Zhai Yali, Hotary Kevin B, Nan Bin, Bosch F Xavier, Muñoz Nubia, Weiss Stephen J, Cho Kathleen R
Department of Pathology, University of Michigan Medical School and Biostatistics Department, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2216, USA.
Cancer Res. 2005 Aug 1;65(15):6543-50. doi: 10.1158/0008-5472.CAN-05-0231.
Membrane type 1 matrix metalloproteinase (MT1-MMP) is frequently expressed by cancer cells and is believed to play an important role in cancer cell invasion and metastasis. However, little is known about the role of MT1-MMP in mediating invasiveness of cervical cancer cells. In this study, we examined MT1-MMP expression in 58 primary human cervical tissue specimens, including normal cervix, low-grade squamous intraepithelial lesions (LSIL), high-grade SILs (HSIL), and invasive carcinomas. We also evaluated MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase-2 expression in several cervical cancer-derived cell lines, human papillomavirus (HPV)-immortalized keratinocytes, and keratinocytes derived from a LSIL. Using in situ hybridization techniques to study the cervical tissue specimens, we found that MT1-MMP expression increases with cervical tumor progression (Spearman correlation coefficient = 0.66; P < 0.0001, exact test). Specifically, MT1-MMP expression is very low or absent in normal cervix and LSILs, is readily detectable in HSILs, and is very strongly expressed in nearly all invasive carcinomas. Most but not all cervical cancer-derived cell lines also expressed significant levels of MT1-MMP and MMP-2. Constitutive expression of exogenous MT1-MMP in cervical carcinoma-derived cells and HPV-immortalized keratinocytes with low endogenous levels of MT1-MMP induced invasiveness in collagen I, but this effect was not observed in LSIL-derived keratinocytes. Our results show that MT1-MMP is a key enzyme mediating cervical cancer progression. However, MT1-MMP alone is not always sufficient for inducing keratinocyte invasiveness at least in the collagen I invasion assay used in this study. Further studies of gene expression in preinvasive and invasive cervical cancers should assist with identification of additional critical factors mediating cervical cancer progression.
膜型1基质金属蛋白酶（MT1-MMP）在癌细胞中经常表达，被认为在癌细胞侵袭和转移中起重要作用。然而，关于MT1-MMP在介导宫颈癌细胞侵袭性中的作用知之甚少。在本研究中，我们检测了58例原发性人宫颈组织标本中MT1-MMP的表达，包括正常宫颈、低级别鳞状上皮内病变（LSIL）、高级别鳞状上皮内病变（HSIL）和浸润癌。我们还评估了几种宫颈癌衍生细胞系、人乳头瘤病毒（HPV）永生化角质形成细胞和LSIL衍生角质形成细胞中MT1-MMP、MMP-2和金属蛋白酶组织抑制剂-2的表达。使用原位杂交技术研究宫颈组织标本，我们发现MT1-MMP表达随宫颈肿瘤进展而增加（Spearman相关系数=0.66；P<0.0001，确切检验）。具体而言，MT1-MMP在正常宫颈和LSIL中表达非常低或缺失，在HSIL中易于检测到，并且在几乎所有浸润癌中都强烈表达。大多数但并非所有宫颈癌衍生细胞系也表达显著水平的MT1-MMP和MMP-2。在MT1-MMP内源性水平低的宫颈癌衍生细胞和HPV永生化角质形成细胞中组成性表达外源性MT1-MMP可诱导其在I型胶原中的侵袭性，但在LSIL衍生的角质形成细胞中未观察到这种效应。我们的结果表明MT1-MMP是介导宫颈癌进展的关键酶。然而，至少在本研究中使用的I型胶原侵袭试验中，单独的MT1-MMP并不总是足以诱导角质形成细胞的侵袭性。对浸润前和浸润性宫颈癌基因表达的进一步研究应有助于识别介导宫颈癌进展的其他关键因素。
