Zhou Bo, Fan Zhuoyang, He Guodong, Zhang Wei, Yang Guowei, Ye Lechi, Xu Jianmin, Liu Rong
Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai 200032, China.
National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
iScience. 2024 Jul 6;27(8):110462. doi: 10.1016/j.isci.2024.110462. eCollection 2024 Aug 16.
Colorectal cancer (CRC) is one of the most common gastrointestinal tumors. Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) mutations occur in human solid tumors, including CRC. However, the function and underlying mechanism in CRC have not been well characterized. We demonstrated that the SHP2 and SHP2 mutations occurred in CRC tissues, and these mutations promoted CRC cell proliferation, migration/invasion, and reduced CDDP-induced cell apoptosis and . Mechanistically, SHP2 and SHP2 promote glycolysis by accelerating pyruvate kinase M2 (PKM2) nuclear translocation through mechanism beyond ERK activation. PKM2-IN-1 attenuates PKM2-dependent glycolysis and reduce glucose uptake, lactate production, and ATP levels promoted by SHP2D and SHP2 in CRC cells. Furthermore, PKM2 upregulates heterogeneous nuclear ribonucleoprotein K (hnRNPK) expression and increases CRC cell proliferation and migration/invasion via regulating hnRNPK ubiquitination. These findings provide evidence that SHP2 and SHP2 regulate CDDP-induced apoptosis, glucose metabolism, and CRC migration/invasion through PKM2 nuclear translocation and PKM2/hnRNPK signaling.
结直肠癌（CRC）是最常见的胃肠道肿瘤之一。含Src同源2结构域的蛋白酪氨酸磷酸酶2（SHP2）突变发生于包括CRC在内的人类实体瘤中。然而，其在CRC中的功能及潜在机制尚未得到充分阐明。我们证实SHP2及SHP2突变存在于CRC组织中，这些突变促进了CRC细胞的增殖、迁移/侵袭，并减少了顺铂诱导的细胞凋亡。机制上，SHP2及SHP2通过ERK激活以外的机制加速丙酮酸激酶M2（PKM2）核转位来促进糖酵解。PKM2-IN-1减弱PKM2依赖性糖酵解并减少CRC细胞中由SHP2D和SHP2促进的葡萄糖摄取、乳酸生成及ATP水平。此外，PKM2上调异质性核糖核蛋白K（hnRNPK）的表达，并通过调节hnRNPK泛素化增加CRC细胞的增殖及迁移/侵袭。这些发现提供了证据，表明SHP2和SHP2通过PKM2核转位及PKM2/hnRNPK信号通路调节顺铂诱导的凋亡、葡萄糖代谢及CRC的迁移/侵袭。
