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Liu S.,Central South University | Tao Y.,Central South University | Tao Y.,Key Laboratory of Carcinogenesis and Cancer Invasion | Tao Y.,Key Laboratory of Carcinogenesis
Biological Reviews | Year: 2013

The dynamic interplay between chromatin modification (e.g. DNA methylation) and RNA polymerase II (Pol II) plays a critical role in gene transcription during stem cell development, establishment, and maintenance and in the cellular response to extracellular stimuli such as those that cause DNA damage. Pol II is recruited to the promoter-proximal regions of numerous inactive genes at high conentrations in a process called Pol II stalling. This is a key process prior to gene activation and it involves many interacting factors. Chromatin modification including nucleosome position is dependent on chromatin structure. Stalled genes create a particular structural conformation of chromatin, which acts as a target for chromatin modification. In this way, Pol II stalling may be regarded as a type of signal for chromatin modification in these regions during the dynamic transition between stalled and activated genes. © 2012 Cambridge Philosophical Society.


Tang H.,Central South University | Tang H.,Center for Skull Base Surgery and Neurooncology | Tang H.,Key Laboratory of Carcinogenesis and Cancer Invasion | Biana Y.,Central South University | And 13 more authors.
Current Cancer Drug Targets | Year: 2013

Many microRNAs reside in clusters in the genome, are generally similar in sequence, are transcribed in the same direction, and usually function synergistically. The miR-183/96/182 cluster is composed of 3 miRNA genes, and increased expression of miR-183, 96 and 182 are implicated in glioma carcinogenesis. Knockdown of individual components or of the entire miR-183/96/182 cluster inhibits the survival of glioma cells by regulating the ROS-induced apoptosis pathway. Furthermore, inhibition of the miR-183/96/182 cluster induced ROS-mediated AKT/survival independent of three target genes FGF9, CPEB1, and FOXO1, and inhibition of the miRNA cluster induced p53/apoptosis signaling, which was dependent on these same genes. In addition, knockdown of the miR-183/96/182 cluster enhanced the anticancer effect of Temozolomide on glioma cells by the ROS-mediated apoptosis pathway. Therefore, the miR- 183/96/182 cluster may be a pleiotropic target for glioma therapy. © 2013 Bentham Science Publishers.


Jiang Y.,Central South University | Jiang Y.,Key Laboratory of Carcinogenesis and Cancer Invasion | Jiang Y.,Key Laboratory of Carcinogenesis | Liu S.,Central South University | And 7 more authors.
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2013

DNA methylation plays an important role in the regulation of gene expression, as it is the first epigenetic modification to take place on a given DNA strand. Several factors may directly or indirectly regulate the dynamic distribution of DNA methylation and demethylation between intergenic and intragenic gene regions, thereby controlling gene expression. CpG islands have direct implications for the understanding of DNA methylation patterns in normal conditions and in some common disease states, including cancer. Here, we summarize several recent studies on the genome-wide distribution of DNA methylation and demethylation and their related factors, and we discuss the potential of DNA methylation and demethylation patterns to contribute to gene transcription patterns in tumorigenesis. © 2012.


Hu Z.-Y.,Central South University | Hu Z.-Y.,Key Laboratory of Carcinogenesis and Cancer Invasion | Hu Z.-Y.,Key Laboratory of Carcinogenesis | Hu Z.-Y.,First Hospital of Changsha City | And 8 more authors.
Journal of Molecular Medicine | Year: 2014

Nearly a hundred years of scientific research has revealed a notable preference of cancer cells to utilize aerobic glycolysis rather than mitochondrial oxidative phosphorylation for glucose-dependent ATP production, which is thought to be the root of tumor formation and growth. Glycolysis is a complex biochemical process that is mediated by multiple glycolytic genes. Besides regulating glucose metabolism, these genes are also suggested to possess various other functions related to cancer, including roles in cancer development and promotion, inhibition of apoptosis, cell cycle progression, and tumor metastasis. This article highlights the biological functions of glycolytic genes beyond their role in regulation of glycolysis and discusses their clinical implications, especially in regard to the use of glycolytic genes as biomarkers for early detection of cancer or as targets for novel anticancer treatments. © 2014 Springer-Verlag.


