中科院上海药物研究所耿美玉课题组、丁健课题组与复旦大学附属中山医院樊嘉课题组合作，在肝炎-肝癌恶性转化与肝癌复发转移生物标志物研究方面取得了重要进展。
肝癌是影响人类健康最常见的恶性肿瘤之一，肝炎和肝癌的发生密切相关，约3/4的肝癌与肝炎病毒HBV/HCV感染相关。目前，手术切除仍是肝癌首选的治疗方式，但术后的高复发率和转移率是制约肝癌病人生存率的瓶颈。近年来，越来越多的研究表明，上皮细胞间充质转化（EMT）作为链接“炎癌转化”的重要纽带，在促进肿瘤转移、肿瘤耐药以及肿瘤干性维持中发挥关键作用。
多聚免疫球蛋白受体pIgR是I型跨膜糖蛋白受体，通过感受炎性微环境介导细胞内多聚免疫球蛋白A和多聚免疫球蛋白M的极性转运，在先天与后天免疫中均发挥重要作用。
pIgR蛋白结构模拟图
上海药物研究所研究团队经过多年潜心研究，首次发现高表达pIgR在体内外均显著诱导肝癌细胞的上皮细胞间充质转化，促进肝癌的早期复发与转移。深入机制探讨表明，pIgR通过在早期内涵体以Smad2为桥梁募集活化Smad复合物，诱发EMT的发生；功能区域剖析结果显示，pIgR胞内段的Ser682与Ser734两个残基在EMT转化事件中发挥关键作用，特别值得指出的是，与pIgR转运功能密切相关的胞外段以及胞内段的Tyr677、Tyr743、Ser673和Ser735四个氨基酸残基均不参与pIgR的EMT恶性转化过程。为了探究pIgR表达与肝癌预后的关联性，通过与中山医院樊嘉课题组合作，发现pIgR高表达与肝癌预后密切相关，在HBV阳性肝癌病人中意义尤为显著。进一步分析表明，pIgR是肝癌早期复发转移的独立预测标志物。
肿瘤研究领域权威学术期刊美国《国立癌症研究所杂志》（J Natl Cancer Inst，影响因子14.697）于10月24日在线刊登了该项研究成果。同期，美国M.D.安德森癌症中心Sendurai A Mani博士以pIgR: Frenemy of inflammation, EMT, and HCC progression为题，对该研究进行了述评，认为不同于pIgR传统的免疫防御功能，该研究报道了首个免疫球蛋白受体pIgR作为关键的炎症介导者，通过诱导EMT促进了肝炎向肝癌的转移转化，在肝癌耐药及肝癌干性维持方面可能发挥着重要的调控作用；pIgR作为肝癌早期复发转移的独立预测标志物，为肝癌的早期诊断和治疗提供了分子标志物与靶标，对规避治疗风险具有重要的指导意义；同时，pIgR介导免疫球蛋白转运与EMT恶性转化功能域的不同，为特异性靶向pIgR介导EMT提供了重要的干预策略，这种选择性作用模式可能是赋予其发挥抗肿瘤复发转移、克服非特异性靶向免疫转运功能所致毒副作用的关键。
该研究工作挑战了对pIgR传统功能认识的局限，为重新定义免疫球蛋白受体家族的“非经典功能”奠定了重要的理论基础，为“炎癌转化”提供了一个全新的研究视角，为免疫球蛋白受体的免疫防御与免疫背叛的两面性研究提供了重要范例。
相关英文论文摘要：
The Role of Polymeric Immunoglobulin Receptor in Inflammation-Induced Tumor Metastasis of Human Hepatocellular Carcinoma
Background Expression of the polymeric immunoglobulin receptor (pIgR), a transporter of polymeric IgA and IgM, is commonly increased in response to viral or bacterial infections, linking innate and adaptive immunity. Abnormal expression of pIgR in cancer was also observed, but its clinical relevance remains uncertain.
Methods A human hepatocellular carcinoma (HCC) tissue microarray (n = 254) was used to investigate the association between pIgR expression and early recurrence. An experimental lung metastasis model using severe combined immune-deficient mice was applied to determine the metastatic potential of Madin–Darby canine kidney (n = 5 mice per group) and SMMC-7721 (n = 12 mice per group) cells overexpressing pIgR vs control cells. RNA interference, immunoprecipitation, and immunoblotting were performed to investigate the potential role for pIgR in the induction of epithelial–mesenchymal transition (EMT). In vitro studies (co-immunoprecipitation, immunoblotting, and migration, invasion, and adhesion assays) were used to determine the mechanisms behind pIgR-mediated metastasis. All statistical tests were two-sided.
Results High expression of pIgR was statistically significantly associated with early recurrence in early-stage HCC and in hepatitis B surface antigen–positive HCC patients (log-rank P = .02). Mice injected with pIgR-overexpressing cells had a statistically significantly higher number of lung metastases compared with respective control cells (Madin–Darby canine kidney cells: pIgR mean = 29.4 metastatic nodules per lung vs control mean = 0.0 metastatic nodules per lung, difference = 29.4 metastatic nodules per lung, 95% confidence interval = 13.0 to 45.8, P = .001; SMMC-7721 cells: pIgR mean = 10.4 metastatic nodules per lung vs control mean = 2.2 metastatic nodules per lung, difference = 8.2 metastatic nodules per lung, 95% confidence interval = 1.0 to 15.5, P = .03). Furthermore, high expression of pIgR was sufficient to induce EMT through activation of Smad signaling.
Conclusions pIgR plays a role in the induction of EMT. Our results identify pIgR as a potential link between hepatitis B virus–derived hepatitis and HCC metastasis and provide evidence in support of pIgR as a prognostic biomarker for HCC and a potential therapeutic target.
英文论文链接：https://www.biodiscover.com/news/immunology/library/1951
