Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity.
Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity.
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DOI：
10.1186/s12885-023-10608-9
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发表时间：
2023-02-15
期刊：
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
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作者：
半乳糖凝集素-3（Galectin-3，Gal-3）是目前唯一的嵌合β-半乳糖苷结合凝集素，由Gal-3 N（N-末端调节肽）和Gal-3C（C-末端糖识别结构域）组成。有趣的是，Gal-3C可以特异性地抑制内源性全长Gal-3以表现出抗肿瘤活性。在此，我们旨在通过开发新的融合蛋白来进一步提高Gal-3C的抗肿瘤活性。 将纤溶酶原的第五个kringle结构域PK 5通过刚性连接体（RL）引入Gal-3C的N端，构建了新型融合蛋白PK 5-RL-Gal-3C。然后，通过多种实验研究了PK 5-RL-Gal-3C的体内外抗肿瘤活性，并探讨了其抗血管生成和细胞毒作用的分子机制。我们的研究结果表明，PK 5-RL-Gal-3C在体内外均能抑制肝癌，无明显毒性，并能显著延长荷瘤小鼠的生存时间。在机制上，我们发现PK 5-RL-Gal-3C抑制血管生成并显示对HCC的细胞毒性。具体地，HUVEC相关和基质胶塞测定表明PK 5-RL-Gal-3C在体内和体外通过调节HIF 1 α/VEGF和Ang-2在抑制血管生成中起重要作用。此外，PK 5-RL-Gal-3C诱导细胞周期停滞在G1期和细胞凋亡，抑制Cyclin D1、Cyclin D3、CDK 4和Bcl-2，但激活p27、p21、caspase-3、-8和-9。新型融合蛋白PK 5-RL-Gal-3C是一种有效的肝癌血管生成抑制剂，也是潜在的Gal-3拮抗剂，为开发新型Gal-3拮抗剂提供了新的策略，促进了其在临床治疗中的应用。在线版本包含补充材料，可通过10.1186/s12885-023-10608-9获得。
Galectin-3 (Gal-3), the only chimeric β-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor activity. Here, we aimed to further improve the anti-tumor activity of Gal-3C via developing novel fusion proteins. PK5 (the fifth kringle domain of plasminogen) was introduced to the N-terminus of Gal-3C via rigid linker (RL) to generate novel fusion protein PK5-RL-Gal-3C. Then, we investigated the anti-tumor activity of PK5-RL-Gal-3C in vivo and in vitro by using several experiments, and figured out their molecular mechanisms in anti-angiogenesis and cytotoxicity to hepatocellular carcinoma (HCC). Our results show that PK5-RL-Gal-3C can inhibit HCC both in vivo and in vitro without obvious toxicity, and also significantly prolong the survival time of tumor-bearing mice. Mechanically, we find that PK5-RL-Gal-3C inhibits angiogenesis and show cytotoxicity to HCC. In detail, HUVEC-related and matrigel plug assays indicate that PK5-RL-Gal-3C plays an important role in inhibiting angiogenesis by regulating HIF1α/VEGF and Ang-2 both in vivo and in vitro. Moreover, PK5-RL-Gal-3C induces cell cycle arrest at G1 phase and apoptosis with inhibition of Cyclin D1, Cyclin D3, CDK4, and Bcl-2, but activation of p27, p21, caspase-3, -8 and -9. Novel fusion protein PK5-RL-Gal-3C is potent therapeutic agent by inhibiting tumor angiogenesis in HCC and potential antagonist of Gal-3, which provides new strategy for exploring novel antagonist of Gal-3 and promotes their application in clinical treatment. The online version contains supplementary material available at 10.1186/s12885-023-10608-9.
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纤溶酶原 kringle 5 通过调节 HIF-1 α 和 GRP78 抑制胃癌
影响因子：
9
作者：
Fang S;Hong H;Li L;He D;Xu Z;Zuo S;Han J;Wu Q;Dai Z;Cai W;Ma J;Shao C;Gao G;Yang X
通讯作者：
Yang X
影响因子：
3.7
作者：
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通讯作者：
Chiriva-Internati M
影响因子：
6.4
作者：
Nangia-Makker, Pratima;Wang, Yi;Raz, Tirza;Tait, Larry;Balan, Vitaly;Hogan, Victor;Raz, Avraham
通讯作者：
Raz, Avraham
影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
DOI：
10.1073/pnas.1525360113
发表时间：
2016-04-19
影响因子：
11.1
作者：
Kloepper, Jonas;Riedemann, Lars;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.