Overexpressed in anaplastic thyroid carcinoma‐1 (<i>OEATC‐1</i>) as a novel gene responsible for anaplastic thyroid carcinoma

Mizutani, Kazunori; Onda, Masamitsu; Asaka, Shinichi; Akaishi, Junko; Miyamoto, B A Shizuyo; Yoshida, Akira; Nagahama, Mitsuji; Ito, Kouichi; Emi, Mitsuru

doi:10.1002/cncr.20988

Cited by 49 publications

(59 citation statements)

References 11 publications

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“…Interestingly, ATF3 and p15 PAF expressions peaked at 2 h after irradiation, suggesting a coordinated regulation with the presence of CPDs (Figure 3). To assess the direct contribution of both genes in the DNA repair process, HaCaT cells were rendered deficient by the transfection of siATF3 and sip15 PAF , 13 or siLuc as a control, 24 h after transfection, DNA damage was induced by irradiation with a single low dose of UVC (5 J/m 2 ). After 24 h of recovery, the presence of CPD-positive cells was assessed.…”

Section: Resultsmentioning

confidence: 99%

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15 PAF . We further show that the expressions of ATF3 and p15 PAF is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15 PAF compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15 PAF expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15 PAF expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15 PAF as novel gatekeepers of genomic integrity after UV exposure. Environmental genotoxic stress is one of the major causes of genomic instability. During such a stress, the maintenance of genomic integrity is of crucial importance to allow correct cellular function. The nucleotide excision repair (NER) machinery is responsible for recognition and incision of DNA lesions caused by ultraviolet (UV) irradiation and chemical agents. 1 Proliferating cell nuclear antigen (PCNA) is responsible for recruitment of Pold and, therefore, mediates DNA resynthesis within the site of the lesion. 1 The importance of such machinery is underscored by the numerous human syndromes, such as xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), caused by the mutation of genes involved in DNA repair. Such mutations compromise genomic integrity, and XP and TTD patients are highly photosensitive and prone to develop skin tumors of keratinocyte origin, such as basal and squamous cell carcinoma. Severe defects in the DNA repair mechanism thus impair the apoptotic pathway responsible for destruction of cells that bear the risk of becoming tumorigenic. The correct DNA damage response is therefore of great importance in the maintenance of a UV-inducible anticancer barrier that elicits growth arrest, repair or cell death.Activating transcription factor 3 (ATF3) is a member of the ATF/CREB subfamily of the basic region leucine zipper (bZIP) family and may be strongly induced in a variety of tissues by different stress signals. 2 Several pathways are responsible for ATF3 induction, such as ATM and Nibrin 1, JNK and NF-kB, in a p53-dependent or -independent manner. 3-5 Induction of ATF3 often correlates with cellular damage, suggesting an important role during the cellular stress response. 6 We have recently reported that the alteration of Egr-1 expression during ...

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Section: Resultsmentioning

confidence: 99%

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

et al. 2009

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“…5 During development, KIAA0101 protein expression is highly restricted in a spatiotemporal manner in mouse embryos, whereas it shows aberrant expression in various cancers, such as breast, uterine cervix, brain, kidney, hepatic, lung, esophageal, and colon cancers. 6,7 However, not all of the clinical studies on KIAA0101 have supported the conclusion that KIAA0101 functions as an oncogene in tumor progression, 6,8 perhaps because some functions of the KIAA0101 protein are related to DNA repair; alteration of the latter activity is usually associated with tumorigenesis, but gaining functions of DNA repair will promote tumor progression and resistance to cisplatin-based chemotherapy. 9 During cancer development, the lack of KIAA0101 activity alters chromosome instability, for example, changes in gene copy number are noted.…”

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confidence: 99%

Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro

Cheng

Diao

et al. 2013

Laboratory Investigation

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The KIAA0101 protein is overexpressed in various human cancers, including esophageal cancer (EC). This study assessed the association of KIAA0101 protein with prognosis and resistance to chemotherapy in EC patients and then explored the role of KIAA0101 in EC cells in vitro. A total of 228 EC patients participated in the study. Tissue samples were collected for immunohistochemical analysis of KIAA0101 expression in tumor and normal tissues for association with clinicopathological and survival data. KIAA0101 cDNA or shRNA were transfected into EC cells for assessment of tumor cell viability, sensitivity to cisplatin treatment, and gene expression. Array-based comparative genomic hybridization (aCGH) was used to detect the changed copy-number alterations in cell lines expressing different levels of KIAA0101. Expression of KIAA0101 protein was upregulated in EC tissues, which was associated with pTNM stage, resistance to chemotherapy, tumor recurrence, and poor survival of EC patients. In vitro experiments showed that expression of KIAA0101 enhanced cell proliferation and upregulated cyclins A and B expression, leading to a reduced G1 phase of the cell cycle. KIAA0101 also induced resistance of EC Eca-109 and TE-1 cell lines to cisplatin treatment through a decrease in apoptosis. The aCGH data showed that levels of KIAA0101 expression altered chromosome stability, affecting genes that are associated with cancer progression. In conclusion, upregulated KIAA0101 expression is associated with EC progression, resistance to chemotherapy, and poor survival of the patients.

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“…Only 27 PDTC have been evaluated by comparative genomic hybridisation (CGH) analysis, and as far as we are aware, there are no microarray studies on this entity (Wreesmann et al, 2002;Rodrigues et al, 2004). In ATC, it was demonstrated that TP53 (Wynford- Thomas, 1997) and b-catenin (Garcia-Rostan et al, 1999) mutations as well as the overexpression of OEATC1 (Mizutani et al, 2005) and AURKB (Sorrentino et al, 2005) were associated with ATC phenotype. These genes were demonstrated to be key effectors in anaplastic transformation, being responsible for evasion to apoptosis, enhanced tumour growth and replicative potential.…”

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confidence: 99%

Poorly differentiated and anaplastic thyroid carcinomas: chromosomal and oligo-array profile of five new cell lines

Rodrigues

Roque

Krug³

et al. 2007

Br J Cancer

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Information on gene alterations associated to poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) is scarce. Using human cancer cell lines as a tool for gene discovery, we performed a cytogenetic and oligo-array analysis in five new cell lines derived from two PDTC and three ATC. In PDTC we evidenced, as important, the involvement of the MAPK/ERK kinase pathway, and downregulation of a group of suppressor genes that include E-cadherin. In ATC, downregulation of a specific group of oncosuppressor genes was also observed. Our ATC cell lines presented chromosomal markers of gene amplification, and we were able to identify for the first time the nature of the involved amplicon target genes. We found that the main molecular differences between the two cell line types were related to signal transduction pathways, cell adhesion and motility process. TaqMan experiments performed for five amplicon target genes and for two genes, which allowed a clear distinction between ATC and PDTC: CDH13 and PLAU corroborated array results, not only in the cell lines, but also in an additional set of primary 14 PDTC and three ATC. We suggest that our findings may represent new tools for the development of more effective therapies to the hitherto untreatable ATC. Thyroid malignant neoplasms of follicular cell origin are classified into four main categories: the differentiated papillary (PTC) and follicular (FTC) carcinomas, the poorly differentiated (PDTC) and the undifferentiated or anaplastic (ATC) carcinomas. The differentiated forms are the most common. Poorly differentiated thyroid carcinomas and ATC account for only 5 -10% of the follicular malignancies; however, although rare, they represent a major challenge in oncology as they have a high morbidity and mortality rate (DeLelllis and Williams, 2004).In recent years some progress has been obtained in the identification of the genomic changes associated to the pathogenesis of DTC. In PTC, it is now clear that, in a substantially fraction of tumours, malignant transformation takes place through the constitutive activation of effectors along the MAPK/ERK kinase pathway (Mellilo et al, 2005), and in FTC, the PAX8/PPRAg fusion gene was determined to be an important event in the development of a subset of these carcinomas (Lacroix et al, 2005). At variance, the genetic information concerning PDTC and ATC is very limited. Only 27 PDTC have been evaluated by comparative genomic hybridisation (CGH) analysis, and as far as we are aware, there are no microarray studies on this entity (Wreesmann et al, 2002;Rodrigues et al, 2004). In ATC, it was demonstrated that TP53 (Wynford-Thomas, 1997) and b-catenin (Garcia-Rostan et al, 1999) mutations as well as the overexpression of OEATC1 (Mizutani et al, 2005) and AURKB (Sorrentino et al, 2005) were associated with ATC phenotype. These genes were demonstrated to be key effectors in anaplastic transformation, being responsible for evasion to apoptosis, enhanced tumour growth and replicative potential. However, although all efforts ma...

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Overexpressed in anaplastic thyroid carcinoma‐1 (OEATC‐1) as a novel gene responsible for anaplastic thyroid carcinoma

Cited by 49 publications

References 11 publications

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress

Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro

Poorly differentiated and anaplastic thyroid carcinomas: chromosomal and oligo-array profile of five new cell lines

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