Overexpression of KIAA0101 predicts poor prognosis in primary lung cancer patients

Department of Thoracic Surgery, Sapporo Minami-Sanjo Hospital, Sapporo 060-0063, Japan.
Lung cancer (Amsterdam, Netherlands) (Impact Factor: 3.96). 06/2011; 75(1):110-8. DOI: 10.1016/j.lungcan.2011.05.024
Source: PubMed


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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    • "PAF15 abundance is correlated with malignancy grade in astrocytoma and hepatocellular carcinoma (Marie et al., 2008; Yuan et al., 2007), and promotes growth and invasion in both adrenal and hepatocellular carcinoma (Jain et al., 2011; Yuan et al., 2007). An increase in PAF15 mRNA levels occurs more common in the patients of younger age with liver cancer (Yuan et al., 2012) and in males with lung cancer (Kato et al., 2012). PAF15 is thought to be a biomarker for treatment response in adrenocortical carcinoma, as PAF15 levels decrease following treatment (Jain et al., 2011). "
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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; 50(1). DOI:10.1016/j.biocel.2014.02.024 · 4.05 Impact Factor
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    • "KIAA0101 has been observed in a variety of human malignancies and plays a key factor in DNA repair and apoptosis in cell cycle regulation. High-level KIAA0101 expression was also identified as an independent prognostic factor for determining postoperative adjuvant treatments for non-small cell lung carcinoma[81]. "
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    ABSTRACT: Background Schizophrenic patients show lower incidences of cancer, implicating schizophrenia may be a protective factor against cancer. To study the genetic correlation between the two diseases, a specific PPI network was constructed with candidate genes of both schizophrenia and hepatocellular carcinoma. The network, designated schizophrenia-hepatocellular carcinoma network (SHCN), was analysed and cliques were identified as potential functional modules or complexes. The findings were compared with information from pathway databases such as KEGG, Reactome, PID and ConsensusPathDB. Results The functions of mediator genes from SHCN show immune system and cell cycle regulation have important roles in the eitology mechanism of schizophrenia. For example, the over-expressing schizophrenia candidate genes, SIRPB1, SYK and LCK, are responsible for signal transduction in cytokine production; immune responses involving IL-2 and TREM-1/DAP12 pathways are relevant for the etiology mechanism of schizophrenia. Novel treatments were proposed by searching the target genes of FDA approved drugs with genes in potential protein complexes and pathways. It was found that Vitamin A, retinoid acid and a few other immune response agents modulated by RARA and LCK genes may be potential treatments for both schizophrenia and hepatocellular carcinoma. Conclusions This is the first study showing specific mediator genes in the SHCN which may suppress tumors. We also show that the schizophrenic protein interactions and modulation with cancer implicates the importance of immune system for etiology of schizophrenia.
    BMC Genomics 10/2013; 14(5). DOI:10.1186/1471-2164-14-S5-S10 · 3.99 Impact Factor
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    • "No other functional domains or motifs have been identified using bioinformatic methods. p15PAF is overexpressed in multiple types of human cancer, including hepatocellular carcinoma [2], lung cancer [3], breast cancer [4], and pancreatic cancer [5], and its overexpression is associated with poor patient outcome [2]–[4]. Overexpression of p15PAF promotes cancer cell growth, whereas attenuation of expression by small interfering RNA (siRNA) leads to reduced cell proliferation [5]. "
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    ABSTRACT: The p15(PAF)/KIAA0101 protein is a proliferating cell nuclear antigen (PCNA)-associated protein overexpressed in multiple types of cancer. Attenuation of p15(PAF) expression leads to modifications in the DNA repair process, rendering cells more sensitive to ultraviolet-induced cell death. In this study, we identified that p15(PAF) expression peaks during the S phase of the cell cycle. We observed that p15(PAF) knockdown markedly inhibited cell proliferation, S-phase progression, and DNA synthesis. Depletion of p15(PAF) resulted in p21 upregulation, especially chromatin-bound p21. We further identified that the p15(PAF) promoter contains 3 E2F-binding motifs. Loss of Rb-mediated transcriptional repression resulted in upregulated p15(PAF) expression. Binding of E2F4 and E2F6 to the p15(PAF) promoter caused transcriptional repression. Overall, these results indicate that p15(PAF) is tightly regulated by the Rb/E2F complex. Loss of Rb/E2F-mediated repression during the G1/S transition phase leads to p15(PAF) upregulation, which facilitates DNA synthesis and S-phase progression.
    PLoS ONE 04/2013; 8(4):e61196. DOI:10.1371/journal.pone.0061196 · 3.23 Impact Factor
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