Publications by authors named "Guoqing Ji"

13 Publications

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Upregulation of Nogo-B by hypoxia inducible factor-1 and activator protein-1 in hepatocellular carcinoma.

Cancer Sci 2021 May 8. Epub 2021 May 8.

Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China.

Nogo-B is an important regulator of tumor angiogenesis. Expression of Nogo-B is remarkably upregulated in multiple tumor types, especially hepatocellular carcinoma (HCC). Here, we show the transcriptional regulation mechanisms of Nogo-B in liver cancer. In response to hypoxia, expression of Nogo-B significantly increased in HCC tissues and cells. The distal hypoxia-responsive element in the promoter was essential for transcriptional activation of Nogo-B under hypoxic conditions, which is the specific site for hypoxia inducible factor-1α (HIF-1α) binding. In addition, Nogo-B expression was associated with c-Fos expression in HCC tissues. Nogo-B expression was induced by c-Fos, yet inhibited by a dominant negative mutant A-Fos. Deletion and mutation analysis of the predicted activator protein-1 binding sites revealed that functional element mediated the induction of Nogo-B promoter activity, which was confirmed by ChIP. These results indicate that HIF-1α and c-Fos induce the expression of Nogo-B depending on tumor microenvironments, such as hypoxia and low levels of nutrients, and play a role in upregulation of Nogo-B in tumor angiogenesis.
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http://dx.doi.org/10.1111/cas.14941DOI Listing
May 2021

Nogo-B promotes tumor angiogenesis and provides a potential therapeutic target in hepatocellular carcinoma.

Mol Oncol 2018 12 26;12(12):2042-2054. Epub 2018 Oct 26.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.

Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti-angiogenic therapeutic targets. We found that the expression level of Nogo-B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo-B depletion inhibited tumor angiogenesis, Nogo-B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo-B regulates tumor angiogenesis based on its association with integrin α β and activation of focal adhesion kinase. Moreover, Nogo-B antibody successfully abolished the function of Nogo-B in tumor angiogenesis in vitro and in vivo. Collectively, our results strongly suggest that Nogo-B is an important tumor angiogenic factor and blocking Nogo-B selectively inhibits tumor angiogenesis.
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http://dx.doi.org/10.1002/1878-0261.12358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275258PMC
December 2018

MicroRNA-34a Promotes Hepatic Stellate Cell Activation via Targeting ACSL1.

Med Sci Monit 2015 Oct 6;21:3008-15. Epub 2015 Oct 6.

Department of Pathology, Changzheng Hospital, The Second Military Medical University, Shanghai, China (mainland).

Background: The incidence of liver fibrosis remains high due to the lack of effective therapies. Our previous work found that microRNA (miR)-34a expression was increased, while acy1-CoA synthetase long-chain family member1 (ACSL1) was decreased, in a dimethylnitrosamine (DNS)-induced hepatic fibrosis rat model. We hypothesized that miR-34a may play a role in the process of hepatic fibrosis by targeting ACSL1.

Material And Methods: From days 2 to 14, cultured primary hepatic stellate cells (HSCs) underwent cell morphology, immunocytochemical staining, and quantitative reverse transcription PCR (RT-qPCR) for alpha smooth muscle actin (a-SMA), desmin, rno-miR-34a, and ACSL1 expression. Wild-type and mutant luciferase reporter plasmids were constructed according to the predicted miR-34a binding site on the 3'-untranslated region (UTR) of the ACSL1 mRNA and then transfected into HEK293 cells. rno-miR-34a was silenced in HSCs to confirm that rno-miR-34a negatively regulates ACSL1 expression. mRNA and protein expression of α-SMA, type I collagen, and desmin were assayed in miR-34a-silenced HSCs.

