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Huang J.,Shanghai JiaoTong University | Huang J.,Chinese National Human Genome Center at Shanghai | Zheng D.-L.,Shanghai JiaoTong University | Zheng D.-L.,Chinese National Human Genome Center at Shanghai | And 11 more authors.
Journal of Clinical Investigation | Year: 2010

The epigenetic silencing of tumor suppressor genes is a crucial event during carcinogenesis and metastasis. Here, in a human genome-wide survey, we identified scavenger receptor class A, member 5 (SCARA5) as a candidate tumor suppressor gene located on chromosome 8p. We found that SCARA5 expression was frequently downregulated as a result of promoter hypermethylation and allelic imbalance and was associated with vascular invasion in human hepatocellular carcinoma (HCC). Furthermore, SCARA5 knockdown via RNAi markedly enhanced HCC cell growth in vitro, colony formation in soft agar, and invasiveness, tumorigenicity, and lung metastasis in vivo. By contrast, SCARA5 overexpression suppressed these malignant behaviors. Interestingly, SCARA5 was found to physically associate with focal adhesion kinase (FAK) and inhibit the tyrosine phosphorylation cascade of the FAK-Src-Cas signaling pathway. Conversely, silencing SCARA5 stimulated the signaling pathway via increased phosphorylation of certain tyrosine residues of FAK, Src, and p130Cas; it was also associated with activation of MMP9, a tumor metastasis-associated enzyme. Taken together, these data suggest that the plasma membrane protein SCARA5 can contribute to HCC tumorigenesis and metastasis via activation of the FAK signaling pathway.

Li T.,Peking University | Li T.,Tsinghua University | Wan B.,Chinese National Human Genome Center at Shanghai | Huang J.,National Engineering Center for Biochip at Shanghai | Zhang X.,Tsinghua University
Molecular Genetics and Genomics | Year: 2010

Proliferation of liver cells can be observed in hepatocarcinogenesis, at diVerent stages of liver development, and during liver regeneration after an injury. Does it imply that they share similar molecular mechanisms? Here, the transcriptional proWles of hepatocellular carcinoma (HCC), liver development, and liver regeneration were systematically compared as a preliminary attempt to answer this question. From the comparison, we found that advanced HCC mimics early development in terms of deprived normal liver functions and activated cellular proliferation, but advanced HCC and early development diVer in expressions of cancer-related genes and their transcriptional controls. HCC and liver regeneration demonstrate diVerent expression patterns as a whole, but regeneration is similar to dysplasia (pre-stage of HCC) in terms of their proximity to the normal state. In summary, of these three important processes, the carcinogenic progress carries the highest variance in expression; HCC pre-stage shares some resemblance with liver regeneration; and advanced HCC stage displays similarity with early development. © Springer-Verlag 2010.

Li D.,Chongqing Cancer Institute | Zhou Q.,Chongqing Cancer Institute | Liu Y.,Chongqing Cancer Institute | Yang Y.,National Engineering Center for Biochip at Shanghai | Li Q.,Chongqing Cancer Institute
Medical Oncology | Year: 2012

This study aimed to investigate association between single-nucleotide polymorphisms (SNPs) of excision repair cross-complementing gene 1 (ERCC1), excision repair cross-complementing gene 2 (ERCC2), and X-ray repair cross-complementing group 1 (XRCC1) with sensitivity of advanced non-small cell lung cancer (NSCLC) patients to platinum-based chemotherapy. A total of 89 NSCLC patients were recruited and treated with two cycles of platinum-based chemotherapy. DNA was extracted from peripheral lymphocytes for detection of SNPs of ERCC1 Asn118Asn, ERCC2 Lys751Gln, and XRCC1 Arg399Gln. The overall response rate of these patients was 29.2%. There was no statistically significant difference of treatment response between the wild genotypes and the variant genotypes for the ERCC1 Asn118Asn and ERCC2 Lys751Gln gene. The distributions of genotypes XRCC1 Arg399Gln differed significantly between the response and non-response groups (76.9 vs. 23.1%, P = 0.001). The XRCC1 399Arg/Arg genotype carriers had a higher response rate than that of the Gln genotype carriers (OR = 4.81, 95%CI = 1.778-13.013, P = 0.002). The combination of the favorable genotypes of ERCC1, ERCC2, and XRCC1 had a higher response rate compared to that of patients with other genotypes. The combined polymorphisms of ERCC1, ERCC2, and XRCC1 may be associated with sensitivity of NSCLC to platinum-based chemotherapy. Further studies will verify these SNPs as biomarkers for prediction of platinum-based chemotherapy responses of NSCLC patients. © Springer Science+Business Media, LLC 2011.

Yu H.,Taizhou Peoples Hospital | Duan B.,Tongji University | Jiang L.,Taizhou Peoples Hospital | Lin M.,Taizhou Peoples Hospital | And 6 more authors.
American Journal of Translational Research | Year: 2014

MicroRNA-200c (miR-200c) influences sensitivity to chemotherapy and radiotherapy in vitro. This study was designed to investigate the prognostic potential of serum miR-200c in patients with advanced esophageal squamous cancer (ESCC). The serum levels of miR-200c was assayed by quantitative RT-PCR in 157 healthy subjects and 157 patients with advanced ESCC who were treated with platinum-based chemotherapy. The serum levels of miR-200c in advanced ESCC patients was significantly increased compared with those in controls (P < 0.001). Serum miR-200c expression was significantly associated with TNM stage (P = 0.037) and treatment response (P = 0.021). Patients with high expression of serum miR-200c had a higher risk for death than those with low expression of serum miR-200c (adjusted hazard ratios = 1.665, 95% confidence intervals: 1.135-2.443, P = 0.009). In conclusion, serum miR-200c may serve as predictor of survival for advanced ESCC and provide information for personalized therapy in advanced ESCC.

Fei T.,Tsinghua University | Xia K.,CAS Institute of Genetics and Developmental Biology | Li Z.,Tsinghua University | Zhou B.,CAS Institute of Genetics and Developmental Biology | And 7 more authors.
Genome Research | Year: 2010

Embryonic stem (ES) cells are under precise control of both intrinsic self-renewal gene regulatory network and extrinsic growth factor-triggered signaling cascades. How external signaling pathways connect to core self-renewal transcriptional circuits is largely unknown. To probe this, we chose BMP signaling, which is previously recognized as a master control for both self-renewal and lineage commitment of murine ES cells. Here, we mapped target gene promoter occupancy of SMAD1/5 and SMAD4 on a genome-wide scale and found that they associate with a large group of developmental regulators that are enriched for H3K27 trimethylation and H3K4 trimethylation bivalent marks and are repressed in the self-renewing state, whereas they are rapidly induced upon differentiation. Smad knockdown experiments further indicate that SMAD-mediated BMP signaling is largely required for differentiation-related processes rather than directly influencing self-renewal. Among the SMAD-associated genes, we further identified Dpysl2 (previously known as Crmp2) and the H3K27 demethylase Kdm6b (previously known as Jmjd3) as BMP4-modulated early neural differentiation regulators. Combined with computational analysis, our results suggest that SMAD-mediated BMP signaling balances self-renewal versus differentiation by modulating a set of developmental regulators. © 2010 by Cold Spring Harbor Laboratory Press.

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