Xiao-Geng Deng

Overexpression of miR-122 promotes the hepatic differentiation and maturation of mouse ESCs through a miR-122/FoxA1/HNF4a-positive feedback loop

microRNA‐122 is the only identified liver‐specific miRNA and plays a crucial role in liver development, maintenance of hepatic homeostasis as well as tumourigenesis. In our previous differentiation of ESCs into hepatocytes, microRNA‐122 (miR‐122) was expressed at a relatively low level. Here, we aim to elucidate the effect and underlying mechanisms of miR‐122 during differentiation of ESCs into hepatocytes.

Hepatitis C virus core protein regulates NANOG expression via the stat3 pathway

HCV Core plays a role in the development of hepatocellular carcinoma. Aberrant expression of NANOG has been observed in many types of human malignancies. However, relationship between Core and NANOG has not been clarified. In this study, we found that Core is capable of up‐regulating NANOG expression. Core‐induced NANOG expression was accompanied by enforced expression of phosphorylated stat3 protein and was attenuated by inhibition of stat3 phosphorylation. ChIP showed that phosphorylated stat3 directly binds to the NANOG promoter. Core‐induced NANOG expression resulted in enhanced cell growth and cell cycle progression. Knockdown of NANOG blocked the cell cycle at the G0/G1 phases and inhibited the cyclin D1 expression. Our findings provide a new insight into the mechanism of hepatocarcinogenesis by HCV infection.

Knockdown of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by reducing MDR1 expression

Multidrug resistance (MDR) is one of the major reasons for the failure of liver cancer chemotherapy, and its suppression may increase the efficacy of chemotherapy. NANOG plays a key role in the regulation of embryonic stem cell self-renewal and pluripotency. Recent studies reported that NANOG was abnormally expressed in several types of tumors, indicating that NANOG is related to tumor development. However, the correlation between NANOG and liver cancer chemoresistance remains uncertain. In this study, RNA interfere technology was employed to knock down NANOG expression in HepG2 human liver cancer cells. We found that the knockdown of NANOG expression in NANOG siRNA-transfected HepG2 cells resulted in decreased colony formation rate and cell migration compared to control HepG2 cells. In addition, HepG2 cells were treated with doxorubicin to evaluate the chemosensitivity to doxorubicin. We found that the doxorubicin sensitivity of HepG2 cells was increased with downregulation of NANOG expression. The expression of MDR1 at both mRNA and protein levels was decreased in HepG2 cells when NANOG was knocked down. These findings suggest that the knockdown of NANOG in HepG2 human cells resulted in decreased MDR1 expression and increased doxorubicin sensitivity, and NANOG could be used as a novel potential therapeutic target to reverse multidrug resistance of liver cancer.

Hepatitis C virus core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma

Hepatitis C virus (HCV) core protein plays an important role in the development of hepatocellular carcinoma. octamer-binding protein 4 (OCT4) is critically essential for the pluripotency and self-renewal of embryonic stem cells. Abnormal expression of OCT4 has been detected in several human solid tumors. However, the relationship between HCV core and OCT4 remains uncertain. In the present study, we found that HCV core is capable of upregulating OCT4 expression. The effect of HCV core-induced OCT4 overexpression was abolished by RNAi-mediated scilencing of HCV core. In addition, HCV core-induced OCT4 overexpression resulted in enhanced cell proliferation and cell cycle progression. Inhibition of OCT4 reduced the CCND1 expression and induced G0/G1 cell cycle arrest. Furthermore, OCT4 protein directly binds to CCND1 promoter and transactivates CCND1. These findings suggest that HCV core protein regulates OCT4 expression and promotes cell cycle progression in hepatocellular carcinoma providing new insight into the mechanism of hepatocarcinogenesis by HCV infection.

Selection of Hepatocyte-Like Cells from Mouse Differentiated Embryonic Stem Cells and Application in Therapeutic Liver Repopulation

Backgroud/Aim: Because of the oncogenic risk, it is important to gain the homogeneous and purified cells from differentiated ESCs before transplantation. Here, we aim to select hepatocyte-like cells from differentiated ESCs, and investigate their growth, differentiation and neoplastic formation after intrahepatic transplantation. Methods: Mouse ESCs were primarily induced by Dexamethesone, FGF-4 and HGF sequentially, then placed to a conditioning selection media consisting of 5% cholestatic sera and cultivated for 2 wks. After labeled by CFDA-SE, the selected cells were transplanted into mouse liver in therapeutic liver repopulation models. Results: In the early stage of screening cultivation, most cells were suffered from apoptosis or even death. 1w later, some hepatocyte-like colony-forming units were observed, then the selected cells could grow and tend to be more mature, as assessed by morphological and functional tests. After intrahepatic transplantation, the labeled cells could proliferate and expressed albumin. Moreover, teratoma didn’t form over 3 months. Conclusion: Our conditioning selection media could not only effectively select hepatocyte-like cells from differentiated ESCs, but further promote their growth and differentiation as well. After intrahepatic transplantation in therapeutic liver repopulation models, the selected cells could grow, differentiate and keep partial hepatic function. In particular, the transplantation was safe.