Results: HSCs were deemed quiescent during the first 3 days and activated after 10 days. rno-miR-34a expression increased, and ACSL1 expression decreased, from day 2 to 7 to 14. rno-miR-34a was shown to specifically bind to the 3'-UTR of ACSL1. miR-34a-silenced HSCs showed higher ACSL1and lower α-SMA, type I collagen, and desmin expression than that of matching negative controls and non-transfected cells.

Conclusions: miR-34a appears to play an important role in the process of liver fibrosis by targeting ACSL1 and may show promise as a therapeutic molecular target for hepatic fibrosis.
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http://dx.doi.org/10.12659/MSM.894000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601392PMC
October 2015

MLF1 interacting protein: a potential gene therapy target for human prostate cancer?

Med Oncol 2015 Feb 9;32(2):454. Epub 2015 Jan 9.

Department of Epidemiology, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.

Here, we investigated the role of one gene that has been previously associated with human prostate carcinoma cells-myelodysplasia/myeloid leukemia factor 1 interacting protein (MLF1IP)-in order to better ascertain its role in human prostate carcinogenesis. The prostate cancer cell line PC-3 was lentivirally transfected to silence endogenous MLF1IP gene expression, which was confirmed by real-time quantitative PCR (RT-qPCR). Cellomics ArrayScan VTI imaging and MTT assays were conducted to assess cell proliferation. Cell cycle phase arrest and apoptosis were assayed by flow cytometry. Colony formation was assessed by fluorescence microscopy. MLF1IP gene expression was also analyzed by RT-qPCR in sixteen prostate cancer tissue samples and six healthy control prostate tissue samples from human patients. Cell proliferation was significantly inhibited in MLF1IP-silenced cells relative to control cells. G1 phase, S and G2/M phase cell counts were not significantly changed in MLF1IP-silenced cells relative to control cells. Apoptosis was significantly increased in MLF1IP-silenced cells, while MLF1IP-silenced cells displayed a significantly reduced number of cell colonies, compared to control cells. The 16 human prostate cancer tissue samples revealed no clear upregulation or downregulation in MLF1IP gene expression. MLF1IP significantly promotes prostate cancer cell proliferation and colony formation and significantly inhibits apoptosis without affecting cell cycle phase arrest. Further study is required to conclusively determine whether MLF1IP is upregulated in human prostate cancer tumors and to determine the precise cellular mechanism(s) for MLF1IP in prostate carcinogenesis.
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http://dx.doi.org/10.1007/s12032-014-0454-1DOI Listing
February 2015

TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma.

Biochem Biophys Res Commun 2014 Mar 21;446(1):61-7. Epub 2014 Feb 21.

State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, PR China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China. Electronic address:

TCP10L (T-complex 10 (mouse)-like) has been identified as a liver and testis-specific gene. Although a potential transcriptional suppression function of TCP10L has been reported previously, biological function of this gene still remains largely elusive. In this study, we reported for the first time that TCP10L was significantly down-regulated in clinical hepatocellular carcinoma (HCC) samples when compared to the corresponding non-tumorous liver tissues. Furthermore, TCP10L expression was highly correlated with advanced cases exceeding the Milan criteria. Overexpression of TCP10L in HCC cells suppressed colony formation, inhibited cell cycle progression through G0/G1 phase, and attenuated cell growth in vivo. Consistently, silencing of TCP10L promoted cell cycle progression and cell growth. Therefore, our study has revealed a novel suppressor role of TCP10L in HCC, by inhibiting proliferation of HCC cells, which may facilitate the diagnosis and molecular therapy in HCC.
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http://dx.doi.org/10.1016/j.bbrc.2014.02.049DOI Listing
March 2014

Membrane palmitoylated protein 3 promotes hepatocellular carcinoma cell migration and invasion via up-regulating matrix metalloproteinase 1.

Cancer Lett 2014 Mar;344(1):74-81

The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, PR China. Electronic address:

Membrane associated guanylate kinase (MAGUK) family, has been extensively studied in cellular adhesion and signal transduction at sites of cell–cell contact. Recently, growing attention has been paid to its role in the initiation and progression of various cancers. However, its role in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that membrane palmitoylated protein 3 (MPP3), a member of MAGUK family, was significantly up-regulated in both high metastatic potential cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading the portal veins. Higher level of MPP3 correlated with poorer survival of patients with HCC. Forced expression of MPP3 significantly enhanced HCC cell migration and invasion, whereas knockdown of this gene inhibited this oncogenic effect. Mechanismly, we found that MPP3 promoted HCC cell migration and invasion via up-regulating matrix metalloproteinase 1 (MMP1). These findings indicate that MPP3 play an important role in HCC metastasis by promoting cell migration and invasion, suggesting that it may serve as a novel prognostic marker and molecular target for therapy of HCC.
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http://dx.doi.org/10.1016/j.canlet.2013.10.017DOI Listing
March 2014

Gene expression profiling in acute Stanford type B aortic dissection.

Vasc Endovascular Surg 2012 May 25;46(4):300-9. Epub 2012 Apr 25.

Department of vascular surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

Objective: To compare the gene expression profiles of the aorta specimens between patients with Stanford type B aortic dissection (AD) and controls.

Materials And Methods: Samples of descending aorta were collected from patients with type B AD (n = 12) and from multiorgan donors as controls (n = 12). Phalanx whole genome microarray was used to analyze differential gene expression.

Results: Of the 6375 probes validated, 623 genes were found to be differentially expressed between patients with type B AD and controls (fold change ≥2). Gene ontology analysis identified significantly enriched gene groups pertaining to cell-cell adhesion, extracellular matrix, cell-matrix adhesion, cytoskeleton, immune and inflammatory response, and apoptosis.

Conclusion: Genes encoding components related to integrity and strength of the aortic wall were downregulated, whereas those related to inflammatory response were upregulated in type B AD. The altered patterns of gene expression indicate preexisting structural defects that are probably a consequence of insufficient remodeling of the aortic wall.
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http://dx.doi.org/10.1177/1538574412443315DOI Listing
May 2012

Characterization of neuritin as a novel angiogenic factor.

Biochem Biophys Res Commun 2011 Dec 31;415(4):608-12. Epub 2011 Oct 31.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, PR China.

Neuritin (NRN1), a neurotrophic factor, plays an important role in neurite growth and neuronal survival. In this study, we identify a new function of neuritin as a novel angiogenic factor in vitro and in vivo. Recombinant neuritin protein had no effect on the proliferation and adhesion of human umbilical vein endothelial cells (HUVEC), but it dose-dependently increased endothelial cell migration. Furthermore, overexpression of neuritin significantly promoted tumor angiogenesis, and surprisingly, it inhibited tumor growth in a xenograft tumor model. Thus, our results indicate that neuritin may act as an important angiogenic factor and serve as a potential target for cancer therapy.
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http://dx.doi.org/10.1016/j.bbrc.2011.10.118DOI Listing
December 2011

Cyclophilin A promotes human hepatocellular carcinoma cell metastasis via regulation of MMP3 and MMP9.

Mol Cell Biochem 2011 Nov 11;357(1-2):387-95. Epub 2011 Jun 11.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.

Cyclophilin A (CypA) is a member of peptidyl prolyl isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds on the NH-terminal side of Pro residues in peptide chains. Altered expression of CypA has been reported in hepatocellular carcinoma (HCC), but the biological functions of CypA in HCC remain unknown. We found that the level of CypA expression correlated with the metastatic capability of two HCC cell lines, MHCC97-L and MHCC97-H. Stable expression of ectopic CypA in SK-Hep1 cells promotes cell adhesion, motility, chemotaxis, and in vivo lung metastasis, without affecting cell proliferation. We further analyzed microarray results to identify target genes controlled by CypA. Twenty-one genes related to metastasis were altered by CypA over-expression. A member of matrix metalloproteinase, MMP3, was identified by microarray analysis. The regulation of MMP3 and its homologue MMP9 by CypA were further confirmed by quantitative real-time RT-PCR and zymography assay. Taken together, our data suggest that CypA promotes HCC cell metastasis at least partially through up-regulation of MMP3 and MMP9.
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http://dx.doi.org/10.1007/s11010-011-0909-zDOI Listing
November 2011

PIDD4, a novel PIDD isoform without the LRR domain, can independently induce cell apoptosis in cytoplasm.

Biochem Biophys Res Commun 2011 Apr 28;407(1):86-91. Epub 2011 Feb 28.

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, PR China.

PIDD1 (P53-induced death domain) is a pro-apoptotic gene which can be induced by p53. So far, three alternative splicing products of human PIDD gene have been identified. Here we report a new splicing variant of this gene and named it PIDD4. The coding sequence of PIDD4 contains intron 3 and a 60 bp insert at the 5' of exon 3. Each insertion has an in-frame stop codon, which makes PIDD4 get translated from exon 5 then. Therefore, PIDD4 protein lacks the 32 KD N-terminal peptide, missing the LRR domain found in the other three isoforms. In this study, we have shown that the expression of PIDD4 is also regulated by p53, and as PIDD2, it is not expressed in heart either. Moreover, PIDD4 is the only isoform which is expressed in skeletal muscle. This isoform mainly localizes in the cytoplasm, and produces a relatively higher proportion of PIDD-CC fragment. Overexpression of PIDD4 independently promotes apoptosis.
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http://dx.doi.org/10.1016/j.bbrc.2011.02.114DOI Listing
April 2011

Proapoptotic function of integrin beta(3) in human hepatocellular carcinoma cells.

Clin Cancer Res 2009 Jan;15(1):60-9

State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai, P.R. China.

Purpose: This study evaluates the proapoptotic function of integrin beta(3) in human hepatocellular carcinoma (HCC).

Experimental Design: The expression of integrin beta(3) in 67 HCC specimens paired with corresponding neighboring nontumorous tissue was studied by quantitative real-time PCR and Western blot. The proapoptotic function of integrin beta(3) in SMMC-7721 human hepatoma cells overexpressing ITGB3 (gene coding integrin beta(3)) was determined through colony formation, serum starvation, and anoikis assay.

Results: Compared with neighboring pathologically normal liver tissue, approximately 60% of the HCC specimens showed a significant down-regulated level of integrin beta(3) expression. Transient expression of integrin beta(3) in SMMC-7721 resulted in an enhanced level of apoptosis and suppression of colony formation. Cell growth inhibition on serum/ligand deprivation and incidences of anoikis were remarkably increased in SMMC-7721 with stable expression of integrin beta(3) in comparison with vector control transfectants. In addition, expression of fibrinogen and vitronectin, two native ligands for integrin alpha(v)beta(3) in liver, was inhibited, which was correlated with the decreased integrin beta(3) expression. Replenishing these ligands to the starved SMMC-7721 stable transfectants effectively restored the proapoptotic function of integrin beta(3).

Conclusions: Down-regulation of integrin beta(3) and its ligands in liver is related to the aggressive growth of HCC. Thus, reconstitution of integrin beta(3) in HCC may be a potential therapeutic approach to inhibit aggressive growth of liver cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658616PMC
January 2009

LAMA4, highly expressed in human hepatocellular carcinoma from Chinese patients, is a novel marker of tumor invasion and metastasis.

J Cancer Res Clin Oncol 2008 Jun 14;134(6):705-14. Epub 2007 Dec 14.

The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, No. 220 Handan Road, Shanghai 200433, People's Republic of China.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Hepatocarcinogenesis is correlated with a series of gene expression alteration. Here, we investigated LAMA4 gene expression in hepatocellular carcinoma on both mRNA and protein levels, expecting to explore the relationship between expressional abundances of LAMA4 and the clinical characteristics of HCC specimens.

