Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

Zhu, Xiaodong; Li, Chenglin; Lang, Z; Gao, George F.; Tien, Po

doi:10.3748/wjg.v10.i8.1141

Cited by 29 publications

(22 citation statements)

References 42 publications

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“…(38,(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) However, with the exception of vinculin (14,15) the genes reported to be associated with early recurrence of HCC in transcriptomic studies were not identified in this study, a fact possibly due to the current detection limitations of 2D-DIGE using the CyDye DIGE Fluor minimal dye. To improve the sensitivity of our proteomic studies, we are now considering the use of prefractionation methods, narrow range IPG gels, more sensitive fluorescent dye such as the CyDye DIGE Fluor saturation dye, and larger format 2D gels.…”

Section: Discussioncontrasting

confidence: 51%

Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery

et al. 2007

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The poor prognosis of patients with hepatocellular carcinoma (HCC) is attributed to intrahepatic recurrence. To understand the molecular background of early intrahepatic recurrence, we conducted a global protein expression study. We compared the protein expression profiles of the primary HCC tissues of 12 patients who showed intrahepatic recurrence within 6 months post surgery with those of 15 patients who had no recurrence 2 years post surgery. Two-dimensional difference gel electrophoresis identified 23 protein spots, the intensity of which was highly associated with early intrahepatic recurrence. To validate the prediction performance of the identified proteins, we examined additional HCC tissues from 13 HCC patients; six with early intrahepatic recurrence and seven without recurrence. We found that all but one of the 13 patients were grouped according to their recurrence status based on the intensity of the 23 protein spots. D espite recent progress in early diagnostic modalities and therapeutic management, the prognosis of hepatocellular carcinoma (HCC) patients remains poor, mainly due to intrahepatic recurrence.(1) The incidence of intrahepatic recurrence in the liver remnant ranges from 50% to 100% of HCC patients who undergo curative resection as a result of either intrahepatic metastasis from the primary tumor or multicentric recurrence (2)(3)(4)(5)(6) and the median survival after recurrence is only 11 months. Although various molecular alterations have been correlated with early recurrence of HCC (8)(9)(10)(11)(12)(13) and studies on such events furthered our understanding of HCC biology, the underlying mechanisms remain obscure. Studies focusing on individual candidate genes may be insufficient for precisely understanding the background of the malignant behavior of tumor cells, because the features of cancer cells are defined by multiple genetic alterations in a functionally coordinated manner. With this notion in mind, global mRNA expression analyses have been conducted to identify the gene network associated with early intrahepatic recurrence. (14)(15)(16)(17) Such molecular pathogenesis studies may lead to the development of gene-based biomarkers and novel therapeutic strategies. However, mRNA expression reflects the protein expression of only a small proportion of genes, probably because of post-translational control of protein quantity. (18)(19)(20)(21) To complement gene expression studies, global protein expression profiling, namely a proteomic approach, has been carried out for the study of HCC.(22-28) Conceptually, proteomics reflects the molecular background of cancer phenotypes more directly, as the final product of genetic and epigenetic events is the proteins contained in the cells.In this study we investigated the protein expression of HCC tissues from patients with early intrahepatic recurrence and from patients without recurrence. We used two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) to generate quantitative protein expression profiles, and data-mining methods...

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Section: Discussioncontrasting

confidence: 51%

Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery

et al. 2007

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“…The extent of elevated gp96 expression in liver tissues was significantly correlated with the disease progression of HBV infection, but high level expression of gp96 did not induce an immunoresponse against HBV infection as expected [13]. Other studies involving gp96 as adjuvant have also indicated that highdose gp96 administration can down-regulate inflammatory events and anti-tumor effect [14,15].…”

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confidence: 75%

Treg suppress CTL responses upon immunization with HSP gp96

Liu

Qiu

et al. 2009

Eur J Immunol

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HSP gp96-based vaccines have been trialled in rodent models and, more recently, in humans. Better understanding of gp96's immunomodulatory role will help with the design of more effective strategies for treatment of cancer and infectious diseases. In this study, we monitored the activities of T cells and activation of Treg in BABL/c mice after immunization using different doses of gp96 as adjuvant. We found that co-injection of gp96 simultaneously stimulated both CTL and Treg activity. Activation of CTL at low dose was far more pronounced than Treg activation. Treg population and suppression increased with gp96 dose, eventually abrogating the T-cell response induced by immunization. Lowdose cyclophosphamide treatment could restore the T-cell responses lost after high-dose gp96 adjuvant injection by suppression of Treg activation. We further examined the effect of different doses of gp96 or N355 peptide administration on tumor rejection. Our results provide new insights into the mechanisms of gp96-mediated balance between regulatory and responder T cells, which may facilitate future development of an effective gp96-based therapeutic vaccine.Key words: CTL . gp96 . Hepatitis B virus . Treg Introduction HSP gp96, a counterpart of the cytosolic HSP90 family residing in the endoplasmic reticulum, plays important roles in the activation of innate and adaptive immunity. This molecule has the unique ability to associate with antigenic peptides from tumor, virus and intracellular bacteria. Peptides bound by gp96 are taken up by APC through cell surface receptor CD91 and can be presented by both MHC class I and MHC class II molecules [1][2][3]. In mouse models, gp96-peptide complexes have been shown to prime and induce MHC class I-restricted CTL responses by crosspresentation of peptides to MHC class I molecules. Additionally, gp96 may act as co-stimulator and activator of CD4 1 and CD8 1T cells [4], increasing cell proliferation and secretion of cytokines. The gp96 protein also induces innate immune responses. Interaction of gp96 with APC (e.g. dendritic cells) leads to maturation or enhanced function of dendritic cells [5]. Recently gp96 was demonstrated to function in the expression of both intracellular and cell surface TLR [6]. In rodent models, autologous tumor-derived gp96-peptide complexes are highly effective in the elimination of tumor burden [7,8]. Immunization of mice with gp96 complexed with specific CTL epitopes derived from various viruses has been shown to elicit virus-specific CTL or protective immunity [1,9,10]. Since gp96 has been demonstrated to act as a powerful adjuvant, clinical trials of gp96-based therapeutic vaccines have been initiated for treatment of cancer [8,11].Previous study in our lab found that gp96 and its N-terminal fragment, N355, have the ability to augment CTL responses against to hepatitis B virus (HBV). However, higher amounts of Ã These authors contributed equally to this work. 3110gp96 were detrimental to the adjuvant effect and decreased the capability of mice to generate an i...

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“…Interestingly, a similar GRP94 distribution pattern has been reported in other tumor cells. 42 Moreover, the increase in GRP94 level was shown to be correlated with the disease progression of HBV infection 66 although unrelated to HCV, HBV shows pathological progress similar to that of HCV. The levels of GRP94 were greatest in HCC patients and lowest in patients with chronic HBV infection, with intermediate levels reported in patients with cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

“…40 Moreover, increased levels of GRP94 were observed when a chronic hepatitis B virus (HBV) infection progressed to cirrhosis and hepatocellular carcinoma (HCC). [41][42][43] Inhibitors of Hsp90 and GRP94 (such as geldanamycin and its less toxic derivative 17-AAG) have been investigated for efficacy in cancer treatment. Geldanamycin and 17-AAG inhibit Hsp90 and GRP94 by binding competitively to its N-terminal adenosine triphosphate-binding site.…”

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confidence: 99%

A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection

et al. 2008

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Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases

Cited by 29 publications

References 42 publications

Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery

Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery

Treg suppress CTL responses upon immunization with HSP gp96

A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection

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