrine markers and docetaxel resistance are the two notable features of NEPC [ 5 , 48 ]. We then tested whether e2e4 affects these features.…”

Section: Resultsmentioning

confidence: 99%

Profile of chimeric RNAs and TMPRSS2-ERG e2e4 isoform in neuroendocrine prostate cancer

et al. 2022

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“…Moreover, Rolseth et al found that compared to control mice, cancer predisposition or increased spontaneous mutation frequencies were not observed in NEIL1/2/3 DNA glycosylases-deficient mice, indicating that NEIL1/2/3 might be essential in cancer prevention [ 22 ]. The cancer-promoting effects of NEIL3 have been proven in multiple cancers, including prostate, liver, and breast cancers [ 17 , 21 , 23 ]. Our results indicate that NEIL3 promotes NSCLC cell proliferation, invasion, and migration partially by regulating the classic PI3K/AKT/mTOR signaling pathway; thus, it might be a promising therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

“…Tumors with overexpressed NEIL3 are often accompanied by anomalous expression levels of homologous recombination genes (BRCA1/2) and mismatch repair genes (MSH2/MSH6) [ 16 ]. Wang et al found that NEIL3 promotes prostate cancer cell proliferation and cisplatin resistance by inhibiting the phosphorylation of ATR and ATM serine/threonine kinase [ 17 ]. Meanwhile, Klattenhoff et al found that the loss of NEIL3 markedly enhances replication-associated double-strand breaks and enhances sensitivity to ATR inhibitors in glioblastoma cells [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

NEIL3 Mediates Lung Cancer Progression and Modulates PI3K/AKT/mTOR Signaling: A Potential Therapeutic Target

Huang

Hua

2022

International Journal of Genomics

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Background. Nei endonuclease VIII-like 3 (NEIL3) is widely involved in pathophysiological processes of the body; however, its role in lung cancer has not been conclusively determined. Objective. This study is aimed at exploring the role of NEIL3 in lung cancer. Methods. The public data used in this study were downloaded from The Cancer Genome Atlas (TCGA) database. “Limma” in R was used for the analysis of differentially expressed genes. Clinical correlations and prognostic analyses were performed using the survival package in R. The proliferative abilities of lung cancer cells were evaluated by the CCK8 and colony formation assays while their invasive and migration abilities were assessed by the transwell and wound healing assays. Quantitative real-time PCR (qRT-PCR) and western blot analyses were utilized to detect RNA and protein levels. Biological differences between groups were determined by gene set enrichment analysis (GSEA). Tumor Immune Dysfunction and Exclusion (TIDE) as well as Genomics of Drug Sensitivity in Cancer (GDSC) was used for immunotherapeutic and chemotherapeutic sensitivity analyses. Results. NEIL3 was upregulated in NSCLC tissues and cell lines, implying that it is involved in lung cancer initiation and progression. Clinical correlation and prognostic analyses showed that NEIL3 was associated with worse clinical features (stage and T and N classifications) and poor prognostic outcomes. In vitro, NEIL3 significantly enhanced NSCLC proliferation, invasion, and migration. GSEA indicated that NEIL3 might be involved in PI3K/AKT/mTOR, G2/M checkpoints, and E2F target pathways. Inhibition of NEIL3 suppressed cyclinD1 and p-AKT protein levels; however, it had no effects on AKT levels, indicating that NEIL3 can partially activate the PI3K/AKT/mTOR signaling pathway. The predicted result of TIDE indicated that immunotherapeutic nonresponders had elevated NEIL3 levels. Moreover, there was a positive correlation between NEIL3 levels and chemosensitivity to cisplatin and paclitaxel. Conclusion. In general, NEIL3 mediates NSCLC progression and affects sensitivity to immunotherapy and chemotherapy; therefore, it is a potential molecular target for treatment.

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“…It has been reported that the loss of NEIL3 in prostate cancer could inhibit cell apoptosis and cell cycle arrest under cisplatin treatment ( Wang et al, 2021 ). UNG rs246079 G/A might contribute to a decreased risk of esophageal cancer and an increased risk of cervical carcinoma ( Yin et al, 2014 ; Ye et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

A DNA Damage Repair Gene Signature Associated With Immunotherapy Response and Clinical Prognosis in Clear Cell Renal Cell Carcinoma

et al. 2022

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Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma with relatively poor clinical outcomes DNA damage repair genes (DDRGs) as potential biomarkers are rarely reported in predicting immunotherapy response and clinical prognosis for ccRCC.Methods: RNA-seq and clinical data of ccRCC cohort were collected form TCGA database. Univariate Cox regression and LASSO analysis were performed to construct a DDRG risk signature. Functional enrichment analysis was performed to explore latently enriched pathways associated with DDRG signature. Immune cell infiltration level was estimated using gene set enrichment analysis, and immune response of ccRCC was predicted by tumor immune dysfunction and exclusion (TIDE) algorithm. To predict 1-, 3-, and 5-years overall survival (OS), a nomogram was constructed based on independent prognostic factors, whose performance would be evaluated by calibration curve.Results: A total of 47 DNA damage repair related genes (DDRGs) with significant prognostic value were identified in the ccRCC cohort (n = 519). A DDRG risk signature comprising six DRRGs (MSH3, RAD54L, RAD50, EME1, UNG, and NEIL3) were constructed by the LASSO analysis. ccRCC patients were then divided into low- and high-risk groups based on the risk score. Survival analysis revealed that patients in high-risk groups exhibited significantly poorer OS and progression-free survival (PFS), as was confirmed by the testing dataset. Functional enrichment analysis indicated that differentially expressed genes (DEGs) between high- and low-risk groups were mainly associated with immune-related biological processes in ccRCC, among which the immunodeficiency pathway was significantly enriched in the high-risk group. Though the risk signature was significantly correlated with the immune cell infiltration, PD-1 and PD-L1 were less expressed in the DDRG signature, which might indicate the poor response to immunotherapy in the high-risk group. Furthermore, the Cox regression analysis indicated that the DDRG signature can be served as an independent prognostic predictor when compared to clinical characteristics. Based on the independent prognostic predictors, we constructed a nomogram with excellent predictive ability in OS prediction for ccRCC patients.Conclusion: We developed a reliable DDRG risk signature that can independently predict the OS and PFS of ccRCC, which is also promising for predicting immunotherapeutic responses in ccRCC patients.

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Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer

Cited by 14 publications

References 41 publications

Profile of chimeric RNAs and TMPRSS2-ERG e2e4 isoform in neuroendocrine prostate cancer

Profile of chimeric RNAs and TMPRSS2-ERG e2e4 isoform in neuroendocrine prostate cancer

NEIL3 Mediates Lung Cancer Progression and Modulates PI3K/AKT/mTOR Signaling: A Potential Therapeutic Target

A DNA Damage Repair Gene Signature Associated With Immunotherapy Response and Clinical Prognosis in Clear Cell Renal Cell Carcinoma

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