Hepatitis C virus core protein increases Snail expression and induces epithelial-mesenchymal transition through the signal transducer and activator of transcription 3 pathway in hepatoma cells: HCV core regulates Snail and EMT in HCC

Aberrant expression of Snail, a mediator of epithelial–mesenchymal transition (EMT), is crucial for cancer invasiveness and metastasis. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, the relationship between HCV core and Snail expression has not been clarified.

Hepatitis C virus core protein increases Snail expression and induces epithelial–mesenchymal transition through the signal transducer and activator of transcription 3 pathway in hepatoma cells

Aberrant expression of Snail, a mediator of epithelial–mesenchymal transition (EMT), is crucial for cancer invasiveness and metastasis. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, the relationship between HCV core and Snail expression has not been clarified.

Comparative Analysis of Modified Laparoscopic Swenson and Laparoscopic Soave Procedure for Short-Segment Hirschsprung Disease in Children.

INTRODUCTION This clinical analysis compared the characteristics and outcomes of modified laparoscopic Swenson (MLSw) and laparoscopic Soave (LS) procedures for short-segment Hirschsprung disease (HD) in children. PATIENTS AND METHODS This clinical analysis involved a retrospective series of 42 pediatric patients with HD who underwent surgery from March 2007 to July 2012. Patients were divided into two groups: the LS group (n = 15) and the MLSw group (n = 27). Preoperative, operative, and postoperative data were collected, through patient follow-up periods ranging from 12 to 48 months, to compare perioperative/operative characteristics, postoperative complications, and outcomes between the two groups. Major measurements were analyzed statistically. RESULTS On average, the patients in the LS group had a longer operating time (mean ± standard deviation, 199 ± 60 minutes) than those in the MLSw group (148 ± 23 minutes) (p < 0.05). Blood loss was significantly less in the MLSw group (10 ± 7 mL) than in the LS group (26 ± 14 mL) (p < 0.05). There was no difference in feeding time between the two groups (p > 0.05). The MLSw group was discharged after a shorter hospitalization time (8 ± 2 days) than the LS group (12 ± 4 days) (p < 0.05). The MLSw group had lower incidences of soiling (5, 18.5% vs. 7, 46.7%) and constipation (1, 3.7% vs. 3, 20%) than the LS group in the early postoperative period, but no difference was found between the two groups in the rate of complications during the late postoperative period. CONCLUSIONS The MLSw procedure did not increase the risk of injury to vital intrapelvic structures or the incidence of complications in surgery for short-segment HD. The early postoperative outcome was much better in the MLSw group than in the LS group, but long-term outcomes were similar. However, the MLSw procedure was simpler, resulting in reduced operating time and less intraoperative blood loss.

LncRNA HOTAIR epigenetically suppresses miR-122 expression in hepatocellular carcinoma via DNA methylation

Background MicroRNA-122 (miR-122), a pivotal liver-specific miRNA, is frequently repressed in hepatocellular carcinoma (HCC) and associated with poor prognosis. Long non-coding RNA (lncRNA) HOTAIR has been proved to function as an oncogene in multiple cancers including HCC. However, the relationship between HOTAIR and miR-122 in HCC remains largely unknown. Methods We investigated the function of HOTAIR and miR-122 in HCC cell models and a xenograft mouse model. The regulatory network between HOTAIR and miR-122 was further detected following overexpression or knockdown of HOTAIR. DNA methylation status of miR-122 promoter region, as well as expression levels of DNMTs, EZH2 and Cyclin G1 were analyzed. Findings In this study, we found that HOTAIR was highly expressed whereas miR-122 was suppressed in HCC, and HOTAIR negatively regulated miR-122 expression in HCC cells. Furthermore, knockdown of HOTAIR dramatically inhibited HCC cell proliferation and induced cell cycle arrest in vitro and suppressed tumorigenicity in vivo by upregulating miR-122 expression. Mechanistically, a CpG island was located in the miR-122 promoter region. HOTAIR epigenetically suppressed miR-122 expression via DNMTs-mediated DNA methylation. Moreover, HOTAIR upregulated DNMTs expression via EZH2. In addition, suppression of miR-122 induced by HOTAIR directly reactivated oncogene Cyclin G1 expression. Collectively, our results suggest that HOTAIR epigenetically suppresses miR-122 expression via DNA methylation, leading to activation of Cyclin G1 and promotion of tumorigenicity in HCC, which provide new insight into the mechanism of HOTAIR-mediated hepatocarcinogenesis via suppressing miR-122.

Hepatitis C virus core protein increases Snail expression and induces Epithelial‐Mesenchymal Transition via STAT3 pathway in hepatoma cells

Aberrant expression of Snail, a mediator of epithelial–mesenchymal transition (EMT), is crucial for cancer invasiveness and metastasis. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, the relationship between HCV core and Snail expression has not been clarified.