Solovуeva N I, Timoshenko O S, Gureeva T A, Kugaevskaya E V
Institute of Biomedical Chemistry, Moscow, Russia.
Biomed Khim. 2015 Nov-Dec;61(6):694-704. doi: 10.18097/PBMC20156106694.
Expression of matrix metalloproteinases (MMPs) and their endogenous regulators has been investigated in squamous cervical carcinoma (SCC). The study included (i) immortalized fibroblasts (IF) and three clones of fibroblasts transformed by oncogene E7 HPV-16 (TF); (ii) cell lines associated with HPV-16 and HPV-18; (iii) tumor tissue samples from patients with SCC, associated with gene E7 HPV-16. Transfection of fibroblasts with the E7 HPV16 oncogen was accompanied by induction of collagenase (MMP-1, MMP-14) and gelatinase (MMP-9) gene expression and the increase in catalytic activity of these MMP, while gelatinase MMP-2 expression remained unchanged. Expression of MMP-9 was found only inTF. MMP-9 may serve as a TF marker. In TF expression mRNA TIMP-1 was decreased. The level of free endogenous inhibitors in TF was significantly lower then the level in IF. Expression MMP correlated with the tumorigenic potential of TF. Invasive potential of cell lines associated with HPV18 (HeLa and S4-1) was more pronounced than that of cell lines associated with HPV16 (SiHa and Caski). The cell lines differed substantially in the level of expression of MMPI and their endogenous regulators. In most cell lines mRNA levels of collagenases MMP-1 and MMP-14 and the activator (uPA) increased, while gelatinase MMP-2 mRNA and tissue inhibitors mRNAs changed insignificantly. MMP-9 expression in cell lines was not detected. Results of studies on these cell lines suggest existence of an imbalance in the system enzyme/inhibitor/activator, that increases destructive potential of these cells. The study of expression of MMP and their endogenous regulators performed using SCC tumor samples associated with HPV16 has shown that the invasive and metastatic potentials of tumor tissue in SCC is obviously determined by the increase of expression of collagenases MMP-1, MT1-MMP and gelatinase MMP-9, decreased expression of inhibitors (TIMP-1 and TIMP-2), and to a lesser extent to increased expression of MMP-2. MMP-1 and MMP-9 can serve as markers of invasive and metastatic potential of the SCC tumor. In adjacent to the tumor normal tissue revealed a significant expression of MMP-1,-2,-9.
在宫颈鳞状细胞癌（SCC）中，对基质金属蛋白酶（MMPs）及其内源性调节因子的表达进行了研究。该研究包括：（i）永生化成纤维细胞（IF）和由致癌基因E7 HPV-16转化的三个成纤维细胞克隆（TF）；（ii）与HPV-16和HPV-18相关的细胞系；（iii）来自与基因E7 HPV-16相关的SCC患者的肿瘤组织样本。用E7 HPV16致癌基因转染成纤维细胞伴随着胶原酶（MMP-1、MMP-14）和明胶酶（MMP-9）基因表达的诱导以及这些MMP催化活性的增加，而明胶酶MMP-2的表达保持不变。仅在TF中发现MMP-9的表达。MMP-9可作为TF的标志物。在TF中，TIMP-1的mRNA表达降低。TF中游离内源性抑制剂的水平明显低于IF中的水平。MMP的表达与TF的致瘤潜能相关。与HPV18相关的细胞系（HeLa和S4-1）的侵袭潜能比与HPV16相关的细胞系（SiHa和Caski）更明显。这些细胞系在MMP1及其内源性调节因子的表达水平上有很大差异。在大多数细胞系中，胶原酶MMP-1和MMP-14以及激活剂（uPA）的mRNA水平升高，而明胶酶MMP-2的mRNA和组织抑制剂的mRNA变化不明显。在细胞系中未检测到MMP-9的表达。对这些细胞系的研究结果表明，酶/抑制剂/激活剂系统存在失衡，这增加了这些细胞的破坏潜能。使用与HPV16相关的SCC肿瘤样本进行的MMP及其内源性调节因子表达的研究表明，SCC肿瘤组织的侵袭和转移潜能明显由胶原酶MMP-1、MT1-MMP和明胶酶MMP-9表达的增加、抑制剂（TIMP-1和TIMP-2）表达的降低以及在较小程度上由MMP-2表达的增加所决定。MMP-1和MMP-9可作为SCC肿瘤侵袭和转移潜能的标志物。在肿瘤邻近的正常组织中发现MMP-1、-2、-9有明显表达。
