ADAM28屬于ADAM基因家族的金屬蛋白酶,，能切割血管性血友病因子（vWF）和抑制VWF介導(dǎo)腫瘤細(xì)胞凋亡，從而提高肺轉(zhuǎn)移,，假如抑制其表達(dá)的話能大幅減少肺轉(zhuǎn)移,，最新研究成果發(fā)表在Journal of The National Cancer Institute雜志上。
ADAMs與腫瘤的生長發(fā)展聯(lián)系在一起,，ADAM28在乳腺癌和非小細(xì)胞肺癌中過度表達(dá),，但ADAM28介導(dǎo)轉(zhuǎn)移的機(jī)制是未知的。
為了弄清ADAM28的作用,，Satsuki Mochizuki博士和同事篩選了ADAM28可能影響的蛋白,，發(fā)現(xiàn)VWF是其主要作用的蛋白。ADAM28影響VWF誘導(dǎo)的細(xì)胞凋亡作用，在小鼠模型研究中發(fā)現(xiàn)其抑制后,，人肺癌和乳腺癌細(xì)胞的肺轉(zhuǎn)移能力減小,。
研究人員發(fā)現(xiàn)抑制ADAM28的表達(dá)或活性能使得肺轉(zhuǎn)移大幅減少，血管中腫瘤細(xì)胞凋亡增加,。在這項(xiàng)研究中,，研究數(shù)據(jù)表明VWF誘導(dǎo)許多人細(xì)胞癌、肺癌,、乳腺癌等腫瘤細(xì)胞凋亡,，但只有當(dāng)這些腫瘤細(xì)胞低表達(dá)ADAM28后，上述現(xiàn)象才出現(xiàn),。研究人員指出該研究的局限性在于該模型不能模擬出自發(fā)的人類癌癥轉(zhuǎn)移的過程，但結(jié)果表明ADAM28有促進(jìn)癌細(xì)胞增殖和自發(fā)轉(zhuǎn)移到遠(yuǎn)處器官的雙向作用,。（生物谷：Bioon.com）
doi:10.1093/jnci/djs232
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Effect of ADAM28 on Carcinoma Cell Metastasis by Cleavage of von Willebrand Factor
Satsuki Mochizuki, Kenji Soejima, Masayuki Shimoda, Hitoshi Abe, Aya Sasaki, Hirotaka James Okano, Hideyuki Okano and Yasunori Okada
Background A disintegrin and metalloproteinase 28 (ADAM28) is implicated in tumor growth and metastasis in human breast and non–small cell lung carcinomas. We explored the mechanism of ADAM28-mediated metastasis by searching for new substrates of ADAM28.
Methods We used a yeast two-hybrid system to screen the human lung cDNA library for ADAM28-binding proteins and identified von Willebrand factor (VWF) as a potential candidate. Binding was confirmed using yeast two-hybrid and protein binding assays, and ADAM28-mediated cleavage of VWF was analyzed by immunoblotting. Exogenous VWF-induced apoptosis in vitro was examined in human lung carcinoma (PC-9 and Calu-3), breast carcinoma (MDA-MB231 and MCF-7), renal cell carcinoma (Caki-2 and 769P), and hepatocellular carcinoma (HepG2) cells, and expression of ADAM28 was assessed by reverse transcription–polymerase chain reaction and immunoblotting. Effect on lung metastasis of PC-9 and MDA-MB231 cells was assessed by knockdown of ADAM28 expression using short hairpin RNAs (ADAM28-shRNA) and small interfering RNAs (ADAM28-siRNA), and inhibition of activity using neutralizing anti-ADAM28 antibody, in a mouse xenograft model by in vivo imaging (n = 9 mice per group). All statistical tests were two-sided.
Results ADAM28 could bind to and cleave native VWF. Cells with very low ADAM28 expression (MCF-7, 769P, and HepG2) were susceptible to VWF-induced apoptosis, whereas cells with high expression (PC-9, Calu-3, MDA-MB231, and Caki-2) were resistant. Knockdown of ADAM28 expression in PC-9 and MDA-MB231 cells by shRNA showed increased carcinoma cell apoptosis mainly in lung blood vessels and statistically significantly decreased lung metastasis at week 3 after injection (PC-9-control [n = 9 mice] vs PC-9-ADAM28-shRNA [n = 9 mice]: mean count = 198 × 106 vs 37 × 106 photons/s, difference = 161 × 106 photons/s, 95% confidence interval = 134 × 106 to 188 × 106 photons/s, P < .001). Similar inhibition of lung metastasis was observed with ADAM28-siRNA and anti-ADAM28 antibody.
Conclusion ADAM28 cleaves and inactivates proapoptotic VWF in carcinoma cells and enhances lung metastasis probably by promoting carcinoma cell survival within the blood vessels.
