Apurinic/apyrimidinic endonuclease 1 (APE1/Ref‐1) overexpression is an independent prognostic marker in prostate cancer without <i>TMPRSS2:ERG</i> fusion

Juhnke, Manuela; Heumann, Asmus; Chirico, Viktoria; Höflmayer, Doris; Menz, Anne; Hinsch, Andrea; Hube‐Magg, Claudia; Kluth, Martina; Lang, Dagmar S.; Möller‐Koop, Christina; Sauter, Guido; Simon, Ronald; Pompe, Raisa S.; Thederan, Imke; Schlomm, Thorsten; Luebke, Andreas M.

doi:10.1002/mc.22670

Cited by 20 publications

(21 citation statements)

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“…Consistently, we showed that the non‐chemosensitive group has a significantly higher level of abnormal expression of APE1/Ref‐1 protein than the chemosensitive group, suggesting that a defective DNA BER mechanism may be one of the important chemoresistance mechanisms in HGSC. And consistent with our observation, several literatures reported that dysregulated APE1/Ref‐1 protein expression also predicts a poor prognosis in prostate cancer and ovarian cancer .…”

Section: Discussionsupporting

confidence: 92%

The expression profile and prognostic value of APE/Ref‐1 and NPM1 in high‐grade serous ovarian adenocarcinoma

Fan

Wen

et al. 2017

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To analyze the expression trends and clinical significance of Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1/Ref-1) and Nucleophosmin (NPM1) proteins in high-grade serous ovarian adenocarcinoma (HGSC). The expressions of APE1/Ref-1 and NPM1 proteins in 94 patients with HGSC were determined using the immunohistochemical (IHC) method, and their relationships with clinicopathological features were analyzed by the χ test or Fisher's exact test. The follow-up data, Cox proportional hazards univariate and multivariate survival analyses were integrated to evaluate the prognostic factors affecting patients with HGSC. In the normal fallopian tubes, APE1/Ref-1 and NPM1 protein were mainly distributed in the nuclear. The HGSC experienced changes in the cellular localization of APE1/Ref-1 and NPM1 protein expressions, which were abnormally expressed in the cytoplasm. The rates of abnormal cytoplasmic expression of APE1/Ref-1 and NPM1 proteins in 94 patients with HGSC were 69.1% and 73.4%, respectively, which were significantly higher than the normal fallopian tube tissues (p < 0.05). The abnormal cytoplasmic APE1/Ref-1 and NPM1 are significantly correlated with the lymph node metastasis, chemosensitivity, FIGO staging, and prognosis. The COX multivariate survival analysis showed that the abnormal expression of APE1/Ref-1 protein, FIGO staging, and lymph node metastasis are independent prognostic factors. Collectively, the abnormal cytoplasmic APE1/Ref-1 and NPM1 proteins are associated with the oncogenic progression and chemoresistance of HGSC, and predict a poor prognosis.

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Section: Discussionsupporting

confidence: 92%

The expression profile and prognostic value of APE/Ref‐1 and NPM1 in high‐grade serous ovarian adenocarcinoma

Fan

Wen

et al. 2017

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“…In our study, we compared the expression of PSCA with molecular attributes associated with genomic instability, chromosomal deletion and tumor cell proliferation [ 37 ]. We found previously that features with a role in cell cycle control (p16 [ 39 ] or APE1 [ 40 ]) were significantly associated with a high Ki67 labeling index. Molecular attributes linked to genomic instability (MSH6/PMS2/MLH1 [ 41 ], ELAV1 [ 42 ], or HOOK3 [ 43 ]) were found to be associated with chromosomal deletion.…”

Section: Discussionmentioning

confidence: 99%

PSCA expression is associated with favorable tumor features and reduced PSA recurrence in operated prostate cancer

