The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is frequently reported to be hyperactivated in hepatocellular carcinoma (HCC) and contributes to HCC recurrence. However, the underlying regulatory mechanisms of mTORC1 signaling in HCC are not fully understood. In the present study, we found that the expression of kinesin family member 18B (KIF18B) was positively correlated with mTORC1 signaling in HCC, and the upregulation of KIF18B and p-mTOR was associated with a poor prognosis and HCC recurrence. Utilizing in vitro and in vivo assays, we showed that KIF18B promoted HCC cell proliferation and migration through activating mTORC1 signaling. Mechanistically, we identified Actin gamma 1 (γ-Actin) as a binding partner of KIF18B. KIF18B and γ-Actin synergistically modulated lysosome positioning, promoted mTORC1 translocation to lysosome membrane, and prohibited p70 S6K from entering lysosomes for degradation, which finally led to the enhancement of mTORC1 signaling transduction. Moreover, we found that KIF18B was a direct target of Forkhead box M1, which explains the potential mechanism of KIF18B overexpression in HCC. Our study highlights the potential of KIF18B as a therapeutic target for the treatment of HCC.

据报道，雷帕霉素复合物 1 (mTORC1) 信号通路的机制靶标在肝细胞癌 (HCC) 中过度激活，并导致 HCC 复发。然而，mTORC1 信号在 HCC 中的潜在调节机制尚不完全清楚。在本研究中，我们发现HCC中驱动蛋白家族成员18B（KIF18B）的表达与mTORC1信号呈正相关，并且KIF18B和p-mTOR的上调与不良预后和HCC复发相关。利用体外和体内测定，我们发现 KIF18B 通过激活 mTORC1 信号传导促进 HCC 细胞增殖和迁移。从机制上讲，我们确定肌动蛋白 gamma 1（γ-肌动蛋白）是 KIF18B 的结合伴侣。KIF18B和γ-Actin协同调节溶酶体定位，促进mTORC1易位至溶酶体膜，并阻止p70 S6K进入溶酶体降解，最终导致mTORC1信号转导增强。此外，我们发现KIF18B是Forkhead box M1的直接靶标，这解释了KIF18B在HCC中过度表达的潜在机制。我们的研究强调了 KIF18B 作为 HCC 治疗靶点的潜力。