Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.
Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.
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DOI：
10.1371/journal.pone.0090571
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shackel NA
中科院分区：
文献类型：
--
作者：
Calabro SR;Maczurek AE;Morgan AJ;Tu T;Wen VW;Yee C;Mridha A;Lee M;d'Avigdor W;Locarnini SA;McCaughan GW;Warner FJ;McLennan SV;Shackel NA
肝损伤的经典范例认为，肝星状细胞（HSC）通过基质金属蛋白酶（MMP）产生、重塑和翻转纤维化的异常细胞外基质（ECM）。在肝外组织中，MMP 的产生受到多种机制的调节，包括糖蛋白 CD147 的表达。之前，我们已经证明 CD147 在肝细胞上表达，但在肝硬化的纤维化间隔内不表达。因此，我们研究了肝细胞是否产生受 CD147 调节的 MMP，这些 MMP 能够独立于 HSC 重塑纤维化 ECM。检查人类和小鼠未患病、纤维化和肝硬化肝脏的 MMP 活性和纤维化标志物。 CD147 表达和 MMP 活性通过原位酶谱法共定位。 CD147 的作用通过肝细胞中 CD147 的 siRNA 进行体外研究，并使用 CD147 抗体干预在 CCl4 诱导肝损伤的小鼠体内研究 CD147 的作用。在人和小鼠的肝纤维化中，MMP 的表达和活性（MMP-2、-9、-13 和 -14）随着进行性损伤而增加，并且局限于肝细胞。此外，正如预期的那样，活化的 HSC 大量表达 MMP。此外，随着进行性纤维化，CD147 表达，其定位于肝细胞，但不定位于 HSC。使用 CD147 的 siRNA 证明了 CD147 对肝细胞 MMP 产生的功能上显着的体外调节，降低了肝细胞 MMP-2 和 -9 的表达/活性。此外，与对照组相比，体内α-CD147抗体干预降低了CCl4处理小鼠的肝脏MMP-2、-9、-13、-14、TGF-β和α-SMA表达。我们已经证明肝细胞产生活性 MMP，并且糖蛋白 CD147 调节肝细胞 MMP 表达。靶向 CD147 可在体外和体内调节肝细胞 MMP 的产生，最终结果是减少体内纤维化基质周转。因此，CD147对肝细胞MMP的调节是一种新的途径，可以成为未来抗纤维化药物的靶点。
The classical paradigm of liver injury asserts that hepatic stellate cells (HSC) produce, remodel and turnover the abnormal extracellular matrix (ECM) of fibrosis via matrix metalloproteinases (MMPs). In extrahepatic tissues MMP production is regulated by a number of mechanisms including expression of the glycoprotein CD147. Previously, we have shown that CD147 is expressed on hepatocytes but not within the fibrotic septa in cirrhosis. Therefore, we investigated if hepatocytes produce MMPs, regulated by CD147, which are capable of remodelling fibrotic ECM independent of the HSC. Non-diseased, fibrotic and cirrhotic livers were examined for MMP activity and markers of fibrosis in humans and mice. CD147 expression and MMP activity were co-localised by in-situ zymography. The role of CD147 was studied in-vitro with siRNA to CD147 in hepatocytes and in-vivo in mice with CCl4 induced liver injury using ãCD147 antibody intervention. In liver fibrosis in both human and mouse tissue MMP expression and activity (MMP-2, -9, -13 and -14) increased with progressive injury and localised to hepatocytes. Additionally, as expected, MMPs were abundantly expressed by activated HSC. Further, with progressive fibrosis there was expression of CD147, which localised to hepatocytes but not to HSC. Functionally significant in-vitro regulation of hepatocyte MMP production by CD147 was demonstrated using siRNA to CD147 that decreased hepatocyte MMP-2 and -9 expression/activity. Further, in-vivo α-CD147 antibody intervention decreased liver MMP-2, -9, -13, -14, TGF-β and α-SMA expression in CCl4 treated mice compared to controls. We have shown that hepatocytes produce active MMPs and that the glycoprotein CD147 regulates hepatocyte MMP expression. Targeting CD147 regulates hepatocyte MMP production both in-vitro and in-vivo, with the net result being reduced fibrotic matrix turnover in-vivo. Therefore, CD147 regulation of hepatocyte MMP is a novel pathway that could be targeted by future anti-fibrogenic agents.
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CD147表达介导肝细胞癌肿瘤细胞侵袭和多药耐药
影响因子：
2.4
作者：
Jia, Li;Xu, Henggui;Zhang, Jianing
通讯作者：
Zhang, Jianing
影响因子：
20.3
作者：
Cho, JY;Fox, DA;Chain, B
通讯作者：
Chain, B
DOI：
10.1111/j.1440-1746.2006.04586.x
发表时间：
2006-10-01
影响因子：
4.1
作者：
Han, Yuan-Ping
通讯作者：
Han, Yuan-Ping
DOI：
10.1165/rcmb.2002-0059oc
发表时间：
2003-05-01
影响因子：
6.4
作者：
Betsuyaku, T;Kadomatsu, K;Senior, RM
通讯作者：
Senior, RM
影响因子：
5
作者：
Ikeda, M;Sugiyama, K;Kato, N
通讯作者：
Kato, N