最新一期国际肝脏病学会官方杂志Liver Internatioal(IF:4.9)在线发表了山东大学齐鲁医院李涛副主任医师关于肝癌生物治疗的研究论文。恶性肿瘤细胞往往伴随着细胞表面糖蛋白结构的改变,而甘露糖在恶性肿瘤细胞表达往往升高。该研究发现肝癌细胞表面甘露糖的表达显著高于正常肝脏细胞,而通过生物基因工程合成的生物制剂PA-MSHA可特异性的识别肝癌细胞表面的甘露糖并与之结合,抑制EGFR/Akt/IκBβ/NF-κB信号通路,从而抑制肝癌的增殖,诱导肝癌细胞的凋亡及细胞周期阻滞,并可通过抑制肝癌上皮间质转化而抑制肝癌在体内的侵袭转移。该研究以肝癌细胞表面糖蛋白为治疗靶点,为肝癌的生物治疗提供了新的思路和方案,有助于提高肝癌患者的预后,减少术后的复发转移,具有积极的临床应用价值。
Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway
Li Tao http://onlinelibrary.wiley.com/doi/10.1111/liv.12644/abstract
Abstract
Background and Aims
Elevation of high mannose glycans is a common feature of malignant cells and has been suggested to be the basis for alternative cancer therapy for several years. Here we want to investigate the antitumor effect of pseudomonas aeruginosa-mannosesensitive hemagglutinin (PA-MSHA), a genetically engineered heat-inactivated PA strain with mannose-sensitive binding activity, on hepatocellular carcinoma (HCC).
Methods
Tumorigenicity and metastatic potentials of HCC were studied after PA-MSHA treatment by utilizing the in vitro/in vivo model of HCC. Expression of apoptosis-associated proteins and epithelial-mesenchymal transition (EMT) related genes were evaluated, and possible signaling pathways involved were investigated.
Results
PA-MSHA induced significant cell proliferation inhibition and cell cycle arrest of HCC through decreasing the levels of cyclins D1, cyclins E, CDK2, CDK4, proliferating cell nuclear antigen (PCNA), and increasing the level of p21 and p27. Moreover, PA-MSHA suppressed the invasion, migration and adhesion of HCC through inhibiting epithelial-mesenchymal transition (EMT). PA-MSHA also inhibited EGFR/Akt/IκBβ/NF-κB pathway and overexpression of NF-κB significantly abrogated PA-MSHA induced EMT inhibition. In addition, competitive inhibition of the mannose binding activity of PA-MSHA by D-mannose significantly blocked its effect on cell cycle arrest and EMT. PA-MSHA also abrogated lung metastasis of HCC and significantly inhibited tumor growth in the in vivo study.
Conclusions
Our study demonstrated the essential role of EGFR/Akt/IκBβ/NF-κB pathway in the inhibitory effect of PA-MSHA on invasion and metastasis of HCC through suppressing EMT, and revealed an attractive prospect of PA-MSHA as a novel candidate agent in the treatment of HCC.
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