DEK蛋白在宫颈癌病因学中的意义研究

目的：检测DEK蛋白在正常宫颈、宫颈上皮内瘤变（CIN）及宫颈癌组织中的表达情况,探讨其在宫颈癌发病机制中的作用。方法：采用免疫组织化学方法检测DEK蛋白在35例宫颈癌组织,30例宫颈上皮内瘤变（CIN）及20例正常宫颈组织的表达情况,分析DEK蛋白的表达与宫颈癌发生的关系。结果：宫颈癌组织中DEK蛋白表达率（74．3％）高于宫颈上皮内瘤变组织（23．3％）和正常组织（15．0％）,差异具有显著性意义（P〈0．05）,宫颈上皮内瘤变组织和正常组织,二者无统计学意义（P〉0．05）。结论：DEK蛋白在宫颈癌中表达升高,可能与宫颈癌的发生有关,DEK蛋白可作为宫颈癌病因学的一个新指标。     

癌基因DEK和转录因子AP-2α协同促进乳腺癌中HER2的高表达

目的探讨癌基因DEK与转录因子AP-2α在乳腺癌变中的相互作用及在HER2过量表达、乳腺癌变中的病理学意义。方法用Western blot检测组织中DEK、AP-2α和HER2蛋白水平之间的相关性;免疫共沉淀检测DEK和AP-2α在MDA-MB-453乳腺癌细胞中的相互作用;通过siRNA抑制MDA-MB-453细胞中DEK和AP-2α的表达,用半定量RT-PCR和Western blot检测HER2的表达。结果乳腺癌组织中DEK、AP-2α和HER2的蛋白水平之间显示一定的相关性,DEK和AP-2α在MDA-MB-453细胞内有相互作用,siRNA抑制DEK和AP-2α的表达可协同抑制MDA-MB-453细胞中HER2mRNA和蛋白的表达。结论癌基因DEK和转录因子AP-2α协同促进乳腺癌中HER2的高表达。     

Distribution of the chromatin protein DEK distinguishes active and inactive CD21/CR2 gene in pre- and mature B lymphocytes

DEK is an abundant and ubiquitous chromatin protein that has only recently attracted attention. DEK preferentially binds to cruciform and superhelical DNA and induces positive supercoils into closed circular DNA. It is quite likely therefore that DEK performs an important architectural function in chromatin. However, it is not known how DEK is distributed in chromatin. As the first study of its kind, we investigate the distribution of DEK at the CD21/complement receptor 2 gene regulatory regions in two B lymphocyte lines, namely Ramos, which expresses the CD21 gene, and Nalm-6, which does not. We use a chromatin immunoprecipitation approach and show that DEK appears to be distributed over various regions of the expressed and silent genes, but occurs in 2- to 3-fold higher amounts at a promoter-proximal site of the expressed gene. Moreover, induction of CD21 expression in Nalm-6 cells leads to accumulation of DEK at this site. We propose that the accumulation of DEK is functionally linked to gene expression.     

