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NF-kB 是炎症相关肿瘤的启动因子
NF-B functions as a tumour promoter in inflammation-associated cancer
ELI PIKARSKY1,*, RINNAT M. PORAT1,*, ILAN STEIN1,2,*, RINAT ABRAMOVITCH3, SHARON AMIT2, SHAFIKA KASEM1, ELENA GUTKOVICH-PYEST2, SIMCHA URIELI-SHOVAL4, EITHAN GALUN3 & YINON BEN-NERIAH2
1 Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
2 The Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel
3 Goldyne Savad Institute of Gene Therapy, Jerusalem 91120, Israel
4 Hematology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem 91120, Israel
* These authors contributed equally to this work
Correspondence and requests for materials should be addressed to E.P. (peli@hadassah.org.il) and Y.B.-N. (yinon@cc.huji.ac.il).
The causes of sporadic human cancer are seldom recognized, but it is estimated that carcinogen exposure and chronic inflammation are two important underlying conditions for tumour development, the latter accounting for approximately 20% of human cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that activation of the nuclear factor B (NF-, a hallmark of inflammatory responses that is frequently detected in tumours, may constitute a missing link between inflammation and cancer. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-B through upregulation of tumour-necrosis factor- (TNF) in adjacent endothelial and inflammatory cells. Switching off NF-B in mice from birth to seven months of age, using a hepatocyte-specific inducible IB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-B inhibition through anti-TNF treatment or induction of IB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Our studies thus indicate that NF-B is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.
Hepatocellular carcinoma (HCC), the third leading cause of cancer mortality worldwide, commonly develops in the background of chronic hepatitis8. We confirmed and extended previous results6, 9, according to which tumour development in the Mdr2-knockout mouse, similarly to human HCC8, progresses through distinct phases: inflammation, dysplasia, dysplastic nodules (adenoma-like), carcinoma and metastasis (Supplementary Fig. 1a, b). Hepatitis is the earliest sign of disease in the Mdr2-knockout mice, and is characterized by an extensive periductular and periportal mixed inflammatory infiltrate, rich in CD3-positive cells (Supplementary Fig. 1c).
NF-B activation is often observed in human HCC, particularly following hepatitis8. The possibility that NF-B activation is involved in Mdr2-knockout hepatocarcinogenesis was investigated by RelA (p65) immunostaining (Fig. 1a). Nuclear staining, indicative of NF-B activation, was evident in knockout livers of mice at all ages, but not in normal, age-matched mice; this prompted a search for the source of NF-B activation in the knockout mice. In some neoplasms such as Hodgkin's disease and certain lymphomas, NF-B activation is an intrinsic, tumour autonomous feature, possibly related to mutations in its signalling pathway10. If a similar mechanism occurs in Mdr2-knockout HCC, one would observe nuclear NF-B activation in all neoplastic hepatocytes. However, this was not the case; NF-B activation appeared scattered at the parenchyma, predominantly adjacent to inflamed portal tracts (Fig. 1e, left panel), suggesting an inflammation-induced phenomenon. To evaluate this possibility, we fed knockout and wild-type mice with the non-steroidal anti-inflammatory drug (NSAID) ibuprofen for 10 days. This treatment resulted in decreased inflammation, evident by histological analysis (Fig. 1b), decreased serum alanine aminotransferase (ALT), a marker for hepatocyte damage, (Fig. 1c) and fewer neutrophils (Fig. 1c, d). p65 immunostaining showed that the degree of hepatocyte NF-B activation in the NSAID-treated group was significantly lower than in the controls (Fig. 1e). In contrast, ibuprofen had no effect on hepatocyte NF-B activation following intraperitoneal TNF administration (data not shown). Hence, it seems that NF-B activation in the knockout hepatocytes is secondary to parenchymal infiltration by inflammatory cells.
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作者:admin@医学,生命科学 2011-01-22 17:14
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