Yang X.,Fudan University | Yang X.,Key Laboratory of Carcinogenesis and Cancer Invasion | Zhang X.-F.,Fudan University | Zhang X.-F.,Key Laboratory of Carcinogenesis and Cancer Invasion | And 12 more authors.
Hepatology | Year: 2014

MicroRNA (miR)-26a can suppress tumor growth and metastasis of hepatocellular carcinoma (HCC). Since angiogenesis is important for tumor growth and metastasis, we investigated the possible roles of miR-26a in tumor angiogenesis. Down-regulation of miR-26a was found to correlate with an increased angiogenic potential of HCC. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit vascular endothelial growth factor A (VEGFA) expression in HCC cells and then suppress the promoting effects of HCC cells on in vitro proliferation, migration, and capillary tube formation of endothelial cells, as well as in vivo tumor angiogenesis of HCC. Hepatocyte growth factor (HGF) was identified as a target of miR-26a. HGF simulation antagonized the effects induced by miR-26a up-regulation. In contrast, silencing HGF induced similar effects to miR-26a. We further found that miR-26a exerted its antiangiogenesis function, at least in part, by inhibiting HGF-hepatocyte growth factor receptor (cMet) and its downstream signaling pathway, in turn, suppressing VEGFA production in HCC cells and impairing VEGFR2-signaling in endothelial cells. HCC patients who had high miR-26a, low HGF, low VEGFA, or low microvessel density (MVD) in tumor tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, or in combination with HGF, was demonstrated to be an independent prognostic indicator for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor angiogenesis of HCC through HGF-cMet signaling, and it is a new hopeful therapeutic target and prognostic marker for HCC. © 2014 by the American Association for the Study of Liver Diseases.


Zhou Z.-J.,Fudan University | Zhou Z.-J.,Key Laboratory of Carcinogenesis and Cancer Invasion | Dai Z.,Fudan University | Dai Z.,Key Laboratory of Carcinogenesis and Cancer Invasion | And 20 more authors.
Cancer Research | Year: 2014

Expression of heterogeneous nuclear ribonucleoprotein AB (HNRNPAB) has been reported to be dysregulated in tumors, but its specific contributions to tumor formation and progression are not fully understood. Here, we demonstrate that HNRNPAB is overexpressed in highly metastatic cells and tumor tissues from patients with hepatocellular carcinoma (HCC) with recurrence. We found that HNRNPAB overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with HCC metastasis in vitro and in vivo. RNA interference-mediated silencing of the EMT factor SNAIL attenuated HNRNPAB-enhanced cell invasion in vitro and lung metastasis in vivo. Mechanistically, HNRNPAB acted to transactivate SNAIL1 transcription, which in turn inhibited transcription of the pivotal SNAIL target gene E-cadherin. Overexpression of HNRNPAB in HCC samples correlated with higher SNAIL levels, shorter overall survival, and higher tumor recurrence. HNRNPAB overexpression, alone or in combination with SNAIL, was found to be a significant independent risk factor for recurrence and survival after curative resection. In conclusion, our findings define HNRNPAB as an activator of EMT and metastasis in HCC that predicts poor clinical outcomes. Cancer Res; 74(10); 2750-62. © 2014 American Association for Cancer Research.


Zhou J.,Fudan University | Zhou J.,Key Laboratory of Carcinogenesis and Cancer Invasion | Shi Y.-H.,Fudan University | Shi Y.-H.,Key Laboratory of Carcinogenesis and Cancer Invasion | And 2 more authors.
Seminars in Oncology | Year: 2012

Hepatocellular carcinoma (HCC) is considered to be a fatal disease because of its late diagnosis, underlying liver disease, and refractoriness to systemic treatments. Biomarkers with high sensitivity and specificity that are minimally invasive, reproducible, and easily available have important clinical utility for early diagnosis, prognostication, and pharmacodynamics evaluation. Until now, most of the circulating HCC biomarkers used in clinical practice were protein molecules. However, these biomarkers often had low sensitivity and specificity. In the past decade, circulating cell-free nucleic acids (cfNAs) have been extensively studied. We review the studies that evaluated cfNAs as circulating HCC biomarkers and discuss recent advances with regard to their diagnostic and prognostic significance. © 2012 Elsevier Inc.


