Expression of functional CD40 in human hepatocellular carcinoma

Sugimoto, Kazushi; Shiraki, Katsuya; Ito, Takeshi; Fujikawa, Katsuhiko; Takase, Koujiro; Tameda, Yukihiko; Moriyama, Masami; Nakano, Takeshi

doi:10.1002/hep.510300424

Cited by 44 publications

(34 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the plausible explanations is that antiapoptotic mechanisms such as reduced expression of Fas and expression of antiapoptotic proteins, for example, bcl-2 or XIAP, in addition to survivin or receptormediated survival signals are involved in the progression of antiapoptosis of HCC cells. [29][30][31][32] The findings of both our in vitro and in vivo studies were in good agreement; this confirmed that stable knockdown of survivin abrogated its function in cell cycle regulation, and although it cannot induce spontaneous apoptosis directly and immediately, it sensitizes HCC cells to apoptotic stimuli. Most importantly, our result was consistent with the results of a previous clinical study that survivin expression in HCC tissues strongly correlated with the proliferation index, but did not significantly correlate with the apoptosis index.…”

Section: Discussionsupporting

confidence: 76%

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Zhang

Zheng

et al. 2009

Cancer Gene Ther

View full text Add to dashboard Cite

Abnormal high activation of survivin is involved in carcinogenesis of various types of cancer. Survivin has been shown to promote cell proliferation in human hepatocellular carcinoma (HCC). Survivin-targeting approaches have become a promising strategy for treating HCC. Here, we used a reporter system to screen effective survivin siRNA sequences. The effect of vector-based survivin short hairpin RNA (shRNA) on the malignant phenotype of HCC cells in vitro and in vivo was determined, and an adenovirusmediated shRNA expression vector was developed to decrease survivin expression of the established HCC tumor in nude mice. In vitro study showed that stable survivin knockdown inhibited cancer cell proliferation, enhanced apoptotic susceptibility, arrested cell cycle in the G1 phase and resulted in apparent mitotic catastrophe. Moreover, cells stably expressing survivin shRNA showed decreased tumorigenicity in nude mice. An additional in vivo study showed that intratumoral injection of adenovirus-delivered survivin shRNA suppressed tumor growth by spontaneous apoptosis of cancer cells and significantly prolonged animal survival. In conclusion, we proved the therapeutic potential of survivin shRNA for the treatment of HCC. And our results indicated that adenovirus-delivered shRNA may serve as a novel therapeutic for HCC.

show abstract

Section: Discussionsupporting

confidence: 76%

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Zhang

Zheng

et al. 2009

Cancer Gene Ther

View full text Add to dashboard Cite

show abstract

“…Indeed, the NF-B family of transcription factors has been shown to regulate proliferation in several cell types (Hoshi et al, 2000;Brantley et al, 2001;Lim et al, 2001). Endothelial cell proliferation in response to CD40 could be important not only in chronic inflammation but also in angiogenesis and tumor vascularization where 60% of hepatocellular carcinomas express high levels of CD40 (Sugimoto et al, 1999). Our recent data (Russell, Adams, and Afford, unpublished data) suggest that CD40 ligation on IHECs can modulate other endothelial cell functions, including expression of adhesion molecules and chemokines in a manner similar to that reported with endothelial cells from other tissues (Van Kooten, 2000).…”

Section: Discussionmentioning

confidence: 99%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

View full text Add to dashboard Cite

CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-κB activity in hepatocytes ,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-κB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH2-terminal kinase 1/2) and expression of inhibitor κBα were entirely consistent, and thus confirmed the profiles of NF-κB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-κB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH2-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by ∼50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-κB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-κB activation and a lack of AP-1 activation in IHECs result in proliferation.

show abstract

“…To analyze the expression of CD154 and CD69 on CD4 ϩ T cells, and CD40 or Fas/FasL on hepatocytes, FACS analysis was performed as previously described. 23,32,33 Statistical Analysis. All data are expressed as the mean Ϯ SEM.…”

Section: Methodsmentioning

confidence: 99%

CD154–CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis†

Zhou¹,

Ajuebor²,

Beck³

et al. 2005

Hepatology

View full text Add to dashboard Cite

The CD154 -CD40 interaction is a critical costimulatory pathway modulating the cellular immune response. Moreover, fulminant hepatitis of various etiologies is characterized by a hepatic influx of CD154-expressing T cells and an upregulation of CD40 expression on Kupffer cells and hepatocytes, implicating this pathway in the pathogenesis of fulminant hepatitis. In this study, we used a murine model of fulminant hepatitis induced by concanavalin A (con A) and documented a significant influx of CD154-expressing T cells into the livers of mice treated with con A, in association with markedly increased expression of CD40 restricted mainly to hepatocytes in damaged areas of the liver. Furthermore, con A hepatitis in CD154-deficient mice was significantly attenuated compared with that in wildtype controls and was associated with a decrease in hepatic tumor necrosis factor ␣ (TNF-␣) levels and hepatocyte death.

show abstract

Expression of functional CD40 in human hepatocellular carcinoma

Cited by 44 publications

References 42 publications

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

CD154–CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis†

Contact Info

Product

Resources

About