State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90001, USA.
Biochim Biophys Acta Mol Basis Dis. 2025 Jan;1871(1):167515. doi: 10.1016/j.bbadis.2024.167515. Epub 2024 Sep 13.
Pancreatic cancer is a highly malignant tumor characterized by high mortality and low survival rates. The mitotic interactor and substrate of Plk1 (MISP) is a cancer-associated protein that regulates mitotic spindle localization and is highly expressed in several malignant tumors, contributing to tumor development. However, the function and regulatory mechanisms of MISP in pancreatic cancer remain unclear. In this study, we analyzed RNA sequencing data related to pancreatic cancer from the TCGA and GEO databases, identifying MISP as a potential prognostic marker for the disease. MISP was significantly upregulated in pancreatic cancer cells and tissues compared to normal pancreatic cells and tissues. Notably, in pancreatic cancer cells, high MISP protein expression promoted cell proliferation and growth. Mechanistically, the upregulation of MISP facilitated the nuclear accumulation of β-catenin, thereby activating the Wnt/β-catenin signaling pathway and promoting pancreatic cancer growth. In search of effective inhibitors of MISP expression, we screened an FDA-approved drug library and identified Fisetin as a potential suppressor of MISP expression. Fisetin was found to downregulate the transcription factor MYB, thereby reducing MISP expression. Further experiments demonstrated that Fisetin effectively inhibited the in vitro and in vivo growth of pancreatic cancer by suppressing the MISP/Wnt/β-catenin signaling axis. In summary, our research has identified MISP as a novel therapeutic target in pancreatic cancer and uncovered its associated regulatory mechanisms.
胰腺癌是一种高度恶性肿瘤，其死亡率高，存活率低。有丝分裂原相互作用蛋白和 Plk1 的底物（MISP）是一种癌相关蛋白，它调节有丝分裂纺锤体定位，在几种恶性肿瘤中高度表达，促进肿瘤的发展。然而，MISP 在胰腺癌中的功能和调节机制尚不清楚。在这项研究中，我们分析了 TCGA 和 GEO 数据库中与胰腺癌相关的 RNA 测序数据，确定 MISP 是该疾病的一个潜在的预后标志物。与正常胰腺细胞和组织相比，MISP 在胰腺癌细胞和组织中显著上调。值得注意的是，在胰腺癌细胞中，高 MISP 蛋白表达促进了细胞增殖和生长。机制上，MISP 的上调促进了β-catenin 的核积累，从而激活了 Wnt/β-catenin 信号通路，促进了胰腺癌的生长。为了寻找 MISP 表达的有效抑制剂，我们筛选了一个 FDA 批准的药物库，发现非瑟酮是 MISP 表达的潜在抑制剂。非瑟酮被发现下调转录因子 MYB，从而降低 MISP 的表达。进一步的实验表明，非瑟酮通过抑制 MISP/Wnt/β-catenin 信号轴，有效地抑制了胰腺癌的体外和体内生长。总之，我们的研究确定了 MISP 是胰腺癌的一个新的治疗靶点，并揭示了其相关的调节机制。
