Department of Medicine II, Liver Center Munich, University Hospital, Ludwig‑Maximilians‑University of Munich, Munich 81377, Germany.
Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Int J Oncol. 2021 Jun;58(6). doi: 10.3892/ijo.2021.5205. Epub 2021 Apr 13.
Septin 6 (SEPT6) is a member of the GTP‑binding protein family that is highly conserved in eukaryotes and regulates various biological functions, including filament dynamics, cytokinesis and cell migration. However, the functional importance of SEPT6 in hepatocellular carcinoma (HCC) is not completely understood. The present study aimed to investigate the expression levels and roles of SEPT6 in HCC, as well as the underlying mechanisms. The reverse transcription quantitative PCR, western blotting and immunohistochemistry staining results demonstrated that SEPT6 expression was significantly elevated in HCC tissues compared with corresponding adjacent non‑tumor tissues, which indicated that SEPT6 expression may serve as a marker of poor prognosis for HCC. By performing plasmid transfection and G418 treatment, stable SEPT6‑knockdown and SEPT6‑overexpression cell lines were established. The Cell Counting Kit‑8, flow cytometry and Transwell assay results demonstrated that SEPT6 overexpression significantly increased HCC cell proliferation, cell cycle transition, migration and invasion compared with the Vector group, whereas SEPT6 knockdown displayed significant suppressive effects on HCC cell lines compared with the control group. Mechanistically, SEPT6 might facilitate F‑actin formation, which induced large tumor suppressor kinase 1 dephosphorylation, inhibited Hippo signaling, upregulated yes‑associated protein (YAP) expression and nuclear translocation, and upregulated cyclin D1 and matrix metallopeptidase 2 (MMP2) expression. Furthermore, YAP overexpression significantly reversed SEPT6 knockdown‑induced inhibitory effects on HCC, whereas YAP knockdown significantly inhibited the oncogenic effect of SEPT6 overexpression on HCC. Collectively, the present study demonstrated that SEPT6 may promote HCC progression by enhancing YAP activation, suggesting that targeting SEPT6 may serve as a novel therapeutic strategy for HCC.
六聚蛋白 6（SEPT6）是真核生物中高度保守的 GTP 结合蛋白家族的成员，调节多种生物学功能，包括丝状体动态、胞质分裂和细胞迁移。然而，SEPT6 在肝细胞癌（HCC）中的功能重要性尚不完全清楚。本研究旨在探讨 SEPT6 在 HCC 中的表达水平和作用及其潜在机制。逆转录定量 PCR、western blot 和免疫组化染色结果表明，SEPT6 在 HCC 组织中的表达明显高于相应的癌旁非肿瘤组织，表明 SEPT6 表达可能是 HCC 预后不良的标志物。通过质粒转染和 G418 处理，建立了稳定的 SEPT6 敲低和 SEPT6 过表达细胞系。CCK-8 细胞计数试剂盒、流式细胞术和 Transwell 小室实验结果表明，与 Vector 组相比，SEPT6 过表达显著增加了 HCC 细胞的增殖、细胞周期转换、迁移和侵袭，而 SEPT6 敲低与对照组相比对 HCC 细胞系表现出显著的抑制作用。机制上，SEPT6 可能促进 F-肌动蛋白的形成，导致大肿瘤抑制激酶 1 的去磷酸化，抑制 Hippo 信号通路，上调 yes 相关蛋白（YAP）的表达和核转位，并上调细胞周期蛋白 D1 和基质金属蛋白酶 2（MMP2）的表达。此外，YAP 过表达显著逆转了 SEPT6 敲低对 HCC 的抑制作用，而 YAP 敲低显著抑制了 SEPT6 过表达对 HCC 的致癌作用。综上所述，本研究表明，SEPT6 可能通过增强 YAP 激活促进 HCC 进展，提示靶向 SEPT6 可能成为 HCC 的一种新的治疗策略。
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