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ABSTRACT: Inappropriate gene silencing and subsequent promiscuous activity define the transformation of many solid tumours including renal cell carcinoma (RCC). Here, we report that UNC5C, one of the Netrin-1 receptors, was frequently inactivated in RCC cell lines and primary tumours. UNC5C protein was expressed in the proximal convoluted tubules of the human kidney, the presumed origin of clear cell RCC (ccRCC) and papillary RCC (pRCC). Compared to paired adjacent non-malignant tissues, both UNC5C mRNA and protein expression were significantly down-regulated in RCC. Immunohistochemical analysis showed that UNC5C was inactivated in 94.3% of the samples and the loss of UNC5C occurred at the early stage of RCC. Methylation specific PCR showed that UNC5C promoter was methylated in two renal carcinoma cell lines. Pharmacologic demethylation alone or in combination with inhibition of deacetylation dramatically induced UNC5C expression. Furthermore, bisulfite genomic sequencing (BGS) confirmed that dense methylation existed in UNC5C promoter. In paired tumour samples, UNC5C methylation was observed in 12 out of 44 patients (27.3%). Moreover, we analysed the loss of heterozygosity (LOH) of UNC5C in renal cell carcinoma, the LOH was observed in 27 out of 44 patients (61.4%). Finally, restoration of UNC5C expression suppressed the colony formation of renal carcinoma cells. In addition, UNC5C inhibited tumour cell proliferation, migration and enhanced chemosensitivity to cisplatin and etoposide. Therefore, UNC5C acts as a tumour suppressor in RCC and is down-regulated in RCC. Loss of heterozygosity and DNA methylation contribute to the inactivation of UNC5C in renal cell carcinoma.
European journal of cancer (Oxford, England: 1990) 05/2011; 47(13):2068-76. · 4.12 Impact Factor
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Baoxi Wang,
Wei Yang,
Wen Wen,
Jing Sun,
Bin Su,
Bo Liu,
Donglai Ma, Dan Lv,
Yaran Wen,
Tao Qu,
Min Chen,
Miao Sun,
Yan Shen,
Xue Zhang
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ABSTRACT: Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic, recurrent, inflammatory disease of hair follicles that often runs in families. We studied six Chinese families with features of AI as well as additional skin lesions on back, face, nape, and waist and found independent loss-of-function mutations in PSENEN, PSEN1, or NCSTN, the genes encoding essential components of the γ-secretase multiprotein complex. Our results identify the γ-secretase component genes as the culprits for a subset of familial AI, implicate the γ-secretase-Notch pathway in the molecular pathogenesis of AI, and demonstrate that familial AI can be an allelic disorder of early-onset familial Alzheimer's disease.
Science 10/2010; 330(6007):1065. · 31.20 Impact Factor
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ABSTRACT: Familial dilated cardiomyopathy (FDCM) is caused by defective genes and specific medicines are not currently available to treat this. Ginsenoside-Rb1 provides cardioprotection in the experimental models of myocardial ischemia-reperfusion injury. Here we investigate Rb1's effect on DCM in cTnT(R141W) transgenic mouse. The transgene-positive mice aged 2 months were randomized into the model group and Rb1 [70 mg/(kg.day)] group; transgene-negative mice were used as a control. After 4-month treatment, cardiac function was assessed by echocardiography; cardiac tissues were prepared for histology and electron microscopy. Expression levels of molecular markers of cardiac hypertrophy, fibrosis, and intercalated disc proteins were detected by RT-PCR. Rb1 significantly decreased mortality, chamber dilation, and contractile dysfunction in cTnT(R141W) mice. Rb1 attenuated cardiac hypertrophy, interstitial fibrosis, ultrastructural degeneration, and intercalated disc remodeling in DCM hearts. Western blotting showed that Rb1 significantly decreased heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression and signal transduction and activators of transcription 3 (STAT3) activation, which were gradually increased in DCM hearts. Our results showed that Rb1 clearly alleviated cardiac dysfunction and remodeling in the cTnT(R141W) transgenic mouse, indicating its potential utility in the treatment of FDCM.
Journal of Pharmacological Sciences 01/2010; 112(2):214-22. · 2.08 Impact Factor
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Miao Sun,
Ning Li,
Wu Dong,
Zugen Chen,
Qing Liu,
Yiming Xu,
Guang He,
Yongyong Shi,
Xin Li,
Jiajie Hao, [......],
Yaran Wen,
Lihua Cao,
Alan D Irvine,
W H Irwin McLean,
Qi Dong,
Ming-Rong Wang,
Jun Yu,
Lin He,
Wilson H Y Lo,
Xue Zhang
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ABSTRACT: Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.
The American Journal of Human Genetics 07/2009; 84(6):807-13. · 10.60 Impact Factor
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ABSTRACT: Mutations in ROR2, encoding the receptor tyrosine kinase-like orphan receptor 2, cause two distinct skeletal diseases: autosomal dominant brachydactyly type B1 (BDB1) and autosomal recessive Robinow syndrome. In a large Chinese family with a limb phenotype, consisting of atypical BDB1 and cutaneous syndactyly of varying degrees, we performed a two-point linkage analysis using microsatellite markers on 2q33-q37 and 9q22.31, and found a significant linkage to the ROR2 locus. We identified a novel single-base deletion in ROR2, c.2243delC (p.W749fsX24), and confirmed its segregation with the limb phenotype in the family. This deletion is predicted to produce a truncated ROR2 protein with an additional C-terminal polypeptide of 24 amino-acid residues. To the best of our knowledge, the deletion represents the second ROR2 mutation associated with a BDB1-syndactyly phenotype.
Journal of Human Genetics 06/2009; 54(7):422-5. · 2.57 Impact Factor
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ABSTRACT: By dimerizing with E2F proteins, TFDP has profound influence on cellular E2F activities. While TFDP1 and 2 enhance the DNA binding and the transcriptional activity of E2F, the newly identified member of the DP family, TFDP3 primarily functions as a negative regulator. To further characterize the inhibitory property of TFDP3, the present study specifically examined the modulatory role of TFDP3 on E2F1-induced cell death. HEK-293 cells underwent apoptosis following ectopic expression of E2F1. This effect was virtually abolished by co-transfection with TFDP3. In the meantime, the accumulation of p53 proteins and the increased expression of the pro-apoptotic molecules, including Bax, Puma, Noxa, and Bid were found to be suppressed. These data suggest a new mechanism for the regulation of E2F1-induced apoptosis and provide further evidence for the general involvement of TFDP3 in the regulation of E2F functions.
Biochemical and Biophysical Research Communications 10/2007; 361(1):20-5. · 2.48 Impact Factor
