Yan Zilong, Da Qingen, Li Zhangfu, Lin Qirui, Yi Jing, Su Yanze, Yu Guanyin, Ren Qingqi, Liu Xu, Lin Zewei, Qu Jianhua, Yin Weihua, Liu Jikui
Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China.
Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China.
Front Oncol. 2022 Feb 10;12:812655. doi: 10.3389/fonc.2022.812655. eCollection 2022.
NIMA-related kinase 7 (NEK7) is a serine/threonine kinase involved in cell cycle progression mitotic spindle formation and cytokinesis. It has been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer, and colorectal cancer. Moreover, NEK7 regulated the NLRP3 inflammasome to activate Caspase-1, resulting in cell pyroptosis. In the present study, we investigated whether NEK7 is involved in cell pyroptosis of hepatocellular carcinoma (HCC). Interestingly, we found that NEK7 was significantly related to expression of pyroptosis marker GSDMD in HCC. We found that NEK7 expression was significantly correlated with GSDMD expression in bioinformatics analysis, and NEK7 expression was significantly co-expressed with GSDMD in our HCC specimens. Cell viability, migration, and invasion capacity of HCC cell lines were inhibited, and the tumor growth in the xenograft mouse model was also suppressed following knockdown of NEK7 expression. Mechanistic studies revealed that knockdown of NEK7 in HCC cells significantly upregulated the expression of pyroptosis markers such as NLRP3, Caspase-1, and GSDMD. Coculture of HCC cells stimulated hepatic stellate cell activation by increasing p-ERK1/2 and α-SMA. Knockdown of NEK7 impaired the stimulation of HCC cells. Therefore, downregulation of NEK7 inhibited cancer-stromal interaction by triggering cancer cell pyroptosis. Taken together, this study highlights the functional role of NEK7-regulated pyroptosis in tumor progression and cancer-stromal interaction of HCC, suggesting NEK7 as a potential target for a new therapeutic strategy of HCC treatment.
NIMA相关激酶7（NEK7）是一种丝氨酸/苏氨酸激酶，参与细胞周期进程、有丝分裂纺锤体形成和胞质分裂。它与多种癌症相关，包括乳腺癌、肝细胞癌、肺癌和结直肠癌。此外，NEK7调节NLRP3炎性小体以激活半胱天冬酶-1，导致细胞焦亡。在本研究中，我们调查了NEK7是否参与肝细胞癌（HCC）的细胞焦亡。有趣的是，我们发现NEK7与HCC中焦亡标志物GSDMD的表达显著相关。我们发现在生物信息学分析中NEK7表达与GSDMD表达显著相关，并且在我们的HCC标本中NEK7表达与GSDMD显著共表达。敲低NEK7表达后，HCC细胞系的细胞活力、迁移和侵袭能力受到抑制，异种移植小鼠模型中的肿瘤生长也受到抑制。机制研究表明，在HCC细胞中敲低NEK7显著上调了焦亡标志物如NLRP3、半胱天冬酶-1和GSDMD的表达。HCC细胞的共培养通过增加p-ERK1/2和α-SMA刺激肝星状细胞活化。敲低NEK7削弱了HCC细胞的刺激作用。因此，NEK7的下调通过触发癌细胞焦亡抑制癌-基质相互作用。综上所述，本研究突出了NEK7调节的焦亡在HCC肿瘤进展和癌-基质相互作用中的功能作用，表明NEK7作为HCC治疗新策略的潜在靶点。
