Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells
Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells
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DOI：
10.1158/0008-5472.can-07-1204
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发表时间：
2007-11-01
期刊：
影响因子：
11.2
通讯作者：
Melendez, J. Andres
中科院分区：
文献类型：
--
作者：
Connor, Kip M.;Hempel, Nadine;Melendez, J. Andres
在某些癌症中，锰超氧化物歧化酶(Sod2)表达的显著升高与肿瘤侵袭和转移的频率增加有关。这项研究的目的是检验Sod2活性的增加是否调节了肿瘤细胞的迁移潜力，从而促进了它们的转移行为。在HT-1080纤维肉瘤细胞中过表达Sod2使其在伤口愈合实验中的迁移能力显著增加2倍，在跨孔侵袭实验中显著增加3倍。侵袭的严重程度与Sod2的表达水平直接相关，在253J膀胱肿瘤细胞中也观察到这种侵袭表型，其中Sod2的表达导致侵袭的程度是对照组的3倍。此外，过表达过氧化氢酶后，表达Sod2的细胞的迁移和侵袭受到抑制，表明表达Sod2的细胞的迁移/侵袭表型依赖于H_2O_2。Sod2的过度表达与在共表达过氧化氢酶的细胞中恢复的纽蛋白阳性的局灶性粘连的丧失有关。NCR裸鼠尾静脉注射表达Sod2-GFP的HT-1080细胞可形成高表达Sod2-GFP的肺转移结节。分离的肿瘤在培养中保持着高的Sod2活性，基质降解蛋白基质金属蛋白酶-1水平升高，从肿瘤结节中长出的细胞群体中观察到了迁移表型。这些发现表明，SOD2活性增加和癌症预后不良之间的关联可以归因于它们的迁移和侵袭能力的改变。
Clinically significant elevations in the expression of manganese superoxide dismutase (Sod2) are associated with an increased frequency of tumor invasion and metastasis in certain cancers. The aim of this study was to examine whether increases in Sod2 activity modulate the migratory potential of tumor cells, contributing to their enhanced metastatic behavior. Overexpression of Sod2 in HT-1080 fibrosarcoma cells significantly enhanced their migration 2-fold in a wound healing assay and their invasive potential 3-fold in a transwell invasion assay. Severity of invasion was directly correlated to Sod2 expression levels and this invasive phenotype was similarly observed in 253J bladder tumor cells, in which Sod expression resulted in a 3-fold increase in invasion compared with controls. Further, migration and invasion of the Sod2-expressing cells was inhibited following overexpression of catalase, indicating that the promigratory/ invasive phenotype of Sod2-expressing cells is H2O2 dependent. Sod2 overexpression was associated with a loss of vinculin-positive focal adhesions that were recovered in cells coexpressing catalase. Tail vein injections of Sod2-GFP-expressing HT-1080 cells in NCR nude mice led to the development of pulmonary metastatic nodules displaying high Sod2-GFP expression. Isolated tumors were shown to retain high Sod2 activity in culture and elevated levels of the matrix degrading protein matrix metalloproteinase-1, and a promigratory phenotype was observed in a population of cells growing out from the tumor nodule. These findings suggest that the association between increased Sod2 activity and poor prognosis in cancer can be attributed to alterations in their migratory and invasive capacity.