Connor Kip M, Hempel Nadine, Nelson Kristin K, Dabiri Ganary, Gamarra Aldo, Belarmino James, Van De Water Livingston, Mian Badar M, Melendez J Andres
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
Cancer Res. 2007 Nov 1;67(21):10260-7. doi: 10.1158/0008-5472.CAN-07-1204.
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 H(2)O(2) 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.
在某些癌症中，锰超氧化物歧化酶（Sod2）表达的临床显著升高与肿瘤侵袭和转移频率增加有关。本研究的目的是检验Sod2活性的增加是否会调节肿瘤细胞的迁移潜能，从而导致其转移行为增强。在HT - 1080纤维肉瘤细胞中过表达Sod2，在伤口愈合试验中其迁移能力显著增强2倍，在Transwell侵袭试验中其侵袭潜能增强3倍。侵袭的严重程度与Sod2表达水平直接相关，并且在253J膀胱肿瘤细胞中也观察到了类似的侵袭表型，与对照相比，Sod表达使侵袭增加了3倍。此外，过氧化氢酶过表达后，表达Sod2的细胞的迁移和侵袭受到抑制，这表明表达Sod2的细胞的促迁移/侵袭表型依赖于H(2)O(2)。Sod2过表达与纽蛋白阳性粘着斑的丧失有关，而在共表达过氧化氢酶的细胞中粘着斑得以恢复。将表达Sod2 - GFP的HT - 1080细胞经尾静脉注射到NCR裸鼠体内，导致出现显示高Sod2 - GFP表达的肺转移结节。分离出的肿瘤在培养中显示保留高Sod2活性以及基质降解蛋白基质金属蛋白酶 - 1水平升高，并且在从肿瘤结节长出的细胞群体中观察到促迁移表型。这些发现表明，癌症中Sod2活性增加与预后不良之间的关联可归因于其迁移和侵袭能力的改变。
