NF-kappaB functions as a tumour promoter in inflammation-associated cancer.
NF-kappaB functions as a tumour promoter in inflammation-associated cancer.
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发表时间：
2004
期刊：
影响因子：
64.8
通讯作者：
E. Pikarsky;R. Porat;I. Stein;R. Abramovitch;S. Amit;Shafika Kasem;Elena Gutkovich-Pyest;S. Urieli-Sh
中科院分区：
文献类型：
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作者：
E. Pikarsky;R. Porat;I. Stein;R. Abramovitch;S. Amit;Shafika Kasem;Elena Gutkovich-Pyest;S. Urieli-Sh
散发性人类癌症的病因很少被认识，但据估计，致癌物质暴露和慢性炎症是肿瘤发展的两个重要潜在条件，后者约占人类癌症的20%。虽然致癌物质暴露与癌症之间的因果关系已被深入研究，但将慢性炎症与肿瘤发生联系起来的分子和细胞机制在很大程度上仍未得到解决。我们提出，核因子kappaB （NF-kappaB）的激活，是肿瘤中经常检测到的炎症反应的标志，可能构成炎症和癌症之间缺失的一环。为了验证这一假设，我们研究了mdr2敲除小鼠品系，该品系自发发展为胆汁淤积性肝炎，随后发展为肝细胞癌，这是炎症相关癌症的一种原型。我们监测了mdr2基因敲除小鼠的肝炎和癌症进展，在这里我们发现炎症过程通过上调邻近内皮细胞和炎症细胞中的肿瘤坏死因子- α (TNFalpha)来触发肝细胞NF-kappaB。在出生至7个月大的小鼠中，使用肝细胞特异性诱导的ikappab超抑制基因关闭NF-kappaB，对肝炎的病程没有影响，也不会影响肝细胞转化的早期阶段。相比之下，在肿瘤发展的后期，通过抗tnfalpha治疗或诱导ikappab -超抑制因子抑制NF-kappaB抑制可导致转化肝细胞凋亡，不能进展为肝细胞癌。因此，我们的研究表明NF-kappaB对于促进炎症相关癌症至关重要，因此是慢性炎症性疾病中预防癌症的潜在靶点。
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 kappaB (NF-kappaB), 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-kappaB through upregulation of tumour-necrosis factor-alpha (TNFalpha) in adjacent endothelial and inflammatory cells. Switching off NF-kappaB in mice from birth to seven months of age, using a hepatocyte-specific inducible IkappaB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kappaB inhibition through anti-TNFalpha treatment or induction of IkappaB-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-kappaB is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.