Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
Gut. 2023 Sep;72(9):1722-1737. doi: 10.1136/gutjnl-2022-327492. Epub 2023 Feb 24.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression.
We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study.
The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses β-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP.
SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from β-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.
胰腺导管腺癌（PDAC）是一种具有有限治疗选择的高度致命肿瘤。在这里，我们鉴定了 syndecan 结合蛋白（SDCBP），也称为 syntenin1，作为促进 PDAC 肿瘤进展的新型靶向因子。我们还探索了抑制 SDCBP 表达的治疗策略。
我们使用来自 PDAC 患者的样本、人类类器官模型、LSL-KrasG12D/+ 小鼠、LSL-Trp53R172H/+ 和 Pdx1-Cre（KPC）小鼠模型以及 PDX 小鼠模型进行了这项研究。进行了免疫染色、集落形成测定、乙炔基-2-脱氧尿苷掺入测定、实时细胞分析、细胞凋亡测定、自动细胞跟踪、侵袭小窝检测和明胶降解测定、共免疫沉淀和下拉测定。
高 SDCBP 组的中位总生存期和无复发生存率明显短于低 SDCBP 组。体外和体内研究表明 SDCBP 促进 PDAC 的增殖和转移。机制上，SDCBP 抑制 CK1δ/ε 介导的 YAP-S384/S387 磷酸化，通过直接与 YAP1 相互作用，进一步抑制 β-TrCP 介导的 YAP1 泛素化和蛋白酶体降解。SDCBP 与 YAP1 的 TAD 结构域相互作用，主要通过其 PDZ1 结构域。临床前 KPC 小鼠队列表明，吡啶硫酮锌（ZnPT）通过抑制 SDCBP 抑制 PDAC 肿瘤进展。
SDCBP 通过阻止 YAP1 被 β-TrCP 介导的蛋白酶体降解来促进 PDAC 的增殖和转移。因此，ZnPT 可能是通过抑制 SDCBP 来抑制 PDAC 进展的一种很有前途的治疗策略。