Expression and significance of tumor-related genes in HCC

AIM: To investigate the expression and clinical significance of DEK, cyclin D1, insulin-like growth factor Ⅱ (IGF-Ⅱ), glypican 3 (GPC3), ribosomal phosphoprotein 0 (rpPO) mRNA in hepatocellular carcinoma (HCC) and its paraneoplastic tissues. METHODS: The expression of mRNAs of DEK, cyclin D1, IGF-Ⅱ, GPC3 and rpP0 mRNA was detected in HCC and its paraneoplastic tissues by multiplex RT-PCR. RESULTS: By the simplex RT-PCR, the overexpression of mRNAs of DEK, cyclin D1, IGF-Ⅱ, GPC3, rpP0 mRNA in HCC and its paraneoplastic tissues was 78.1%, 87.5%, 87.5%, 75.0%, 81.3% and 15.6%, 40.6%, 37.5%, 21.9%, 31.3% respectively (P<0.05). By the multiplex RT-PCR, at least one of the mRNAs was detected in all HCC samples and in 75.0% of paraneoplastic samples (P>0.05). However, all these five mRNAs were found in 68.8% of HCC samples, but only in 9.4% of paraneoplastic tissues (P<0.05). The positive expression of mRNAs of DEK, cyclin D1, IGF-Ⅱ, GPC3, rpP0 in well- and poorly-differentiated HCC was 89.0%, 66.7%, 66.7%, 66.7%, 77.8% and 73.9%, 95.7%, 95.7%, 95.7%, 82.6%, respectively (P>0.05). The expression of these genes in HCCs with α-feto protein (AFP) negative and positive was 90.0%, 80.0%, 90.0%, 90.0%, 90.0% and 72.7%, 86.3%, 77.3%, 90.9%, 68.2% respectively (P>0.05). CONCLUSION: The expression of DEK, cyclin D1, IGF-Ⅱ, GPC3, rpP0 mRNA in HCC is much higher in HCC than in its paraneoplastic tissues. Multiplex RT-PCR assay is an effective, sensitive, accurate, and cost-effective diagnostic method of HCC.     

Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC.     

DEK expression in melanocytic lesions

The diagnosis of malignant melanoma presents a clinical challenge and relies principally on histopathological evaluation. Previous studies have indicated that increased expression of the DEK oncogene, a chromatin-bound factor, could contribute to the development of melanoma and may be a frequent event in melanoma progression. Here, we investigated DEK expression by immunohistochemistry in a total of 147 melanocytic lesions, including ordinary nevi, dysplastic nevi, Spitz nevi, melanoma in situ, primary invasive melanomas, and metastatic melanomas. Most benign nevi (ordinary, dysplastic, and Spitz nevi) were negative or exhibited weak staining for DEK, with only 4 of 49 cases showing strong staining. Similar to benign nevi, melanoma in situ also demonstrated low levels of DEK expression. In contrast, the expression of DEK in primary invasive melanomas was significantly higher than benign nevi (P < .0001). Moreover, DEK expression was significantly increased in deep melanomas (Breslow depth >1 mm) and metastatic melanomas as compared with superficial melanomas (Breslow depth ≤1 mm) (P < .05). Our findings indicate that DEK overexpression may be a frequent event in invasive melanomas, and further augmentation of DEK expression may be associated with the acquisition of ominous features such as deep dermal invasion and metastasis. These data suggest a role of DEK in melanoma progression.     

DEK overexpression in uterine cervical cancers

The purpose of the present paper was to investigate the significance of DEK protein expression in uterine cervical lesions and its relationship with HPV infection status. DEK protein expression was studied in 253 cervical lesions, including 30 non-neoplastic cervix with or without squamous metaplasia, 64 cervical intra-epithelial neoplasias (CIN; CIN-1, n  = 28; CIN-2, n  = 17; CIN-3, n  = 19), 102 squamous cell carcinomas (SCC), 51 adenocarcinomas, and six adenosquamous cell carcinomas (adenoSCC) on immunohistochemistry. For comparison, HPV-positive and -negative cervical cancer cell lines were also included. The HPV screening was performed using TaKaRa polymerase chain reaction. On immunohistochemistry DEK was found to be negative in all 30 non-neoplastic cervical epithelia, but it was positive in 96.1% of SCC (98/102), 92.2% of adenocarcinomas (47/51), 100% of adenoSCC (6/6), 85.7% of CIN-1 (24/28), 94.1% of CIN-2 (16/17), and 89.5% of CIN-3 (17/19). There was no significant difference between HPV-positive and -negative cervical lesions. Also, strongly positive staining was observed in all aforementioned cervical cancer cell lines regardless of HPV infection, according to immunocytochemistry. In summary, DEK plays an important role in the carcinogenesis of cervical cancers, and can be helpful for early diagnosis, and is a potential therapeutic target.