The Expression of Hypoxia-Inducible Factor-1α in Hepatitis B Virus-Related Hepatocellular Carcinoma: Correlation with Patients’ Prognosis and Hepatitis B Virus X Protein

Xie, Hui; Song, Jiugang; Liu, Kaige; Ji, Hanxu; Shen, Huiqin; Hu, Shengjuan; Yang, Guitao; Du, Yulei; Zou, Xingxing; Jin, Haifeng; Li, Yan; Liu, Jie; Fan, Daiming

doi:10.1007/s10620-008-0296-9

Cited by 51 publications

(59 citation statements)

References 28 publications

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“…A general principle of targeted therapy is that patient selection is based on the demonstration that increased expression or activity of the target is associated with poor prognosis. Based on this reasoning, patients with HIF-1␣ overexpression demonstrated by immunohistochemistry on biopsy of cancers in which this phenotype is associated with increased mortality, such as prostate and hepatocellular carcinoma (8,9), may be particularly good candidates for inclusion of daily DXR or DNR in a treatment regimen. Clinical trials are warranted to test these hypotheses, and additional preclinical studies are needed to investigate the effects of daily anthracycline therapy on other aspects of cancer biology that are regulated by HIF-1, including tumor metabolism, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

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RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Lee¹,

Qian²,

Rey³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

273

209

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Using a cell-based reporter gene assay, we screened a library of drugs in clinical use and identified the anthracycline chemotherapeutic agents doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. These drugs inhibited HIF-1 by blocking its binding to DNA. Daily administration of doxorubicin or daunorubicin potently inhibited the transcription of a HIF-1-dependent reporter gene as well as endogenous HIF-1 target genes encoding vascular endothelial growth factor, stromal-derived factor 1, and stem cell factor in tumor xenografts. CXCR4 ؉ /sca1 ؉ , VEGFR2 ؉ /CD34 ؉ , and VEGFR2 ؉ / CD117 ؉ bone-marrow derived cells were increased in the peripheral blood of SCID mice bearing prostate cancer xenografts but not in tumor-bearing mice treated for 5 days with doxorubicin or daunorubicin, which dramatically reduced tumor vascularization. These results provide a molecular basis for the antiangiogenic effect of anthracycline therapy and have important implications for refining the use of these drugs to treat human cancer more effectively.hypoxia ͉ xenograft ͉ adriamycin ͉ endothelial progenitor cells ͉ hepatocellular carcinoma

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Section: Discussionmentioning

confidence: 99%

“…In prostate cancer patients treated with radiotherapy or radical prostatectomy, increased HIF-1␣ levels are associated with reduced time to disease progression (8). In hepatocellular carcinoma, increased HIF-1␣ levels are associated with venous and lymph node invasion and patient mortality (9).…”

mentioning

confidence: 99%

RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Lee¹,

Qian²,

Rey³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

273

209

View full text Add to dashboard Cite

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“…HCCs are known to overexpress both HIF-a-subunits correlating with poor patient prognosis. 5,16 Taking into account that HIF isoforms differentially regulate gene expression during tumor progression, an analysis of the specific functions of each subunit is needed. Therefore, we established HepG2 tumor spheroids deficient for HIF-1a, HIF2a, or HIF-1b as an HCC in vitro tumor model to elucidate cell death regulation.…”

Section: Discussionmentioning

confidence: 99%

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

et al. 2010

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Hypoxia-inducible factors (HIFs) provoke adaptation to hypoxic stress occurring in rapidly growing tumor tissues. Therefore, overexpression of HIF-1 or HIF-2 is a common feature in hepatocellular carcinoma but their specific function is still controversially discussed. To analyze HIF function in hypoxia-induced cell death we created a stable knockdown of HIF-1a and HIF-2a in HepG2 cells and generated tumor spheroids as an in vitro hepatocellular carcinoma model. Knockdown of HIF-1a enhanced expression of HIF-2a and vice versa. Unexpectedly, knockdown of HIF-1a or HIF-2a increased cell viability as well as spheroid size and decreased caspase-3 activity. Antiapoptotic Bcl-X L expression increased in both knockdown spheroids, whereas proapoptotic Bax was only reduced in HIF-1a-knockdown cells. Furthermore, an HIF-2a-knockdown significantly increased Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression in an HIF-1a-dependent manner. Concomitantly, electron microscopy revealed a substantial increase in autophagosomal structures in HIF-2a-knockdown spheroids and mito-/lysotracker costaining confirmed lysosomal activity of these autophagosomes. Blocking autophagosome maturation using 3-methyladenine restored cell death in HIF-2a-knockdown clones comparable to wildtype cells. Conclusion: An HIF-1a-knockdown increases HIF-2a expression and shifts the balance of Bcl-2 family members toward survival. The knockdown of HIF-2a raises autophagic activity and attenuates apoptosis by enhancing HIF-1a expression. Our data indicate that enhanced expression of one HIF-isoform causes a survival advantage in hepatocellular carcinoma development. (HEPATOLOGY 2010;51:2183-2192

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“…Upregulated HIF-1α in HCC is correlated well with portal vein invasion, lymph node metastasis, and is an adverse prognostic factor for HCC patients [Xie et al, 2008].…”

Section: Hbx Regulation Of Ca IX Expression In Human Hepatocellular Cmentioning

confidence: 99%

Role of the HBx oncoprotein in carbonic anhydrase 9 induction

Holotnakova¹,

Tylková²,

Takáčová³

et al. 2009

Journal of Medical Virology

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International audienceCarbonic anhydrase 9 (CA9), as one of the most hypoxia-responsive genes, has been associated almost exclusively with hypoxic tumours. Its principal role is in pH regulation which helps tumour cells overcome intracellular acidosis and survive extended periods of time with low oxygen. Hypoxia-inducible factor 1 (HIF-1) is the main transcriptional activator of CA9. Hepatitis B virus X protein (HBx) has been shown to increase the transcriptional activity of HIF-1. HBx is often expressed from the gene integrated in the hepatocytes infected persistently and contributes significantly to alterations in host gene expression that can lead to the development of hepatocellular carcinoma (HCC) associated with HBV. The aim of this study was to determine the effect of HBx on expression of CA9. Transient transfection of HBx led to an increase in the expression of CA9 as assessed by RT-PCR and Western blotting. HBx was able to increase CA9 promoter activity significantly in several cell lines. The effect was mediated via HIF-1 and a functional HRE element located –10/–3 bp upstream of the CA9 transcription initiation site. These data suggest that CA9 may be involved in the development of HCC by contributing to the survival of hepatocytes infected with HBV in liver tissue with fibrosis

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The Expression of Hypoxia-Inducible Factor-1α in Hepatitis B Virus-Related Hepatocellular Carcinoma: Correlation with Patients’ Prognosis and Hepatitis B Virus X Protein

Cited by 51 publications

References 28 publications

RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

Role of the HBx oncoprotein in carbonic anhydrase 9 induction

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