Zhang Wei, Jiang Tingting, Zhang Huiqing, Wei Fang, Li Xiaojia, Xie Keping
Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong, 510006, China.
The South China University of Technology Comprehensive Cancer Center, Guangzhou, Guangdong, 510006, China.
Cell Oncol (Dordr). 2025 Sep 1. doi: 10.1007/s13402-025-01084-3.
Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal malignancies with limited early diagnostic and therapeutic options. Although receptor for activated C kinase 1 (RACK1) is an evolutionarily conserved scaffold protein, its functional role and mechanistic involvement in PDA pathogenesis remain elusive.
Using multimodal approaches including: (1) genetically engineered mouse models of pancreatitis and carcinogenesis, (2) patient-derived PDA tissues with matched normal specimens, (3) primary acinar cell 3D cultures, and (4) orthogonal gain/loss-of-function assays in PDA cell lines, we systematically investigated RACK1's spatiotemporal expression patterns and functional impacts. Mechanistic dissection was performed through gene expression profiling and pathway enrichment analyses with functional validation.
RACK1 exhibited progressive silencing across pancreatic lesion progression: acinar cells (normal) > ADM > pancreatic intraepithelial neoplasia (PanIN) > PDA. This acinar-specific protein was undetectable in ductal/islet lineages and was further suppressed under inflammatory challenge. Functionally, RACK1 depletion accelerated ADM initiation and enhanced PDA cell motility and metastatic dissemination in vivo, whereas its overexpression exerted tumor-suppressive effects. Mechanistically, caerulein/TGF-α stimulation and Kras activation converged to inhibit RACK1 while activating MAP2K3-SRC-RELA(p65) signaling nodes, establishing a pro-inflammatory feedforward loop.
RACK1 serves as a gatekeeper restraining inflammation-driven ADM transformation, with its downregulation constituting an early molecular event in PDA pathogenesis. The RACK1-MAP2K3 axis orchestrates malignant transition through simultaneous NF-κB activation (inflammatory priming) and MAPK hyperactivation (proliferative drive). Our findings nominate RACK1 as both a stratification biomarker for high-risk pancreatic lesions and a druggable node for intercepting preneoplastic progression.
胰腺导管腺癌（PDA）仍然是最致命的恶性肿瘤之一，早期诊断和治疗选择有限。尽管活化C激酶1受体（RACK1）是一种进化保守的支架蛋白，但其在PDA发病机制中的功能作用和机制仍不清楚。
使用多模态方法，包括：（1）胰腺炎和致癌作用的基因工程小鼠模型，（2）患者来源的PDA组织及匹配的正常标本，（3）原代腺泡细胞3D培养，以及（4）PDA细胞系中的正交功能获得/缺失测定，我们系统地研究了RACK1的时空表达模式和功能影响。通过基因表达谱分析和通路富集分析进行机制剖析，并进行功能验证。
RACK1在胰腺病变进展过程中表现出逐渐沉默：腺泡细胞（正常）＞腺泡化生（ADM）＞胰腺上皮内瘤变（PanIN）＞PDA。这种腺泡特异性蛋白在导管/胰岛谱系中无法检测到，并且在炎症刺激下进一步受到抑制。在功能上，RACK1缺失加速了ADM起始，并增强了PDA细胞在体内的运动性和转移扩散，而其过表达则发挥肿瘤抑制作用。机制上，蛙皮素/TGF-α刺激和Kras激活共同抑制RACK1，同时激活MAP2K3-SRC-RELA（p65）信号节点，建立一个促炎前馈环。
RACK1作为一种守门蛋白，可抑制炎症驱动的ADM转化，其下调是PDA发病机制中的早期分子事件。RACK1-MAP2K3轴通过同时激活NF-κB（炎症启动）和MAPK过度激活（增殖驱动）来协调恶性转化。我们的研究结果表明，RACK1既是高危胰腺病变的分层生物标志物，也是拦截肿瘤前进展的可药物作用节点。
