Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China.
Hepatology. 2017 Jun;65(6):1948-1962. doi: 10.1002/hep.29036. Epub 2017 Apr 28.
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 proto-oncogene 1, Src family tyrosine kinase (Yes) activation, which is required for pIgR-induced oncogenic growth. Specifically, pIgR activates the Yes-DNAX-activating protein of 12 kDa-spleen tyrosine kinase-Rac1/CDC42-MEK (extracellular signal-regulated kinase kinase)/ERK (extracellular signal-regulated kinase) 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-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.
Our findings reveal the molecular mechanism by which pIgR promotes cancer malignancy, suggest the clinical potential of targeting this pathway in HCC, and provide new insight into the oncogenic role of immunoglobulin receptors. (Hepatology 2017;65:1948-1962).
免疫系统的失调被认为是癌症恶性的原因之一，这导致了最近在促进抗肿瘤免疫方面的治疗突破。在恶性环境中，免疫球蛋白受体作为人体免疫系统的基本组成部分，在癌症发病机制中发挥着矛盾的作用。本研究描述了多聚免疫球蛋白受体（pIgR）在促进细胞转化和增殖方面的以前未被认识的致癌作用。从机制上讲，pIgR 的过表达与 YES 原癌基因 1、Src 家族酪氨酸激酶（Yes）的激活有关，这是 pIgR 诱导致癌生长所必需的。具体而言，pIgR 通过依赖免疫受体酪氨酸激活基序（ITAM）的方式激活 Yes-DNAX-激活蛋白 12 kDa-脾酪氨酸激酶-Rac1/CDC42-MEK（细胞外信号调节激酶激酶）/ERK（细胞外信号调节激酶）级联，从而促进细胞转化和肿瘤生长，尽管 pIgR 本身不含 ITAM 序列。此外，pIgR 和磷酸化 Yes（p-Yes）水平的组合可作为乙型肝炎表面抗原阳性和早期肝细胞癌（HCC）患者的预后标志物。此外，根据我们在基于癌症细胞系的异种移植和原发性患者来源的异种移植中的结果，MEK/ERK 或 Yes 的药理学靶向可能成为 pIgR/p-Yes 阳性 HCC 患者亚组的治疗选择。
我们的研究结果揭示了 pIgR 促进癌症恶性的分子机制，提示了靶向该途径治疗 HCC 的临床潜力，并为免疫球蛋白受体的致癌作用提供了新的见解。（《肝脏病学》2017；65：1948-1962）。
