PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression
PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression
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DOI：
10.1158/0008-5472.can-05-1213
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Klein-Szanto, AJP
中科院分区：
文献类型：
--
作者：
Bassi, DE;De Cicco, RL;Klein-Szanto, AJP
IV型胶原降解导致正常基底膜结构的破坏和破裂，这是肿瘤微侵袭结缔组织的起始的关键过程。PACE 4是一种前蛋白转化酶，激活膜型基质金属蛋白酶（MT-MMPs），进而加工IV型胶原酶。由于PACE 4在皮肤癌中过表达，并且体外过表达PACE 4导致侵袭性增强，我们研究了体内PACE 4表达是否导致获得侵袭性和增加肿瘤发生。通过将PACE 4靶向至表皮基底角质形成细胞来设计两个转基因小鼠系。转基因角质形成细胞表现出MT 1-MMP和MT 2-MMP的加工增加，导致IV型胶原酶活化和IV型胶原降解。较高的胶原溶解活性部分破坏了正常的基底膜结构，有利于上皮内生菌生长到真皮中，并加速化学致癌后的侵袭和转移。PACE 4过表达导致对癌变和肿瘤进展的易感性增强，这指向阻断肿瘤细胞侵袭的新靶点。
Collagen type IV degradation results in disruption and breakdown of the normal basement membrane architecture, a key process in the initiation of tumor microinvasion into the connective tissue. PACE4, a proprotein convertase, activates membrane type matrix metalloproteinases (MT-MMPs) that in turn process collagenase type IV. Because PACE4 is overexpressed in skin carcinomas and in vitro overexpression of PACE4 resulted in enhanced invasiveness, we investigated whether or not in vivo PACE4 expression leads to the acquisition of invasiveness and increased tumorigenesis. Two transgenic mouse lines were designed by targeting PACE4 to the epidermal basal keratinocytes. Transgenic keratinocytes showed increased processing of MT1-MMP and MT2-MMP resulting in collagenase IV activation and collagen type IV degradation. Higher collagenolytic activity partially disrupted normal basement membrane architecture favoring epithetial endophytic growth into the dermis and accelerating invasion and metastasis after chemical carcinogenesis. PACE4 overexpression resulted in enhanced susceptibility to carcinogenesis and tumor progression pointing to a new target for blocking tumor cell invasiveness.