Background & Aims

Kinesin family member 18A (KIF18A) is notable for its aberrant expression across various cancer types and its pivotal role is driving cancer progression. In this study, we aim to investigate the intricate molecular mechanisms underlying the impact of KIF18A on the progression of HCC.

Methods

Western blotting assays, a quantitative real-time PCR and immunohistochemical analyses were performed to quantitatively assess KIF18A expression in HCC tissues. We then performed genetic manipulations within HCC cells by silencing endogenous KIF18A using short hairpin RNA (shRNA) and introducing exogenous plasmids to overexpress KIF18A. We monitored cell progression, analyzed cell cycle and cell apoptosis and assessed cell migration and invasion both in vitro and in vivo. Moreover, we conducted RNA-sequencing to explore KIF18A-related signaling pathways utilizing Reactome and KEGG enrichment methods and validated these critical mediators in these pathways.

Results

Analysis of the TCGA-LIHC database revealed pronounced overexpression of KIF18A in HCC tissues, the finding was subsequently confirmed through the analysis of clinical samples obtained from HCC patients. Notably, silencing KIF18A in cells led to an obvious inhibition of cell proliferation, migration and invasion in vitro. Furthermore, in subcutaneous and orthotopic xenograft models, suppression of KIF18A sgnificantly redudce tumor weight and the number of lung metastatic nodules. Mechanistically, KIF18A appears to facilitate cell proliferation by upregulating MAD2 and CDK1/CyclinB1 expression levels, with the activation of SMAD2/3 signaling contributing to KIF18A-driven metastasis.

Conclusion

Our study elucidates the molecular mechanism by which KIF18A mediates proliferation and metastasis in HCC cells, offering new insights into potential therapeutic targets.

中文翻译：

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驱动蛋白家族成员 18A (KIF18A) 促进肝细胞癌的细胞增殖和转移

背景与目标

驱动蛋白家族成员 18A (KIF18A) 以其在各种癌症类型中的异常表达而闻名，其关键作用是推动癌症进展。在本研究中，我们旨在研究 KIF18A 对 HCC 进展影响的复杂分子机制。

方法

进行蛋白质印迹分析、定量实时 PCR 和免疫组织化学分析来定量评估 HCC 组织中 KIF18A 的表达。然后，我们通过使用短发夹 RNA (shRNA) 沉默内源 KIF18A 并引入外源质粒来过度表达 KIF18A，从而在 HCC 细胞内进行遗传操作。我们监测细胞进展，分析细胞周期和细胞凋亡，并评估体外和体内细胞迁移和侵袭。此外，我们利用 Reactome 和 KEGG 富集方法进行 RNA 测序来探索 KIF18A 相关信号通路，并验证这些通路中的这些关键介质。

结果

TCGA-LIHC 数据库的分析显示 HCC 组织中 KIF18A 明显过度表达，随后通过对 HCC 患者临床样本的分析证实了这一发现。值得注意的是，在体外沉默细胞中的KIF18A会导致细胞增殖、迁移和侵袭明显受到抑制。此外，在皮下和原位异种移植模型中，抑制 KIF18A 显着减少肿瘤重量和肺转移结节的数量。从机制上讲，KIF18A 似乎通过上调 MAD2 和 CDK1/CyclinB1 表达水平来促进细胞增殖，而 SMAD2/3 信号传导的激活有助于 KIF18A 驱动的转移。

结论

我们的研究阐明了 KIF18A 介导 HCC 细胞增殖和转移的分子机制，为潜在的治疗靶点提供了新的见解。