School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou Province, China.
Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China.
J Exp Clin Cancer Res. 2024 Mar 25;43(1):91. doi: 10.1186/s13046-024-03008-9.
Pancreatic cancer (PC) is a highly malignant gastrointestinal tumor, which is characterized by difficulties in early diagnosis, early metastasis, limited therapeutic response and a grim prognosis. Therefore, it is imperative to explore potential therapeutic targets for PC. Currently, although the involvement of the Pellino E3 Ubiquitin Protein Ligase 1 (PELI1) in the human growth of some malignant tumors has been demonstrated, its association with PC remains uncertain.
Bioinformatics, qRT-PCR, Western blot and IHC were used to detect the expression of PELI1 in pancreas or PC tissues and cells at mRNA and protein levels. The effects of PELI1 on the proliferation and metastatic ability of pancreatic cancer in vitro and in vivo were investigated using CCK8, cloning formation, EdU, flow cytometry, IHC, Transwell assay, wound healing, nude mice subcutaneous tumorigenesis and intrasplenic injection to construct a liver metastasis model. The interactions of PELI1 with proteins as well as the main functions and pathways were investigated by protein profiling, Co-IP, GST-pull down, Immunofluorescence techniques, immunohistochemical co-localization and enrichment analysis. The rescue experiment verified the above experimental results.
The mRNA and protein expression levels of PELI1 in PC tissues were upregulated and were associated with poor prognosis of patients, in vitro and in vivo experiments confirmed that PELI1 can affect the proliferation and metastatic ability of PC cells. Co-IP, GST-pull down, and other experiments found that PELI1 interacted with Ribosomal Protein S3 (RPS3) through the FHA structural domain and promoted the polyubiquitination of RPS3 in the K48 chain, thereby activates the PI3K/Akt/GSK3β signaling pathway. Moreover, ubiquitinated degradation of RPS3 further reduces Tumor Protein P53 (p53) protein stability and increases p53 degradation by MDM2 Proto-Oncogene (MDM2).
PELI1 is overexpressed in PC, which increased ubiquitination of RPS3 proteins and activates the PI3K/Akt/GSK3β signaling pathway, as well as reduces the protective effect of RPS3 on p53 and promotes the degradation of the p53 protein, which facilitates the progression of PC and leads to a poor prognosis for patients. Therefore, PELI1 is a potential target for the treatment of PC.
胰腺癌（PC）是一种高度恶性的胃肠道肿瘤，其特点是早期诊断困难、早期转移、治疗反应有限和预后不良。因此，探索 PC 的潜在治疗靶点迫在眉睫。目前，虽然已经证实 Pellino E3 泛素蛋白连接酶 1（PELI1）参与了一些恶性肿瘤的人类生长，但它与 PC 的关系尚不确定。
使用生物信息学、qRT-PCR、Western blot 和 IHC 检测 PELI1 在胰腺或 PC 组织和细胞中的 mRNA 和蛋白水平表达。使用 CCK8、克隆形成、EdU、流式细胞术、IHC、Transwell 测定、划痕愈合、裸鼠皮下肿瘤形成和脾内注射构建肝转移模型，研究 PELI1 对体外和体内胰腺癌增殖和转移能力的影响。通过蛋白质谱分析、Co-IP、GST-pull down、免疫荧光技术、免疫组化共定位和富集分析研究 PELI1 与蛋白质的相互作用以及主要功能和途径。通过 rescue 实验验证了上述实验结果。
PC 组织中 PELI1 的 mRNA 和蛋白表达水平上调，并与患者的不良预后相关，体外和体内实验证实 PELI1 可影响 PC 细胞的增殖和转移能力。Co-IP、GST-pull down 等实验发现，PELI1 通过 FHA 结构域与核糖体蛋白 S3（RPS3）相互作用，并促进 RPS3 在 K48 链上的多泛素化，从而激活 PI3K/Akt/GSK3β 信号通路。此外，RPS3 的泛素化降解进一步降低了肿瘤蛋白 P53（p53）蛋白的稳定性，并增加了 MDM2 原癌基因（MDM2）对 p53 的降解。
PELI1 在 PC 中过度表达，增加了 RPS3 蛋白的泛素化，激活了 PI3K/Akt/GSK3β 信号通路，降低了 RPS3 对 p53 的保护作用，并促进了 p53 蛋白的降解，促进了 PC 的进展，并导致患者预后不良。因此，PELI1 是治疗 PC 的潜在靶点。
