Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis.
Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis.
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DOI：
10.1016/j.neo.2021.06.001
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Tanaka J
中科院分区：
文献类型：
--
作者：
Ozaki S;Umakoshi A;Yano H;Ohsumi S;Sumida Y;Hayase E;Usa E;Islam A;Choudhury ME;Nishi Y;Yamashita D;Ohtsuka Y;Nishikawa M;Inoue A;Suehiro S;Kuwabara J;Watanabe H;Takada Y;Watanabe Y;Nakano I;Kunieda T;Tanaka J
CLIC 2在良性、侵袭性较小和转移性较小的肿瘤中高度表达。CLIC 2的强制表达防止动物肿瘤模型中的转移和侵袭。CLIC 2与肿瘤块中血管通透性降低相关。CLIC 2是一种可分泌的可溶性蛋白，可结合并抑制MMP 14。细胞外CLIC 2可以抑制恶性细胞的侵袭。侵袭周围组织和转移到远处器官的能力是区分恶性肿瘤和良性肿瘤的最显著特征。然而，其阻止良性肿瘤细胞侵袭和转移的机制尚不清楚。利用我们自己的大鼠远处转移模型，比较原发性肿瘤和转移性肿瘤细胞的基因表达。在许多不同的基因表达，我们集中在氯细胞内通道蛋白2（CLIC 2），离子通道蛋白的功能尚不清楚，这是主要在原发性肿瘤中表达。我们创建了CLIC 2过表达的大鼠胶质瘤细胞系，并利用了具有天然高CLIC 2表达的良性人脑膜瘤细胞。CLIC 2在良性人脑肿瘤中的表达水平高于恶性脑肿瘤。此外，它的高表达与大鼠转移和脑肿瘤模型中的生存期延长以及脑肿瘤患者的无进展生存期相关。CLIC 2还可能通过增加细胞粘附分子的含量而与血管通透性降低相关。我们发现CLIC 2分泌到细胞外，并与基质金属蛋白酶（MMP）14结合。此外，CLIC 2阻止MMP 14在质膜中的定位，并抑制其酶活性。事实上，过表达CLIC 2和重组CLIC 2蛋白有效地抑制恶性细胞侵袭，而CLIC 2敲低逆转了这些作用。因此，CLIC 2至少部分地通过抑制MMP 14活性来抑制良性肿瘤的侵袭和转移。
CLIC2 is highly expressed in benign, less invasive and less metastatic tumors. Forced expression of CLIC2 prevents metastasis and invasion in animal tumor models. CLIC2 is associated with decreased vascular permeability in tumor masses. CLIC2, a secretable soluble protein, can bind to and inhibit MMP14. Extracellular CLIC2 can suppress malignant cell invasion. The abilities to invade surrounding tissues and metastasize to distant organs are the most outstanding features that distinguish malignant from benign tumors. However, the mechanisms preventing the invasion and metastasis of benign tumor cells remain unclear. By using our own rat distant metastasis model, gene expression of cells in primary tumors was compared with that in metastasized tumors. Among many distinct gene expressions, we have focused on chloride intracellular channel protein 2 (CLIC2), an ion channel protein of as-yet unknown function, which was predominantly expressed in the primary tumors. We created CLIC2 overexpressing rat glioma cell line and utilized benign human meningioma cells with naturally high CLIC2 expression. CLIC2 was expressed at higher levels in benign human brain tumors than in their malignant counterparts. Moreover, its high expression was associated with prolonged survival in the rat metastasis and brain tumor models as well as with progression-free survival in patients with brain tumors. CLIC2 was also correlated with the decreased blood vessel permeability likely by increased contents of cell adhesion molecules. We found that CLIC2 was secreted extracellularly, and bound to matrix metalloproteinase (MMP) 14. Furthermore, CLIC2 prevented the localization of MMP14 in the plasma membrane, and inhibited its enzymatic activity. Indeed, overexpressing CLIC2 and recombinant CLIC2 protein effectively suppressed malignant cell invasion, whereas CLIC2 knockdown reversed these effects. Thus, CLIC2 suppress invasion and metastasis of benign tumors at least partly by inhibiting MMP14 activity.
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影响因子：
4
作者：
Hakulinen, Juha;Sankkila, Lotta;Keski-Oja, Jorma
通讯作者：
Keski-Oja, Jorma
影响因子：
2.9
作者：
Abbruscato, TJ;Davis, TP
通讯作者：
Davis, TP
影响因子：
6.3
作者：
Matsumoto, Hiroaki;Kumon, Yoshiaki;Tanaka, Junya
通讯作者：
Tanaka, Junya
影响因子：
5.7
作者：
Li Z;Takino T;Endo Y;Sato H
通讯作者：
Sato H
DOI：
10.1016/j.neo.2016.02.006
发表时间：
2016-04
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Kobayashi K;Yano H;Umakoshi A;Matsumoto S;Mise A;Funahashi Y;Ueno Y;Kamei Y;Takada Y;Kumon Y;Ohnishi T;Tanaka J
通讯作者：
Tanaka J