Department of General Surgery, The First Affiliated Hospital of Nanchang University, No.17 Yongwaizheng Street, Donghu District, Nanchang, 330006, Jiangxi, China.
Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
J Physiol Biochem. 2021 Feb;77(1):25-34. doi: 10.1007/s13105-020-00776-8. Epub 2020 Nov 17.
Never in mitosis gene A-related kinase 2 (NEK2) has been recognized as an oncogene involved in the initiation and progression of various human cancers. However, our knowledge is still lacking in regard to the function of NEK2 in gastric cancer, the most common cancer in Eastern Asia associated with poor prognosis. Therefore, in the present study, we investigated the association of NEK2 with gastric cancer. We found that the development of gastric cancer is associated with NEK2 overexpression, particularly in patients with large tumor size and lymph node metastasis. We also provided evidence that NEK2 overexpression binds to and inhibits protein phosphatase 1 (PP1), which subsequently activates AKT and the downstream oncogenic pathways. As a result, via AKT/HIF1α axis, the glucose metabolism is reprogrammed towards aerobic glycolysis to provide rapid energy for the growth of gastric cancer cells. Moreover, the autophagic activity is suppressed via AKT/mTOR axis, leading to impaired response to cancer treatment and enhanced cell survival. In contrast, inactivating AKT by NEK2 silencing decreases aerobic glycolysis and promotes autophagic cell death, which eventually inhibits the growth of gastric cancer cell. All these results revealed that NEK2 promotes gastric cancer progression via activating AKT-mediated signaling pathways, which expanded our knowledge on gastric cancer pathogenesis and also provided novel target for clinical treatment.
在有丝分裂基因 A 相关激酶 2（NEK2）中，从未被认为是涉及各种人类癌症的起始和进展的致癌基因。然而，我们对 NEK2 在东亚最常见的与预后不良相关的胃癌中的功能的了解仍然不足。因此，在本研究中，我们研究了 NEK2 与胃癌的关系。我们发现胃癌的发展与 NEK2 的过表达有关，特别是在肿瘤体积大且有淋巴结转移的患者中。我们还提供了证据表明，NEK2 过表达与蛋白磷酸酶 1（PP1）结合并抑制其活性，从而激活 AKT 和下游致癌途径。结果，通过 AKT/HIF1α 轴，葡萄糖代谢被重新编程为有氧糖酵解，为胃癌细胞的生长提供快速能量。此外，通过 AKT/mTOR 轴抑制自噬活性，导致对癌症治疗的反应受损和细胞存活能力增强。相比之下，通过沉默 NEK2 使 AKT 失活会减少有氧糖酵解并促进自噬性细胞死亡，最终抑制胃癌细胞的生长。所有这些结果表明，NEK2 通过激活 AKT 介导的信号通路促进胃癌的进展，这扩展了我们对胃癌发病机制的认识，并为临床治疗提供了新的靶点。
