J Natl Cancer Inst 2011 Nov;103 (22): 1696-712. [IF:14.697]
The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma.
Ai J , Tang Q , Wu Y , Xu Y , Feng T , Zhou R , Chen Y , Gao X , Zhu Q , Yue X , Pan Q , Xu S , Li J , Huang M , Daugherty-Holtrop J , He Y , Xu HE , Fan J , Ding J , Geng M .
PhD and Jian Ding, Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai 201203, People's Republic of China. mygeng@mail.shcnc.ac.cn.
北京大学蛋白质与植物基因研究国家重点实验室，中国科学院上海药物研究所
Abstract
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.
摘要：
背景：多聚免疫球蛋白受体pIgR作为多聚IgA和多聚IgM的转运者，其表达在病毒或细菌等感染中普遍反应性增加，在先天与后天免疫中均发挥重要作用。pIgR的异常表达在癌症中也可被观察到，但其临床意义仍未确定。方法：我们采用人类肝细胞癌(HCC)的组织芯片(n = 254), 探讨了pIgR表达量和肝癌早期复发的联系。一例利用重型联合免疫缺陷小鼠制成的实验性肺转移模型被运用来确定过量表达pIgR的犬肾上皮细胞（每组5只老鼠）和的肝癌SMMC-7721细胞（每组12只老鼠）相对于对照组的转移潜能。RNA干涉，免疫沉淀，免疫印迹等技术均被用于探究pIgR在上皮间质转化（EMT）的诱导过程的可能作用。通过体外研究（免疫共沉淀，免疫印迹和转移，侵袭，粘附实验等）确定pIgR介导的转移机制，所有进行的统计试验都是双向的。结果：pIgR高表达与早期肝细胞癌和乙肝表面抗原（+）的肝细胞癌的早期复发有着显著性统计意义的关联（对数秩检验P=0.02），注射过度表达pIgR细胞的小鼠相对于各自的对照组细胞有着显著性统计意义的高发肺转移（犬肾上皮细胞：pIgR，平均每肺29.4转移性小瘤vs对照组平均每肺0.0转移性小瘤，差异值为平均每肺29.4转移性小瘤95%可信区间为13.0-45.8，P=0.001; SMMC-7721细胞系：pIgR，平均每肺10.4转移小瘤 vs对照组,平均每肺2.2转移性小瘤，差异为每肺8.2转移性小瘤，95%可信区间为1.0-15.0，Ｐ＝0.03）。此外，ｐＩｇＲ的高量表达足以通过激活Smad信号通路来诱导上皮间质转化（EMT）。结论：ｐＩｇＲ在上皮间质转化（EMT）的诱导过程中起着重要的作用，我们的研究确定了pIgR为乙型肝炎病毒相关肝炎和肝细胞癌转移之间的一个潜在的联系，并为pIgR在肝细胞癌中作为预后的分子标志和潜在性治疗靶标提供支持证据。
