Hepatology:中科院上海药物所耿美玉研究组等揭示pIgR/p-Yes亚群分型
近日，国际肝病学领域著名学术期刊《Hepatology》在线发表了中国科学院上海药物所耿美玉课题组、丁健课题组与复旦大学附属中山医院合作的一篇研究论文，研究报道了pIgR/p-Yes亚群分型是肝癌患者生存的预后标志物。
pIgR通常感受炎性微环境调控，介导细胞内多聚免疫球蛋白IgA和IgM的极性转运，是粘膜上皮组织最为重要的一个连接天然免疫和获得性免疫的免疫球蛋白受体。中国科学院上海药物研究所的科研人员在前期工作中首次发现了pIgR感受炎性微环境上调，通过募集活化Smad复合物，显著诱导肝癌细胞的上皮细胞间充质转化(EMT)，促进肝癌的早期复发与转移(J Natl Cancer Inst. 2011;103(22):1696-712)。
经科研人员近期的研究表明，高表达pIgR体内外显著促进肝癌细胞恶性增殖和肿瘤生长。分子机制研究表明，介导pIgR免疫转运的关键激酶Yes参与调控了pIgR介导的肿瘤生长效应;深入机制研究发现，pIgR通过募集活化Yes，启动了基于ITAM基序的经典免疫受体相关通路介导肿瘤生长。在对254例肝癌临床组织样本分析后发现，pIgR/p-Yes这个亚群是肝癌预后不良的重要预测标志物，在HBV阳性及早期病人中意义尤为显著;pIgR/p-Yes双阳性是肝癌总存活、总复发的独立预后标志物，对肝癌早期诊断具有重要的指导意义。更为重要的是，科研人员采用已上市药物，对于pIgR/p-Yes这个亚群提出了针对性的靶向治疗策略(Dasatinib/MEK抑制剂)，并在肝癌病人来源的PDX模型研究中进行了验证，Dasatinib/MEK抑制剂可以显著抑制pIgR/p-Yes双阳性亚群的肿瘤生长。
该研究挑战了对pIgR传统功能认识的局限，为免疫球蛋白受体的两面性提供了重要范例。pIgR采用生理条件下免疫转运相关通路介导肿瘤细胞恶性生长，为pIgR免疫背叛的深入理解奠定了基础。同时，研究工作也有效拓展了Dasatinib、MEK抑制剂的新敏感群体，对该类药物的临床应用具有重要的指导意义。
pIgR/p-Yes亚群分型是肝癌患者生存的预后标志物
原文链接：
Polymeric immunoglobulin receptor promotes tumor growth in hepatocellular carcinoma
原文摘要：
Deregulation of the immune system is believed to contribute to cancer malignancy, which has led to recent therapeutic breakthroughs facilitating antitumor immunity. In a malignant setting, immunoglobulin receptors, which are fundamental components of the human immune system, fulfill paradoxical roles in cancer pathogenesis. This study describes a previously unrecognized pro-oncogenic function of polymeric immunoglobulin receptor (pIgR) in the promotion of cell transformation and proliferation. Mechanistically, pIgR overexpression is associated with Yes activation, which is required for pIgR-induced oncogenic growth. Specifically, pIgR activates the Yes-Dap12-Syk-Rac1/CDC42-MEK/ERK cascade in an immunoreceptor tyrosine-based activating motif (ITAM)-dependent manner to promote cell transformation and tumor growth, although pIgR itself does not contain an ITAM sequence. Additionally, the combination of pIgR and phosphorylated Yes (p-Yes) levels serves as a prognostic biomarker for hepatitis B surface antigen (HBsAg)-positive and early stage hepatocellular carcinoma (HCC) patients. Moreover, pharmacological targeting of MEK/ERK or Yes represents a therapeutic option for the subgroup of patients with pIgR/p-Yes-positive HCC based on our results with both cancer cell line-based xenografts and primary patient-derived xenografts.
作者：耿美玉
