分泌型热休克蛋白90α在肿瘤发生和转移中的作用机理
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摘要
热休克蛋白90α(Hsp90α)是一个伴侣蛋白,能够辅助蛋白折叠和维持细胞内多种信号传导蛋白的稳定,从而促进细胞存活和生长。在肿瘤细胞中,Hsp90α能够使过度激活或突变的信号传导蛋白保持活性,加速了肿瘤细胞的恶性转变。目前,Hsp90α已成为重要的抗肿瘤治疗靶点。
除胞内形式以外,Hsp90α还能被分泌到胞外。分泌型Hsp90α在肿瘤细胞、神经细胞、皮肤上皮细胞和免疫细胞中均被发现,但其功能和作用机理仍不清楚。本工作首先检测了分泌型Hsp90α在恶性程度不同的乳腺癌细胞系及正常乳腺上皮细胞系培养基中的含量,发现Hsp90α的分泌水平随肿瘤细胞侵袭程度的增加而升高,表明分泌型Hsp90α与肿瘤的侵袭密切相关。接下来,本工作克隆了人Hsp90α的基因,制备了人Hsp90α的重组蛋白及抗体;体外实验证明,分泌型Hsp90α能够促进肿瘤细胞侵袭,而对增殖没有明显作用。进一步的,在黑色素瘤转移模型中,Hsp90α小鼠单抗能够明显抑制肿瘤的肺转移,更为显著的是,肿瘤的淋巴结转移被完全抑制。更进一步的,本工作证明Hsp90α能够在血浆中被检测到,肿瘤病人血浆中Hsp90α的含量与肿瘤的恶性程度,尤其是转移正相关,有希望成为肿瘤诊断和预后的标志物。
同时,本工作探讨了分泌型Hsp90α促进肿瘤侵袭的机理。已有报道称,分泌型Hsp90α与基质金属蛋白酶-2(MMP-2)相互作用,Hsp90α的抑制剂能够降低MMP-2的活性,进而抑制肿瘤细胞侵袭;但对分泌型Hsp90α调节MMP-2活性的分子机制还没有解释。本研究证明分泌型Hsp90α能够通过与MMP-2的Hemopexin结构域相互作用,阻止MMP-2在Glu~(443)-Leu~(444)位点被酶切,进而阻止MMP-2降解失活。进一步的,我们还发现以上机制也存在于激活的内皮细胞中,分泌型Hsp90α能够促进肿瘤的新生血管生成。以上发现对分泌型Hsp90α的功能首次给予了分子机制上的解释,为分泌型Hsp90α新的相互作用蛋白的发现和机理研究提供了思路。
Heat shock protein 90-α(Hsp90α) is an intracellular molecular chaperone. It functions to maintain the normal protein folding environment and promote the cell survival under stress conditions. In tumor cells, the chaperoning activity of Hsp90αis subverted to retain the functions of mutant proteins and thus facilitate the malignant transformation. Meanwhile, Hsp90αcan also be secreted by tumor cells, but the functions of this extracellular form remains far from clear. Therefore, my study focuses on the functions of secreted Hsp90αon tumor cells and the underlying mechanisms. We demonstrate that secreted Hsp90αcan promote tumor invasiveness and is highly correlated with tumor malignancy. The blockage of secreted Hsp90αresults in significant inhibition on tumor invasion and complete prevention of lymph node metastasis. In addition, the level of plasma Hsp90αis positively correlated with tumor malignancy in cancer patients, indicating it is a potential diagnostic marker for tumor malignancy in clinical application.
Since we found that the secreted Hsp90αis highly correlated with tumor malignancy, we next investigated the mechanism behind this phenomenon. It is reported that secreted Hsp90αinteracts with MMP-2 and the inhibition of extracellular Hsp90αreduces the activity of MMP-2. In the present study, by the means of over-expressing, knocking down and also antibody blockage, we demonstrate that the pro-invasiveness activity of extracellular Hsp90αis dependent on MMP-2. But the regulatory mechanism of Hsp90αon the activity of MMP-2 is still unknown. We find that Hsp90αcan stabilize MMP-2 and prevent the proteolytic processing of MMP-2 via directly binding to the hemopexin domain. We further demonstrated that Hsp90αcan be secreted by endothelial cells and is a positive regulator of angiogenesis. Moreover, the antibody of Hsp90αpromotes MMP-2 processing and thus retards the angiogenesis and tumor invasiveness in vitro and in vivo.