Method: Total RNA was extracted from 48 cases of surgically resected HCC specimens and their corresponding peripheral tumor-free liver tissues. After the optimal reverse transcription polymerase chain reaction condition was established, the mRNA levels of LAMA4 in tumor and peripheral tumor-free tissues were examined semi-quantitatively. The relationship between expression levels of LAMA4 and clinical pathological characteristics was further analyzed by two-tailed t-test and chi2 test. We also used anti-LAMA4 antibody to detect the in vivo distribution of LAMA4 protein by tissue immunofluorescence staining in HCC specimens and their peripheral tumor-free tissues.

Results: The expression level of LAMA4 in 48 cases of human hepatocellular carcinoma tissues was significantly higher than that in their corresponding peripheral tumor-free tissues (0.37 +/- 0.25 vs. 0.18 +/- 0.12, P < 0.01). LAMA4 gene was up-regulated in 30 (62.50%) cases of HCC, down regulated in 4 (8.33%) cases, and showed no significant changes in 14 (29.17%) cases. Analysis of relationship between LAMA4 gene expression abundances and clinical characteristics by chi2 test showed that up-regulation of LAMA4 was strongly correlated with tumor invasion (79.31%), incomplete or no envelope (75.00%) and tumor bolt (86.67%). Additionally, tissue immunofluorescence staining against LAMA4 protein detected strong signal only in HCC tissues but not their corresponding peripheral tumor-free liver tissues. To our attention, LAMA4 protein showed specific in vivo distribution along the basement membrane of tumor blood vessels, bringing insights into its potential role in tumor angiogenesis.

Conclusions: LAMA4 is specifically up-regulated on both mRNA and protein levels in hepatocelluar carcinoma. The strong correlation between high expression abundances of LAMA4 with tumor invasion and metastasis, as well as, LAMA4 specific in vivo distribution in tumor basement membrane, indicated LAMA4's potential role in hepatocarcinogenesis and tumor progression. Therefore, we hypothesize that LAMA4 is probably a novel supplementary marker for HCC diagnosis, and might be a molecular target in the future cancer therapy.
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http://dx.doi.org/10.1007/s00432-007-0342-6DOI Listing
June 2008

Hepatitis B virus (HBV) vaccine-induced escape mutants of HBV S gene among children from Qidong area, China.

Virus Res 2004 Jan;99(1):63-8

Institute of Genetics, School of Life Sciences, Fudan University, 200433 Shanghai, PR China.

Hepatitis B virus (HBV) infection is the main factor, which induces hepatocellular carcinoma (HCC) in Qidong high-risk area, China. To prevent HBV infection is the most important strategy to inhibit the HCC carcinogenesis. A large project was performed in Qidong area to protect newborn babies from the HBV infection that 80,000 children born between 1984 and 1990 were vaccinated. After three times of follow-up studies, 15 screened children were found to have symptoms of illness showing persistent elevation of serum glutamic-pyruvic transaminase (ALT). From these previously collected data, we found that the ALT levels of five vaccinees with negative hepatitis B surface antigen (HBsAg) were significantly higher than those of 10 vaccinees with positive HBsAg. Furthermore, with the passage of time, the difference of ALT levels between the two groups (HBsAg negative and positive groups) diminishes. After cloning and sequencing of the HBsAg "a" epitope coding sequences, we found that mutations in "a" epitope were correlated with the absence of detectable anti-HBsAg, while no mutations were seen in the anti-HBsAg positive infections. We also found that majority of point mutations were occurred in the coding sequences of the first loop structure in "a" epitope. The structure of double loop conformation in "a" epitope was conservative, and important for HBV antigenicity. These changes in a double loop conformation would escape neutralization by vaccine-induced antibody.
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http://dx.doi.org/10.1016/j.virusres.2003.10.007DOI Listing
January 2004