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

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 χ2 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.

[1]  G. Tell,et al.  Prognostic significance of Ape1/ref-1 subcellular localization in non-small cell lung carcinomas. , 2001, Anticancer research.

[2]  A. Leonardi,et al.  Specific Inhibition of the Redox Activity of Ape1/Ref-1 by E3330 Blocks Tnf-Α-Induced Activation of Il-8 Production in Liver Cancer Cell Lines , 2013, PloS one.

[3]  O. Lavrik,et al.  Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1). , 2017, Bioorganic & medicinal chemistry.

[4]  M. Kumar,et al.  Phosphorylation of multifunctional nucleolar protein nucleophosmin (NPM1) by aurora kinase B is critical for mitotic progression , 2014, FEBS letters.

[5]  X. Zhang,et al.  Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression , 2015, Oncogene.

[6]  M. Bookman.  First-line chemotherapy in epithelial ovarian cancer. , 2012, Clinical obstetrics and gynecology.

[7]  R. Levine,et al.  Molecular therapy for acute myeloid leukaemia , 2016, Nature Reviews Clinical Oncology.

[8]  Ilya Shmulevich,et al.  Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers. , 2015, Journal of the National Cancer Institute.

[9]  D. Owen,et al.  Nucleophosmin 1, upregulated in adenomas and cancers of the colon, inhibits p53‐mediated cellular senescence , 2013, International journal of cancer.

[10]  K. O'Byrne,et al.  Nucleophosmin: from structure and function to disease development , 2016, BMC Molecular Biology.

[11]  A. Leonardi,et al.  APE1/Ref-1 Interacts with NPM1 within Nucleoli and Plays a Role in the rRNA Quality Control Process , 2009, Molecular and Cellular Biology.

[12]  Jan Lubinski,et al.  Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Z. Szallasi,et al.  Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. , 2012, Cancer discovery.

[14]  L. Federici,et al.  Molecules that target nucleophosmin for cancer treatment: an update , 2016, Oncotarget.

[15]  G. Sauter,et al.  Apurinic/apyrimidinic endonuclease 1 (APE1/Ref‐1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion , 2017, Molecular carcinogenesis.

[16]  B. Jeon,et al.  Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein , 2016, Chonnam medical journal.

[17]  L. Luo,et al.  Silencing of Apurinic/Apyrimidinic Endonuclease 1 Inhibits the Growth and Migration in Ovarian Cancer Cell via Activator-Protein-1 Signaling , 2016, Gynecologic and Obstetric Investigation.

[18]  K. Gatter,et al.  Nuclear expression of human apurinic/apyrimidinic endonuclease (HAP1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome. , 2001, International journal of radiation oncology, biology, physics.

[19]  B. Schöttker,et al.  Reduction-oxidation pathways involved in cancer development: a systematic review of literature reviews. , 2017, Oncotarget.

[20]  L. Yue,et al.  Both high expression of nucleophosmin/B23 and CRM1 predicts poorer prognosis in human gastric cancer , 2016, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[21]  D. Bowtell,et al.  The changing view of high-grade serous ovarian cancer. , 2012, Cancer research.

[22]  Robert Brown,et al.  Promoter CpG Island Methylation of Genes in Key Cancer Pathways Associates with Clinical Outcome in High-Grade Serous Ovarian Cancer , 2013, Clinical Cancer Research.

[23]  W. Ahrens,et al.  A Rare Truncating BRCA2 Variant and Genetic Susceptibility to Upper Aerodigestive Tract Cancer , 2015, Journal of the National Cancer Institute.

[24]  J. Tainer,et al.  The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once. , 2014, DNA repair.

[25]  Lin Guo,et al.  APE1 overexpression promotes the progression of ovarian cancer and serves as a potential therapeutic target. , 2016, Cancer biomarkers : section A of Disease markers.

[26]  C. Vascotto,et al.  Expression and prognostic significance of APE1/Ref-1 and NPM1 proteins in high-grade ovarian serous cancer. , 2014, American journal of clinical pathology.