In sum, here we reveal that secreted Hsp90αfunctions as a pro-invasiveness factor extracellularly and its level in plasma is positively correlated with the tumor malignancy, especially tumor metastasis. Meanwhile, we demonstrate that extracellular Hsp90αstabilizes MMP-2 and prevent its proteolytic processing via binding to the hemopexin domain, providing novel mechanistic explanations for both the function of extracellular Hsp90αand the regulatory mechanism of MMP-2 activity.
除胞内形式以外,Hsp90α还能被分泌到胞外。分泌型Hsp90α在肿瘤细胞、神经细胞、皮肤上皮细胞和免疫细胞中均被发现,但其功能和作用机理仍不清楚。本工作首先检测了分泌型Hsp90α在恶性程度不同的乳腺癌细胞系及正常乳腺上皮细胞系培养基中的含量,发现Hsp90α的分泌水平随肿瘤细胞侵袭程度的增加而升高,表明分泌型Hsp90α与肿瘤的侵袭密切相关。接下来,本工作克隆了人Hsp90α的基因,制备了人Hsp90α的重组蛋白及抗体;体外实验证明,分泌型Hsp90α能够促进肿瘤细胞侵袭,而对增殖没有明显作用。进一步的,在黑色素瘤转移模型中,Hsp90α小鼠单抗能够明显抑制肿瘤的肺转移,更为显著的是,肿瘤的淋巴结转移被完全抑制。更进一步的,本工作证明Hsp90α能够在血浆中被检测到,肿瘤病人血浆中Hsp90α的含量与肿瘤的恶性程度,尤其是转移正相关,有希望成为肿瘤诊断和预后的标志物。
同时,本工作探讨了分泌型Hsp90α促进肿瘤侵袭的机理。已有报道称,分泌型Hsp90α与基质金属蛋白酶-2(MMP-2)相互作用,Hsp90α的抑制剂能够降低MMP-2的活性,进而抑制肿瘤细胞侵袭;但对分泌型Hsp90α调节MMP-2活性的分子机制还没有解释。本研究证明分泌型Hsp90α能够通过与MMP-2的Hemopexin结构域相互作用,阻止MMP-2在Glu~(443)-Leu~(444)位点被酶切,进而阻止MMP-2降解失活。进一步的,我们还发现以上机制也存在于激活的内皮细胞中,分泌型Hsp90α能够促进肿瘤的新生血管生成。以上发现对分泌型Hsp90α的功能首次给予了分子机制上的解释,为分泌型Hsp90α新的相互作用蛋白的发现和机理研究提供了思路。
Heat shock protein 90-α(Hsp90α) is an intracellular molecular chaperone. It functions to maintain the normal protein folding environment and promote the cell survival under stress conditions. In tumor cells, the chaperoning activity of Hsp90αis subverted to retain the functions of mutant proteins and thus facilitate the malignant transformation. Meanwhile, Hsp90αcan also be secreted by tumor cells, but the functions of this extracellular form remains far from clear. Therefore, my study focuses on the functions of secreted Hsp90αon tumor cells and the underlying mechanisms. We demonstrate that secreted Hsp90αcan promote tumor invasiveness and is highly correlated with tumor malignancy. The blockage of secreted Hsp90αresults in significant inhibition on tumor invasion and complete prevention of lymph node metastasis. In addition, the level of plasma Hsp90αis positively correlated with tumor malignancy in cancer patients, indicating it is a potential diagnostic marker for tumor malignancy in clinical application.
Since we found that the secreted Hsp90αis highly correlated with tumor malignancy, we next investigated the mechanism behind this phenomenon. It is reported that secreted Hsp90αinteracts with MMP-2 and the inhibition of extracellular Hsp90αreduces the activity of MMP-2. In the present study, by the means of over-expressing, knocking down and also antibody blockage, we demonstrate that the pro-invasiveness activity of extracellular Hsp90αis dependent on MMP-2. But the regulatory mechanism of Hsp90αon the activity of MMP-2 is still unknown. We find that Hsp90αcan stabilize MMP-2 and prevent the proteolytic processing of MMP-2 via directly binding to the hemopexin domain. We further demonstrated that Hsp90αcan be secreted by endothelial cells and is a positive regulator of angiogenesis. Moreover, the antibody of Hsp90αpromotes MMP-2 processing and thus retards the angiogenesis and tumor invasiveness in vitro and in vivo.
In sum, here we reveal that secreted Hsp90αfunctions as a pro-invasiveness factor extracellularly and its level in plasma is positively correlated with the tumor malignancy, especially tumor metastasis. Meanwhile, we demonstrate that extracellular Hsp90αstabilizes MMP-2 and prevent its proteolytic processing via binding to the hemopexin domain, providing novel mechanistic explanations for both the function of extracellular Hsp90αand the regulatory mechanism of MMP-2 activity.
引文
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