Serum Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) Level as a Potential Biomarker of Cholangiocarcinoma

Tummanatsakun, Doungdean; Proungvitaya, Tanakorn; Roytrakul, Sittiruk; Limpaiboon, Temduang; Wongkham, Sopit; Wongkham, Chaisiri; Silsirivanit, Atit; Somintara, Ongart; Sangkhamanon, Sakkarn; Proungvitaya, Siriporn

doi:10.3390/biom9090413

Cited by 18 publications

(18 citation statements)

References 38 publications

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“…Also, APEX1 was reported to be associated with some cancer types, including the cancers of colon, stomach, liver, kidney, and breast, as well as osteosarcoma[ 4 - 8 , 33 ]. Recent studies showed that APEX1 is an efficient biomarker for the diagnosis and prognosis of liver cancer[ 6 , 8 , 34 ]. However, the role of APEX2 in cancer is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Identification of APEX2 as an oncogene in liver cancer

Ru¹,

Zhu²,

Hu³

et al. 2020

WJCC

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BACKGROUND DNA damage is one of the critical contributors to the occurrence and development of some cancers. APEX1 and APEX2 are the most important molecules in the DNA damage, and APEX1 has been identified as a diagnostic and prognostic biomarker in liver hepatocellular carcinoma (LIHC). However, the expression of APEX2 and its functional mechanisms in LIHC are still unclear. AIM To examine the expression of APEX2 and the potential mechanism network in LIHC. METHODS We conducted a pan-cancer analysis of the expression of APEX1 and APEX2 using the interactive TIMER tool. GEO datasets, including GSE14520, GSE22058, and GSE64041, were used to compare the APEX2 expression level in tumor tissues and adjacent non-tumor tissues. Then, we calculated the 5-year survival rate according to the web-based Kaplan-Meier analysis. We included the TCGA liver cancer database in GSEA analysis based on the high and low APEX2 expression, showing the potential mechanisms of APEX2 in LIHC. After that, we conducted Pearson correlation analysis using GEPIA2. Next, we performed quantitative polymerase chain reaction (qPCR) assay to examine the APEX2 levels in normal liver cell line LO2 and several liver cancer cell lines, including HepG2, Huh7, SMMC7721, and HCCLM3. APEX2 in HCCLM3 cells was knocked down using small interfering RNA. The role of APEX2 in cell viability was confirmed using CCK-8. Dual-luciferase reporter assay was performed to examine the promoter activity of CCNB1 and MYC . RESULTS APEX1 and APEX2 are both highly expressed in the tumor tissues of BLCA, BRCA, CHOL, COAD, ESCA, HNSC, LIHC, LUAD, LUSC, READ, and STAD. APEX2 overexpression in LIHC was validated using GSE14520, GSE22058, and GSE64041 datasets. The survival analysis showed that LIHC patients with high expression of APEX2 had a lower overall survival rate, even in the AJCC T1 patients. High level of APEX2 could indicate a lower overall survival rate in patients with or without viral hepatitis. The GSEA analysis identified that kinetochore and spindle microtubules are the two main cellular components of APEX2 in GO Ontology. APEX2 was also positively associated with molecular function regulation of chromosome segregation and DNA replication. The results of KEGG analysis indicated that APEX2 expression was positively correlated with cell cycle pathway and pro-oncogenic MYC signaling. Pearson correlation analysis showed that APEX2 had a significant positive correlation with CCNB1 and MYC. APEX2 level was higher in liver cancer cell lines than in normal liver LO2 cells. Small interfering RNA could knock down the APEX2 expression in HCCLM3 cells. Knockdown of APEX2 resulted in a decrease in the viability of HCCLM3 cells as well as the expression and promoter activity of CCNB1 and MYC . CONCLUSION APEX2 i...