et al. 2018

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BackgroundProstate Stem Cell Antigen (PSCA) is frequently expressed in prostate cancer but its exact function is unclear.MethodsTo clarify contradictory findings on the prognostic role of PSCA expression, a tissue microarray containing 13,665 prostate cancers was analyzed by immunohistochemistry.ResultsPSCA staining was absent in normal epithelial and stromal cells of the prostate. Membranous and cytoplasmic PSCA staining was seen in 53.7% of 9642 interpretable tumors. Staining was weak in 22.4%, moderate in 24.5% and strong in 6.8% of tumors. PSCA expression was associated with favorable pathological and clinical tumor features: Early pathological tumor stage (p < 0.0001), low Gleason grade (p < 0.0001), absence of lymph node metastasis (p < 0.0001), low pre-operative PSA level (p = 0.0118), negative surgical margin (p < 0.0001) and reduced PSA recurrence (p < 0.0001). PSCA expression was an independent predictor of prognosis in multivariate analysis (hazard ratio 0.84, p < 0.0001).ConclusionsThe absence of statistical relationship to TMPRSS2:ERG fusion status, chromosomal deletion or high tumor cell proliferation argues against a major role of PSCA for regulation of cell cycle or genomic integrity. PSCA expression is linked to favorable prognosis. PSCA measurement is a candidate for inclusion in multi-parametric prognostic prostate cancer tests.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4547-7) contains supplementary material, which is available to authorized users.

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“…Due to its involvement in essential cellular processes such as genome stability and gene expression regulation, the importance of APE1 in human pathologies such as cancers, neurological diseases, and age-associated disorders is not surprising. Many studies have shown that APE1 is overexpressed in a variety of cancers, suggesting a possible prognostic significance and therapeutic target for this protein [ 26 – 29 ]. Data from different laboratories support a correlation between the increased expression levels of APE1 and HCC progression [ 30 – 33 ] and uphold the hypothesis that APE1 loss of expression suppresses proliferation and migration [ 34 – 36 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial apurinic/apyrimidinic endonuclease 1 enhances mtDNA repair contributing to cell proliferation and mitochondrial integrity in early stages of hepatocellular carcinoma

et al. 2020

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Background Hepatocellular carcinoma (HCC) is the leading cause of primary liver cancers. Surveillance of individuals at specific risk of developing HCC, early diagnostic markers, and new therapeutic approaches are essential to obtain a reduction in disease-related mortality. Apurinic/apyrimidinic endonuclease 1 (APE1) expression levels and its cytoplasmic localization have been reported to correlate with a lower degree of differentiation and shorter survival rate. The aim of this study is to fully investigate, for the first time, the role of the mitochondrial form of APE1 in HCC. Methods As a study model, we analyzed samples from a cohort of patients diagnosed with HCC who underwent surgical resection. Mitochondrial APE1 content, expression levels of the mitochondrial import protein Mia40, and mtDNA damage of tumor tissue and distal non-tumor liver of each patient were analyzed. In parallel, we generated a stable HeLa clone for inducible silencing of endogenous APE1 and re-expression of the recombinant shRNA resistant mitochondrially targeted APE1 form (MTS-APE1). We evaluated mtDNA damage, cell growth, and mitochondrial respiration. Results APE1’s cytoplasmic positivity in Grades 1 and 2 HCC patients showed a significantly higher expression of mitochondrial APE1, which accounted for lower levels of mtDNA damage observed in the tumor tissue with respect to the distal area. In the contrast, the cytoplasmic positivity in Grade 3 was not associated with APE1’s mitochondrial accumulation even when accounting for the higher number of mtDNA lesions measured. Loss of APE1 expression negatively affected mitochondrial respiration, cell viability, and proliferation as well as levels of mtDNA damage. Remarkably, the phenotype was efficiently rescued in MTS-APE1 clone, where APE1 is present only within the mitochondrial matrix. Conclusions Our study confirms the prominent role of the mitochondrial form of APE1 in the early stages of HCC development and the relevance of the non-nuclear fraction of APE1 in the disease progression. We have also confirmed overexpression of Mia40 and the role of the MIA pathway in the APE1 import process. Based on our data, inhibition of the APE1 transport by blocking the MIA pathway could represent a new therapeutic approach for reducing mitochondrial metabolism by preventing the efficient repair of mtDNA.

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Apurinic/apyrimidinic endonuclease 1 (APE1/Ref‐1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion

Cited by 20 publications

References 58 publications

The expression profile and prognostic value of APE/Ref‐1 and NPM1 in high‐grade serous ovarian adenocarcinoma

The expression profile and prognostic value of APE/Ref‐1 and NPM1 in high‐grade serous ovarian adenocarcinoma

PSCA expression is associated with favorable tumor features and reduced PSA recurrence in operated prostate cancer

Mitochondrial apurinic/apyrimidinic endonuclease 1 enhances mtDNA repair contributing to cell proliferation and mitochondrial integrity in early stages of hepatocellular carcinoma

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