The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150040, China.
Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150040, China.
J Transl Med. 2022 May 4;20(1):191. doi: 10.1186/s12967-022-03370-2.
Triosephosphate isomerase 1 (TPI1), as a key glycolytic enzyme, is upregulated in multiple cancers. However, expression profile and regulatory mechanism of TPI1 in breast cancer (BRCA) remain mysterious.
Western blotting and immunohistochemistry (IHC) assays were used to investigate the expression of TPI1 in BRCA specimens and cell lines. TPI1 correlation with the clinicopathological characteristics and prognosis of 362 BRCA patients was analyzed using a tissue microarray. Overexpression and knockdown function experiments in cells and mice models were performed to elucidate the function and mechanisms of TPI1-induced BRCA progression. Related molecular mechanisms were clarified using co-IP, IF, mass spectrometric analysis, and ubiquitination assay.
We have found TPI1 is highly expressed in BRCA tissue and cell lines, acting as an independent indicator for prognosis in BRCA patients. TPI1 promotes BRCA cell glycolysis, proliferation and metastasis in vitro and in vivo. Mechanistically, TPI1 activates phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway to regulate epithelial-mesenchymal transformation (EMT) and aerobic glycolysis, which is positively mediated by cell division cycle associated 5 (CDCA5). Moreover, TPI1 interacts with sequestosome-1 (SQSTM1)/P62, and P62 decreases the protein expression of TPI1 by promoting its ubiquitination in MDA-MB-231 cells.
TPI1 promotes BRCA progression by stabilizing CDCA5, which then activates the PI3K/AKT/mTOR pathway. P62 promotes ubiquitin-dependent proteasome degradation of TPI1. Collectively, TPI1 promotes tumor development and progression, which may serve as a therapeutic target for BRCA.
磷酸丙糖异构酶 1（TPI1）作为一种关键的糖酵解酶，在多种癌症中上调。然而，TPI1 在乳腺癌（BRCA）中的表达谱和调控机制仍然神秘。
使用 Western blot 和免疫组织化学（IHC）检测来研究 TPI1 在 BRCA 标本和细胞系中的表达。使用组织微阵列分析 TPI1 与 362 例 BRCA 患者的临床病理特征和预后的相关性。在细胞和小鼠模型中进行过表达和敲低功能实验，以阐明 TPI1 诱导的 BRCA 进展的功能和机制。使用 co-IP、IF、质谱分析和泛素化测定来阐明相关的分子机制。
我们发现 TPI1 在 BRCA 组织和细胞系中高表达，可作为 BRCA 患者预后的独立指标。TPI1 在体外和体内促进 BRCA 细胞的糖酵解、增殖和转移。在机制上，TPI1 通过激活磷酸肌醇 3-激酶（PI3K）/AKT/雷帕霉素靶蛋白（mTOR）通路来调节上皮-间充质转化（EMT）和有氧糖酵解，这是由细胞分裂周期相关蛋白 5（CDCA5）正向介导的。此外，TPI1 与自噬相关蛋白 1（SQSTM1）/P62 相互作用，P62 通过促进 MDA-MB-231 细胞中 TPI1 的泛素化来降低其蛋白表达。
TPI1 通过稳定 CDCA5 促进 BRCA 进展，进而激活 PI3K/AKT/mTOR 通路。P62 通过促进泛素依赖性蛋白酶体降解 TPI1。总之，TPI1 促进肿瘤的发生和发展，可能成为 BRCA 的治疗靶点。
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