Overexpression of KIAA0101 predicts poor prognosis in primary lung cancer patients.
ABSTRACT High expression of KIAA0101 (p15(PAF)/OEATC-1) which contains a proliferating cell nuclear antigen (PCNA)-binding motif, a key factor in DNA repair and/or apoptosis and cell cycle regulation, has been observed in a variety of human malignancies. The aim of this study was to observe the expression of KIAA0101 in human non-small-cell lung cancer (NSCLC), explore its clinicopathological significance and evaluate KIAA0101 expression as a potential prognostic marker. KIAA0101 transcript was found to be overexpressed in the great majority of lung cancers by semi-quantitative RT-PCR. A total of 357 NSCLCs were analyzed immunohistochemically on tissue microarrays. High-level KIAA0101 expression was observed in 33.9% (121 of 357 cases), and correlated with male gender (P<0.0001), tumor progression (pT status) (P=0.0008), lymph node metastasis (pN status) (P=0.0003), non-adenocarcinoma histological classification (P<0.0001), and smoking history (P<0.0001), but not with patient age or pleural invasion. Patients with tumors displaying high-level KIAA0101 expression showed significantly shorter survival (P<0.0001, log-rank test). Similarly, gender, pT status, pN status, pleural invasion, histological classification, and smoking history were significant prognostic markers in univariate Cox survival analysis. Importantly, high-level KIAA0101 expression was also identified as an independent prognostic factor by multivariate analysis (P=0.0320). These results provide additional information for determining postoperative adjuvant treatment of NSCLC.
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ABSTRACT: Proliferating cell nuclear antigen (PCNA)-Associated Factor (PAF15) is a small protein containing a PCNA interacting motif and sequences for association with ubiquitin enzymes. In interaction with PCNA, PAF15 plays a key role in recruiting DNA replicative polymerase by double monoubiquitination at Lys(15) and Lys(24). Under DNA damage conditions, PAF15 regulates the switch from DNA replicative polymerase to translesion synthesis polymerase in order to bypass the replication-blocking lesions. Overexpression of PAF15 promotes the repair of ultraviolet-induced DNA damage and prevents cell death, whereas attenuation of PAF15 decreases DNA replication and cell survival. Ectopic expression of PAF15 in mouse fibroblasts increases colony formation and tumourigenicity. PAF15 is aberrantly increased in various human malignancies with poor prognosis. Collectively, PAF15 may contribute to carcinogenesis and represents one of the potential therapeutic targets in the treatment of cancer.The international journal of biochemistry & cell biology 03/2014; · 4.89 Impact Factor
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ABSTRACT: We present to our knowledge the first structural characterization of the proliferating-cell-nuclear-antigen-associated factor p15(PAF), showing that it is monomeric and intrinsically disordered in solution but has nonrandom conformational preferences at sites of protein-protein interactions. p15(PAF) is a 12 kDa nuclear protein that acts as a regulator of DNA repair during DNA replication. The p15(PAF) gene is overexpressed in several types of human cancer. The nearly complete NMR backbone assignment of p15(PAF) allowed us to measure 86 N-H(N) residual dipolar couplings. Our residual dipolar coupling analysis reveals nonrandom conformational preferences in distinct regions, including the proliferating-cell-nuclear-antigen-interacting protein motif (PIP-box) and the KEN-box (recognized by the ubiquitin ligase that targets p15(PAF) for degradation). In accordance with these findings, analysis of the (15)N R2 relaxation rates shows a relatively reduced mobility for the residues in these regions. The agreement between the experimental small angle x-ray scattering curve of p15(PAF) and that computed from a statistical coil ensemble corrected for the presence of local secondary structural elements further validates our structural model for p15(PAF). The coincidence of these transiently structured regions with protein-protein interaction and posttranslational modification sites suggests a possible role for these structures as molecular recognition elements for p15(PAF).Biophysical Journal 02/2014; 106(4):865-74. · 3.67 Impact Factor
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ABSTRACT: KIAA0101 always overexpresses in tumor tissues, which is also a marker of tumor recurrence. This study aims to explore whether overexpression of KIAA0101 mRNA in peripheral blood mononuclear cells (PBMCs) could act as a noninvasive and predictive biomarker of hepatic cancer. Real-time polymerase chain reaction (RT-PCR) was employed to detect KIAA0101 mRNA expression in PBMCs isolated from 93 hepatic cancer patients and 55 healthy individuals. The diagnostic sensitivity and specificity of KIAA0101 mRNA, CEA, and CD44V were analyzed and compared. A multivariate logistic regression analysis was utilized to analyze risk factors for overall survival of hepatic cancer patients. A concordance analysis was employed to compare the overexpression of KIAA0101 mRNA with clinicopathological diagnosis. All of the 93 hepatic cancer patients were followed up routinely at least 36 months or until death to analyze the 3-year overall survival rate. The results indicated that KIAA0101 mRNA expression was increased significantly in hepatic patients' PBMCs, when compared with that of healthy individuals (P < 0.05). Both the sensitivity and specificity of KIAA0101 mRNA in PBMCs were enhanced significantly compared with those of the CEA and CD44V biomarkers. The multivariate logistic regression analysis indicated that the KIAA0101 mRNA level and pTNM stage were significantly related with the overall survival of the hepatic patients. There was a better concordance between KIAA0101 mRNA overexpression and clinicopathological diagnosis for hepatic cancer (kappa = 0.914, P < 0.001). KIAA0101 mRNA overexpression in PBMCs decreased the 3-year survival rate significantly. In conclusion, overexpression of KIAA0101 mRNA in PBMCs could act as a predictive biomarker for hepatic cancer and has a better sensitivity and specificity.Tumor Biology 11/2013; · 2.52 Impact Factor