Xia Y.,Xuzhou Medical College | Chen R.,Fudan University | Chen R.,Key Laboratory of Carcinogenesis and Cancer Invasion | Ye S.-L.,Fudan University | And 7 more authors.
Clinical and Experimental Metastasis | Year: 2011

The stroma of hepatocellular carcinoma (HCC) is markedly infiltrated with activated hepatic stellate cells (HSCs), and associated invasion and metastasis of HCC. However, little is known of the role of HSCs in immune responses in HCC. The Buffalo rat HCC model was established. Quiescent HSCs (qHSCs) and intratumoral HSCs (tHSCs) were isolated. Surface molecules of tHSC were detected by flow cytometry, and gene expression was analyzed by fluorescence quantitative RT-PCR. T cell proliferation was monitored by [ 3H]- thymidine ( 3H-TdR) incorporation into DNA, and cytotoxic activity was assessed by measuring the release of 51Cr. The level of cytokine expression by T cells was measured by enzyme-linked immunosorbent assay. T cell apoptosis was detected by double-stained terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and anti-CD3 antibodies. The migration and invasion of HCC was observed by transwell experiments. tHSCs express low levels of major histocompatibility complex (MHC) class I, MHC class II, and costimulatory molecules, and produce varying levels of cytokines. Addition of the tHSCs suppressed thymidine uptake by T cells that were stimulated by alloantigens or by anti-CD3-mediated T-cell receptor ligation. The tHSC-induced T-cell hyporesponsiveness was associated with enhanced T-cell apoptosis, and contributed to the migration and invasion of hepatoma cell. tHSCs was associated with markedly enhanced expression of B7-H1. Blockade of B7-H1/PD-1 ligation significantly reduced HSC immunomodulatory activity, and hepatoma cell migration and invasion. tHSCs can induce T cell apoptosis, suggesting an important role for B7-H1. The interactions between tHSCs and T cells may contribute to hepatic immune tolerance and invasion and migration of HCC. © 2011 Springer Science+Business Media B.V.


Yang X.,Fudan University | Yang X.,Key Laboratory of Carcinogenesis and Cancer Invasion | Liang L.,Fudan University | Liang L.,Key Laboratory of Carcinogenesis and Cancer Invasion | And 27 more authors.
Hepatology | Year: 2013

Down-regulation of microRNA-26a (miR-26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR-26a up-regulation. Moreover, miR-26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The messenger RNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC. © 2013 American Association for the Study of Liver Diseases.


Dong Q.-Z.,Fudan University | Dong Q.-Z.,Key Laboratory of Carcinogenesis and Cancer Invasion | Zhang X.-F.,Fudan University | Zhang X.-F.,Key Laboratory of Carcinogenesis and Cancer Invasion | And 20 more authors.
Hepatology | Year: 2013

Osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, little is known about the impact of OPN polymorphisms on cancer progression. In this study, we first identified the single nucleotide polymorphisms (SNPs) in the OPN promoter region by direct sequencing in 30 HCCs, and then evaluated the prognostic values of the selected ones in two large cohorts of 826 HCC patients. The identified SNPs were functionally analyzed using in vitro and in vivo assays and their correlations with OPN levels were also evaluated. Only SNP at locus -443 and their related haplotypes (Ht2: -1748A/-616G/-443T/-155* [*indicates base deletion]; Ht3: -1748A/-616G/-443C/-155*) were significantly associated with overall survival (OS) and time to recurrence (TTR). The patients with the -443TT/TC genotype or Ht2 had a shorter OS and TTR compared with those with -443CC genotype or Ht3. This was further confirmed in the validation cohort. Moreover, this correlation remained significant in patients with small HCCs (≤5 cm). Multivariate analyses indicated that the prognostic performance of the -443 genotypes (OS, P = 0.031; TTR, P = 0.005) and their related haplotypes (OS, P = 0.002; TTR, P = 0.001) was independent of other clinicopathological factors. The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both in vitro invasion and in vivo tumor growth and lung metastasis of HCC cells (P < 0.05). Conclusion: The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancer progression of HCCs, which is a novel determinant and target for HCC metastasis and prognosis. © 2012 American Association for the Study of Liver Diseases.

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