Regulation of angiogenesis and invasion by human Pituitary tumor transforming gene (PTTG) through increased expression and secretion of matrix metalloproteinase-2 (MMP-2).
Regulation of angiogenesis and invasion by human Pituitary tumor transforming gene (PTTG) through increased expression and secretion of matrix metalloproteinase-2 (MMP-2).
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DOI：
10.1186/1476-4598-5-61
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发表时间：
2006-11-10
期刊：
影响因子：
37.3
通讯作者：
Kakar SS
中科院分区：
文献类型：
--
作者：
Malik MT;Kakar SS
PTTG是一种新发现的癌基因，在大多数肿瘤组织中的表达水平高于正常组织。PTTG水平与肿瘤血管生成和转移之间的关系已被报道。然而，PTTG实现这些功能的机制仍然未知。在本研究中，我们研究了PTTG过表达对HEK 293细胞中转移相关金属蛋白酶-2（MMP-2）的分泌和表达、细胞迁移、侵袭和小管形成的影响。瞬时或稳定转染的HEK 293细胞与PTTG cDNA显示，MMP-2的分泌和表达的显着增加，通过酶谱法，逆转录酶（RT/PCR），ELISA和MMP-2基因启动子活性测量。此外，在我们的研究中，我们发现，在裸鼠中注射组成性表达PTTG的HEK 293细胞后，肿瘤发生，MMP-2 mRNA和蛋白质表达水平以及MMP-2活性都很高。从过表达PTTG的HEK 293细胞收集的条件培养基显示出显著增加人脐静脉内皮细胞（HUVEC）的细胞迁移、侵袭和小管形成。用MMP-2特异性抗体预处理条件培养基显著降低这些作用，表明PTTG可能通过激活蛋白水解促进肿瘤血管生成和转移，并通过调节MMP-2活性和表达增加侵袭。我们的研究结果提供了新的信息，PTTG有助于细胞迁移，侵袭和血管生成诱导MMP-2的分泌和表达。此外，我们发现，在裸鼠注射的HEK 293细胞，组成性表达PTTG诱导MMP-2的表达，并显着增加其功能活性，提示PTTG水平和MMP-2之间的关系，这可能在调节肿瘤生长，血管生成和转移的关键作用。阻断PTTG的功能或下调其在肿瘤中的表达可能通过下调MMP-2的表达和活性而抑制肿瘤的生长和转移。据我们所知，这项研究是第一个研究表明MMP-2的表达和生物活性的调节PTTG。
Pituitary tumor transforming gene (PTTG) is a novel oncogene that is expressed at higher level in most of the tumors analyzed to date compared to normal tissues. Existence of a relationship between PTTG levels and tumor angiogenesis and metastasis has been reported. However, the mechanisms by which PTTG achieve these functions remain unknown. In the present study, we investigated the effect of overexpression of PTTG on secretion and expression of metastasis-related metalloproteinase-2 (MMP-2) in HEK293 cells, cell migration, invasion and tubule formation. Transient or stable transfection of HEK293 cells with PTTG cDNA showed a significant increase in secretion and expression of MMP-2 measured by zymography, reverse transcriptase (RT/PCR), ELISA, and MMP-2 gene promoter activity. Furthermore, in our studies, we showed that tumor developed in nude mice on injection of HEK293 cells that constitutively express PTTG expressed high levels of both MMP-2 mRNA and protein, and MMP-2 activity. Conditioned medium collected from the HEK293 cells overexpressing PTTG showed a significant increase in cell migration, invasion and tubule formation of human umbilical vein endothelial cells (HUVEC). Pretreatment of conditioned medium with MMP-2-specific antibody significantly decreased these effects, suggesting that PTTG may contribute to tumor angiogenesis and metastasis via activation of proteolysis and increase in invasion through modulation of MMP-2 activity and expression. Our results provide novel information that PTTG contributes to cell migration, invasion and angiogenesis by induction of MMP-2 secretion and expression. Furthermore, we showed that tumors developed in nude mice on injection of HEK293 cells that constitutively express PTTG induce expression of MMP-2 and significantly increase its functional activity, suggesting a relationship between PTTG levels and MMP-2 which may play a critical role in regulation of tumor growth, angiogenesis and metastasis. Blocking of function of PTTG or down regulation of its expression in tumors may result in suppression of tumor growth and metastasis, through the down regulation of MMP-2 expression and activity. To our knowledge, this study is the first study demonstrating the modulation of MMP-2 expression and biological activity by PTTG.
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DOI：
10.1083/jcb.121.1.163
发表时间：
1993-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Leavesley DI;Schwartz MA;Rosenfeld M;Cheresh DA
通讯作者：
Cheresh DA
影响因子：
5.8
作者：
Ishikawa, H;Heaney, AP;Melmed, S
通讯作者：
Melmed, S
影响因子：
3.5
作者：
Kato, T;Kure, T;Azar, DT
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Azar, DT
影响因子：
--
作者：
Abbud, RA;Takumi, I;Melmed, S
通讯作者：
Melmed, S
影响因子：
2.9
作者：
HEUSSEN, C;DOWDLE, EB
通讯作者：
DOWDLE, EB