Entity

Time filter

Source Type


Ning B.-F.,Shanghai Changzheng Hospital | Ding J.,Eastern Hepatobiliary Surgery Institute | Yin C.,Shanghai Changzheng Hospital | Zhong W.,Shanghai Changzheng Hospital | And 10 more authors.
Cancer Research | Year: 2010

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function, but its role in hepatocarcinogenesis has yet to be examined. Here, we report evidence of a suppressor role for HNF4α in liver cancer. HNF4α expression was progressively decreased in the diethylinitrosamine- induced rat model of liver carcinogenesis. In human liver tissues, HNF4α expression was decreased in cirrhotic tissue and further decreased in hepatocarcinoma relative to healthy tissue. Notably, an inverse correlation existed with epithelial-mesenchymal transition (EMT). Enforced expression of HNF4α attenuated hepatocyte EMT during hepatocarcinogenesis, alleviated hepatic fibrosis, and blocked hepatocellular carcinoma (HCC) occurrence. In parallel, stem cell marker gene expression was inhibited along with cancer stem/progenitor cell generation. Further, enforced expression of HNF4α inhibited activation of β-catenin, which is closely associated with EMT and hepatocarcinogenesis. Taken together, our results suggest that the inhibitory effect of HNF4α on HCC development might be attributed to suppression of hepatocyte EMT and cancer stem cell generation through an inhibition of β-catenin signaling pathways. More generally, our findings broaden knowledge on the biological significance of HNF4α in HCC development, and they imply novel strategies for HCC prevention through the manipulation of differentiation-determining transcription factors in various types of carcinomas. ©2010 AACR. Source


Qin H.-D.,Sun Yat Sen University | Shugart Y.Y.,National Institute of Mental Health | Bei J.-X.,Sun Yat Sen University | Pan Q.-H.,Sun Yat Sen University | And 8 more authors.
Cancer Research | Year: 2011

DNA repair plays a central role in protecting against environmental carcinogenesis, and genetic variants of DNA repair genes have been reported to be associated with several human malignancies. To assess whether DNA gene variants were associated with nasopharyngeal carcinoma (NPC) risk, a candidate gene association study was conducted among the Cantonese population within the Guangdong Province, China, the ethnic group with the highest risk for NPC. A 2-stage study design was utilized. In the discovery stage, 676 tagging SNPs covering 88 DNA repair genes were genotyped in a matched case-control study (cases/controls = 755/ 755). Eleven SNPs with Ptrend < 0.01 were identified. Seven of these SNPs were located within 3 genes, RAD51L1, BRCA2, and TP53BP1. In the validation stage, these 11 SNPs were genotyped in a separate Cantonese population (cases/controls = 1,568/1,297). Two of the SNPs (rs927220 and rs11158728), both in RAD51L1, remained strongly associated with NPC. The SNP rs927220 had a significant Pcombined of 5.55 × 10-5, with OR = 1.20 (95% CI = 1.10-1.30), Bonferroni corrected P = 0.0381. The other SNP (rs11158728), which is in strong linkage disequilibrium with rs927220 (r 2= 0.7), had a significant Pcombined of 2.0 × 10-4, Bonferroni corrected P = 0.1372. Gene-environment interaction analysis suggested that the exposures of salted fish consumption and cigarette smoking had potential interactions with DNA repair gene variations, but need to be further investigated. Our findings support the notion that DNA repair genes, in particular RAD51L1, play a role in NPC etiology and development. © 2011 American Association for Cancer Research. Source


Jin W.,CAS Shanghai Institutes for Biological Sciences | Xu S.,CAS Shanghai Institutes for Biological Sciences | Wang H.,Chinese National Human Genome Center | Yu Y.,Shanghai JiaoTong University | And 6 more authors.
Genome Research | Year: 2012

It is particularly meaningful to investigate natural selection in African Americans (AfA) due to the high mortality their African ancestry has experienced in history. In this study, we examined 491,526 autosomal single nucleotide polymorphisms (SNPs) genotyped in 5210 individuals and conducted a genome-wide search for selection signals in 1890 AfA. Several genomic regions showing an excess of African or European ancestry, which were considered the footprints of selection since population admixture, were detected based on a commonly used approach. However, we also developed a new strategy to detect natural selection both pre- and post-admixture by reconstructing an ancestral African population (AAF) from inferred African components of ancestry in AfA and comparing it with indigenous African populations (IAF). Interestingly, many selection-candidate genes identified by the new approach were associated with AfA-specific high-risk diseases such as prostate cancer and hypertension, suggesting an important role these disease-related genes might have played in adapting to a new environment. CD36 and HBB, whose mutations confer a degree of protection against malaria, were also located in the highly differentiated regions between AAF and IAF. Further analysis showed that the frequencies of alleles protecting against malaria in AAF were lower than those in IAF, which is consistent with the relaxed selection pressure of malaria in the New World. There is no overlap between the top candidate genes detected by the two approaches, indicating the different environmental pressures AfA experienced pre- and post-population admixture. We suggest that the new approach is reasonably powerful and can also be applied to other admixed populations such as Latinos and Uyghurs. © 2012 by Cold Spring Harbor Laboratory Press. Source


Cheng J.,Shanghai JiaoTong University | Tian L.,Shanghai JiaoTong University | Ma J.,Shanghai JiaoTong University | Gong Y.,Shanghai JiaoTong University | And 6 more authors.
Molecular Oncology | Year: 2015

Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an invitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed using a pan PKC inhibitor GF109203x and a specific PKCδ inhibitor, rottlerin. Additionally, we found significantly increased phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK1/2) in the irradiated Panc1 cells. Mechanistically, PKCδ cleavage was attenuated in both DN_C3 and DN_C7 transduced Panc1 cells, and both Akt and p38 MAPK phosphorylation were attenuated in DN_PKCδ transduced Panc1 cells following radiation. Thus, this report suggests a novel finding that cellular signaling caspase 3/7-PKCδ-Akt/p38 MAPK is crucial to the repopulation in Panc1 cells after radiotherapy. © 2014 Federation of European Biochemical Societies. Source


Fan J.,Shanghai JiaoTong University | Zhang Y.,Shanghai JiaoTong University | Xiong H.,Chinese National Human Genome Center | Wang Y.,Shanghai JiaoTong University | Guo X.,Shanghai JiaoTong University
Journal of General Virology | Year: 2015

Chronic hepatitis B (CHB) is treated with nucleos(t)ide analogues (NAs). The reverse transcriptase (RT) region in the hepatitis B virus (HBV) genome mutates to resist NA treatment, yet the RT mutations have not been well characterized. Furthermore, the HBV genotype might influence RT sequence evolution, NA resistance (NAr) mutation patterns and drug resistance development. We examined 42 NAr mutation sites in 169 untreated and 131 NA-treated CHB patient samples. Patients were identified with HBV-B and HBV-C genotype infections, with a higher prevalence and mutation frequency of HBV-C than HBV-B. Seventeen reported NAr mutation sites and 13 novel mutations were detected. NAr-related mutation prevalence was significantly higher in NA-treated versus untreated patients. Primary antiviral-resistant mutants only existed in NA-treated patients. Sequencing data revealed seven HBV-C-specific mutations and three HBV-B-specific mutations. In conclusion, NA treatment and HBV genotype might constitute the selection basis and promote NA-resistant HBV strain evolution under antiviral therapy. © 2015 The Authors. Source

Discover hidden collaborations