Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4
Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4
复制标题
DOI：
10.1093/carcin/23.4.565
复制
发表时间：
2002-04-01
期刊：
影响因子：
4.7
通讯作者：
Klein-Szanto, AJP
中科院分区：
文献类型：
--
作者：
Mahloogi, H;Bassi, DE;Klein-Szanto, AJP
前蛋白转化酶 (PC) 通过处理包括基质金属蛋白酶 (MMP) 在内的多种底物而参与肿瘤细胞侵袭。 PACE4 是 PC 家族的一员，已被证明可以通过增加肿瘤细胞的侵袭性来促进小鼠皮肤癌的进展。然而，PACE4对恶性转化的影响尚未被研究。在本研究中，我们通过转染全长 PACE4 cDNA、三种没有或很少致瘤潜力的角质形成细胞系，即非致瘤性 BALB/MK-2 细胞、致瘤性非侵袭性 MT1/2 细胞和致瘤性中度侵袭性 p117 小鼠皮肤角质形成细胞，探讨了 PACE4 作为恶性转化触发因素的可能作用。 PACE4 的过度表达导致 Stromelysin-3 的加工显着增加，Stromelysin-3 是该 PC 的一种充分表征的底物。当检测侵袭能力时，PACE4 转染细胞在体外和体内均具有侵袭性，而对照细胞则不然。此外，在 PACE4 转染细胞中检测到 MT2-MMP（PC 的已知底物）的增强处理能力。这伴随着 PACE4 转染子中 MMP-2 和 MMP-9 的激活。当用特异性抗体抑制 PACE4 时，侵袭和 MMP 加工显着减少。通过触发关键的侵袭相关蛋白酶的处理，PACE4不仅能够如之前所证明的那样增强恶性细胞的侵袭能力，而且在将非侵袭性角质形成细胞转化为恶性细胞方面发挥着重要作用。
Proprotein convertases (PCs) have been implicated in tumor cell invasion by processing a variety of substrates including matrix metalloproteinases (MMPs). PACE4, a member of the family of PCs was shown to enhance mouse skin carcinoma progression by increasing tumor cell invasiveness. However, the effects of PACE4 on malignant conversion have not been investigated. In the present study we address the possible role of PACE4 as a trigger of malignant conversion by transfecting with a full-length PACE4 cDNA, three keratinocyte cell lines with no or little tumorigenic potential, i.e. non-tumorigenic BALB/MK-2 cells, tumorigenic non-invasive MT1/2 cells and tumorigenic moderately invasive p117 mouse skin keratinocytes. Overexpression of PACE4 led to a significant increase in the processing of stromelysin-3, a well-characterized substrate of this PC. When assayed for invasive ability, the PACE4-transfected cells were invasive both in vitro and in vivo, whereas their control counterparts were not. In addition, an enhanced processing ability of MT2-MMP a known substrate of PCs was detected in the PACE4-transfected cells. This was accompanied by MMP-2 and MMP-9 activation in PACE4 transfectants. Invasion and MMP processing were remarkably reduced when PACE4 was inhibited with a specific antibody. By triggering the processing of crucial invasion-related proteases, PACE4 is not only able to enhance the invasive ability of malignant cells as demonstrated previously, but also played a significant role in converting non-invasive keratinocytes into malignant cells.