Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth.
Liver-Specific Inactivation of the Proprotein Convertase FURIN Leads to Increased Hepatocellular Carcinoma Growth.
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DOI：
10.1155/2015/148651
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发表时间：
2015
影响因子：
--
通讯作者：
Creemers JW
中科院分区：
文献类型：
--
作者：
Declercq J;Brouwers B;Pruniau VP;Stijnen P;Tuand K;Meulemans S;Prat A;Seidah NG;Khatib AM;Creemers JW
前蛋白转化酶是枯草杆菌蛋白酶样丝氨酸内切蛋白酶，其切割并因此激活多种前蛋白，包括生长因子、受体、金属蛋白酶和细胞外基质蛋白。因此，已经表明，抑制普遍表达的前蛋白转化酶FURIN可能是几种肿瘤类型的良好治疗策略。目前尚不清楚肝细胞癌（HCC）是否也是如此。在HCC小鼠模型中，肿瘤中弗林蛋白酶的表达没有改变，而PC 7、PC 5/6和PACE 4的表达至少在某些时间点显著降低。为了研究弗林蛋白酶抑制对该模型中HCC的发展和进展的影响，在肝脏中基因消融弗林蛋白酶。弗林蛋白酶失活导致5周后肿瘤质量增加。这不是由细胞凋亡减少引起的，因为没有观察到细胞凋亡指数的差异。然而，这至少可以部分解释为5周时肝细胞增殖增加。弗林蛋白酶基因敲除小鼠的肿瘤在组织学上与野生型小鼠的肿瘤相似。总之，肝特异性弗林蛋白酶抑制剂在肝细胞癌中促进肿瘤的形成，并不会是这种肿瘤类型的一个很好的治疗策略。
Proprotein convertases are subtilisin-like serine endoproteases that cleave and hence activate a variety of proproteins, including growth factors, receptors, metalloproteases, and extracellular matrix proteins. Therefore, it has been suggested that inhibition of the ubiquitously expressed proprotein convertase FURIN might be a good therapeutic strategy for several tumor types. Whether this is also the case for hepatocellular carcinoma (HCC) is currently not clear. In a mouse model for HCC expression of Furin was not altered in the tumors, while those of PC7, PC5/6, and PACE4 significantly decreased, at least at some time points. To investigate the impact of Furin inhibition on the development and progression of HCC in this model, Furin was genetically ablated in the liver. Furin inactivation resulted in an increased tumor mass after 5 weeks. This was not caused by decreased apoptosis, since no differences in the apoptosis index could be observed. However, it could at least partially be explained by increased hepatocyte proliferation at 5 weeks. The tumors of the Furin knockout mice were histologically similar to those in wild type mice. In conclusion, liver-specific Furin inhibition in HCC enhances the tumor formation and will not be a good therapeutic strategy for this tumor type.
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影响因子：
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作者：
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