ADAM12 in human liver cancers:: TGF-β-regulated expression in stellate cells is associated with matrix remodeling
ADAM12 in human liver cancers:: TGF-β-regulated expression in stellate cells is associated with matrix remodeling
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DOI：
10.1053/jhep.2003.50205
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发表时间：
2003-05-01
期刊：
影响因子：
13.5
通讯作者：
Théret, N
中科院分区：
文献类型：
--
作者：
Le Pabic, H;Bonnier, D;Théret, N
“崩解蛋白和金属蛋白酶”（ADAMS）形成了具有潜在蛋白酶和细胞粘附活性的CCLL-表面糖蛋白家族。我们已经研究了亚当在人肝癌中的表达及其对肝损伤的几种细胞因子的调节。使用退化性RT-PCR，在人体活化的肝星状细胞（HSC）中鉴定出ADAM9和ADAM12的cDNA编码序列。 Northern印迹分析表明，HSC（而不是肝细胞）表达了ADAM9 Messenger RNA（mRNA）的转录本，而ADAM12的长形式和短形式。该表达与从静止状态到大鼠HSC活化状态的过渡有关，并在肝硬化的人肝脏中显着增加。亚当12但不是ADAM9表达通过人类活化的HSC中转化生长因子β（TGF-β）的上调。 PI3K抑制剂LY294002和有丝分裂原激活的蛋白激酶激酶（MEK）抑制剂UO126阻止了TGF-的ADAM12诱导，这表明PI3K和MEK活性参与。在体内，正常肝脏和良性肿瘤中ADAM9和ADAM12 mRNA水平的稳态几乎是无法检测的，并且在肝细胞癌（分别为3倍和6倍）和来自结肠癌的肝转移（分别为3倍和6倍）中增加分别为40倍）。 ADAM9和ADAM12的上调与基质金属蛋白酶2表达和活性的增加相关。总之，在肝癌中，ADAM9和ADAM12表达与肿瘤的侵袭性和进展有关。
"A disintegrin and metalloproteinases" (ADAMs) form a family of ccll-surface glycoproteins with potential protease and cell-adhesion activities. We have investigated ADAM expression in human liver cancers and their regulation by several cytokines involved in liver injury. Using degenerative RT-PCR, cDNA encoding sequences for ADAM9 and ADAM12 were identified in human activated hepatic stellate cells (HSCs). Northern blot analyses showed that HSCs, but not hepatocytes, expressed transcripts for ADAM9 messenger RNA (mRNA) and both the long and short forms of ADAM12. This expression was associated with the transition from quiescent to activated state of rat HSCs and markedly increased in human livers with cirrhosis. ADAM 12 but not ADAM9 expression was up-regulated by transforming growth factor beta (TGF-beta) in human activated HSCs. The PI3K inhibitor LY294002 and the mitogen-activated protein kinase kinase (MEK) inhibitor UO126 prevented ADAM12 induction by TGF-, suggesting the involvement of PI3K and MEK activities. In vivo, the steady-state of both ADAM9 and ADAM12 mRNA levels was nearly undetectable in both normal livers and benign tumors and increased in hepatocellular carcinomas (up to 3- and 6-fold, respectively) and liver metastases from colonic carcinomas (up to 40- and 60-fold, respectively). The up-regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity. In conclusion, in liver cancers ADAM9 and ADAM12 expression is associated with tumor aggressiveness and progression.