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Section: Discussionmentioning

confidence: 99%

Identification of APEX2 as an oncogene in liver cancer

Ru¹,

Zhu²,

Hu³

et al. 2020

WJCC

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“…Other diagnostic methods like ultrasonography, Computed tomography (CT) and magnetic resonance imaging (MRI) are more convenient than biopsy for liver disease [34]. A recent report shows that serum APEX1 can be used as a biomarker for cholangiocarcinomas [35]. It is plausible that serum APEX1 levels may be elevated in HCC patients and may be a more sensitive diagnostic biomarker.…”

Section: Agingmentioning

confidence: 99%

APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma

Cao

Cheng²,

Jiang³

et al. 2020

Aging

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In this study, we analyzed the expression and clinical significance of apyrimidinic endodeoxyribonuclease 1 (APEX1) in hepatocellular carcinoma (HCC). The APEX1 mRNA and protein levels were significantly higher in HCC than adjacent normal liver tissues in multiple datasets from the Oncomine, GEO and TCGA databases. APEX1 levels were significantly higher in early-stage HCC patients with low alpha-fetoprotein expression. The positive predictive value (PPV) for APEX1 was significantly higher than the PPV for alpha-fetoprotein (67.91% vs. 55.22%) in HCC patients. High APEX1 expression correlated with resistance to sorafenib and anti-programmed death 1 (PD-1) therapies in HCC patients, and it associated with poorer overall survival, disease-specific survival, progression-free survival, and relapse-free survival in early-and advanced-stage HCC patients. High APEX1 expression also associated with poor prognosis in non-alcoholic, vascular invasion-negative, and hepatitis virus-negative HCC patients. These data suggest that APEX1 is a better diagnostic and prognostic biomarker than alpha-fetoprotein in HCC. Gene set enrichment analysis (GSEA) showed that APEX1 expression correlated with the DNA damage repair pathway in HCC tissues. These findings demonstrate that APEX1 is a potential diagnostic and prognostic biomarker in HCC.

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“…However, the clinical signi cance of APEX1 in cancer remains unclear, although APEX1 has been shown to be a positive regulator, contributing to the aggressive behavior of colon cancer behaviors [27]. Many studies have suggested increased APEX1 levels to be diagnostic and prognostic for cancer, and that APEX1 may be a therapeutic target for treatment of advanced cancer [28]. APEX1 expression has been inversely correlated with cellular senescence in human primary cells, while in cancer, low levels of APEX1 expression have been associated with increased senescence [29].…”

Section: Validation Of Apex1-regulated Gene Expression and Alternativmentioning

confidence: 99%

APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer

Peng

Chen

et al. 2020

Preprint

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Background: Aberrant alternative splicing (AS) contributes to tumor progression. Previous studies have shown that apurinic-apyrimidinic endonuclease-1 (APEX1) is involved in tumor progression. It is unknown whether APEX1 functions in tumor progression by regulation of AS. It is also unknown whether APEX1 can regulate non-small-cell lung cancer (NSCLC) proliferation and apoptosis. Methods: We analyzed APEX1 expression levels in 517 lung NSCLC samples from the TCGA (Cancer Genome Atlas) database. The impact of APEX1 over expression on A549 cell proliferation and apoptosis was detected by the methyl thiazolyl tetrazolium assay and by flow cytometry. The transcriptome of A549 cells with and without APEX1 over expression was determined by Illumina sequencing, followed by analysis of AS. RT-qPCR validated APEX1 in A549 cells. Results: We have successfully applied RNA-seq technology to demonstrate APEX1 regulation of AS. APEX1 expression was shown to be upregulated in NSCLC samples and to reduce cell proliferation and induce apoptosis of A549 cells. Further, APEX1 regulated AS of key tumorigenesis genes involved in cancer proliferation and apoptosis within the MAPK and Wnt signaling pathways. Each of these pathways are involved in lung cancer progression. Validated AS events regulated by APEX1 were located in key tumorigenesis genes; AXIN1 (axis inhibition protein 1), GCNT2 (N-acetyl glucosaminyl transferase 2), and SMAD3 (SMAD Family Member 3). These genes encode signaling pathway transcription regulatory factors. Conclusions: We found that increased expression of APEX1 in NSCLC is an independent prognostic factor related to tumor progression. Therefore, APEX1 regulation of AS may serve as a molecular marker or therapeutic target for NSCLC treatment.

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Serum Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) Level as a Potential Biomarker of Cholangiocarcinoma

Cited by 18 publications

References 38 publications

Identification of APEX2 as an oncogene in liver cancer

Identification of APEX2 as an oncogene in liver cancer

APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma

APEX1 regulates alternative splicing of key tumorigenesis genes in non-small-cell lung cancer

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