Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer.
Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer.
复制标题
DOI：
10.18632/oncotarget.10529
复制
发表时间：
2017-04-11
期刊：
影响因子：
--
通讯作者：
Lokeshwar VB
中科院分区：
文献类型：
--
作者：
Jordan AR;Lokeshwar SD;Lopez LE;Hennig M;Chipollini J;Yates T;Hupe MC;Merseburger AS;Shiedlin A;Cerwinka WH;Liu K;Lokeshwar VB
肿瘤细胞源性透明质酸酶（HYAL-1）将透明质酸（HA）降解为血管生成片段（AGF: 10-12双糖）。AGF支持肿瘤生长和进展。尿和组织HAase/HYAL-1水平是高级别膀胱癌（BCa）及其转移的敏感标志物。在BCa的临床前模型中，我们评估了o-硫酸盐AGF （sHA-F）是否抑制HAase活性并具有抗肿瘤活性。在HAase活性抑制IC50 （5 ~ 20 μg/ml [0.4 ~ 1.7 μM]）下，sHA-F显著抑制表达HYAL-1的BCa细胞（25j - lung, HT1376, UMUC-3）的增殖、运动和侵袭，P<0.001。sHA-F不影响不表达HYAL-1的BCa（5637、RT4、T24、TCCSUP）和正常尿路上皮（Urotsa、SV-HUC1）细胞的生长。sHA-F通过死亡受体途径诱导细胞凋亡。sHA-F下调HA受体（CD44、RHAMM）、p-AKT、β-catenin、p- β-catenin （S552）、Snail和Twist的转录本和/或蛋白水平，但上调p- β-catenin （T41/S45）、pGSK-3α/β(S21/S9)和E-cadherin的水平。sHA-F还能抑制CD44/磷酸肌肽3激酶（PI-3K）复合物的形成和PI-3K的活性。AGF的加入或肉豆蔻酰化akt的过表达减弱了sHA-F的作用。相反，HYAL-1表达使RT4细胞对sHA-F敏感。在25j - l和HT1376异种移植物模型中，sHA-F治疗显著抑制肿瘤生长（P<0.001），可能是通过抑制血管生成和HA受体- pi - 3k /AKT信号传导。这项研究表明，sHA-F靶向肿瘤相关的HA-HAase系统，可能在BCa治疗中有潜在的用途。
Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for high-grade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 μg/ml [0.4-1.7 μM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P<0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, β-catenin, pβ-Catenin(S552), Snail and Twist but increased levels of pβ-Catenin(T41/S45), pGSK-3α/β(S21/S9) and E-cadherin. sHA-F also inhibited CD44/Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL-1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P<0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment.