Xu Xiaoyu, Fang Zhengxuying, Jiang Wei, Chou Jianbo, Lu Yi
1Department of Oncology, The Yuyao People's Hospital, Ningbo, China; 2Department of Health Science Center, Medical College of Ningbo University, Ningbo, China; 3Department of Oncology, The Ningbo 7th People's Hospital, Ningbo, China; 4Department of Radiation Oncology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
Transl Cancer Res. 2025 Jun 30;14(6):3772-3784. doi: 10.21037/tcr-2025-987. Epub 2025 Jun 27.
Ras-related C3 botulinum toxin substrate 1 (), a pivotal Rho guanosine triphosphatases (GTPase) implicated in oncogenic processes and radiotherapeutic resistance across malignancies, has not been extensively examined within the context of hepatocellular carcinoma (HCC) radiotherapy. Therefore, this study aimed to evaluate the expression and prognostic significance of RAC1 in HCC, investigate the molecular mechanisms by which radiation-induced RAC1 GTPase activity mediates radioresistance, and validate targeted inhibition of this activity as a potential strategy to enhance HCC radiosensitivity.
expression was assessed in HCC versus adjacent tissues via The Cancer Genome Atlas (TCGA) and immunohistochemical (IHC) staining of clinical specimens. Its prognostic significance was rigorously evaluated using Cox regression models and visualized via nomogram construction. Radiation-induced RAC1 GTP activity in MHCC97-H cells was quantified by G-protein-linked immunosorbent assay (G-LISA), with downstream signaling (p-IκBα/Bcl-xL) and cell cycle dynamics analyzed via Western blotting and flow cytometry. NSC23766, a RAC1 GTP inhibitor, was employed to identify the pathway-specific effects.
exhibited marked overexpression in HCC tissues, correlating with advanced pathological stages and inferior prognosis. Radiation triggered RAC1 GTP activation in MHCC97-H cells, driving p-IκBα/Bcl-xL antiapoptotic signaling and G2/M arrest. NSC23766 suppressed radiation-induced IκBα phosphorylation (P<0.05), Bcl-xL upregulation, and cell cycle arrest attenuating radioresistance.
overexpression portends poor HCC prognosis and mediates radioresistance through GTP-dependent activation of antiapoptotic pathways and cell cycle modulation. Targeting RAC1 GTP activity may enhance the radiosensitivity of HCC.
Ras相关的C3肉毒杆菌毒素底物1（RAC1）是一种关键的Rho鸟苷三磷酸酶（GTP酶），参与致癌过程和多种恶性肿瘤的放射治疗耐药性，但在肝细胞癌（HCC）放疗背景下尚未得到广泛研究。因此，本研究旨在评估RAC1在HCC中的表达及预后意义，探讨辐射诱导的RAC1 GTP酶活性介导放射抗性的分子机制，并验证靶向抑制该活性作为增强HCC放射敏感性的潜在策略。
通过癌症基因组图谱（TCGA）以及临床标本的免疫组织化学（IHC）染色评估HCC组织与癌旁组织中RAC1的表达。使用Cox回归模型严格评估其预后意义，并通过列线图构建进行可视化。通过G蛋白偶联免疫吸附测定（G-LISA）定量MHCC97-H细胞中辐射诱导的RAC1 GTP活性，通过蛋白质印迹和流式细胞术分析下游信号传导（p-IκBα/Bcl-xL）和细胞周期动态。使用RAC1 GTP抑制剂NSC23766确定通路特异性效应。
RAC1在HCC组织中显著过表达，与晚期病理阶段和较差的预后相关。辐射触发MHCC97-H细胞中的RAC1 GTP激活，驱动p-IκBα/Bcl-xL抗凋亡信号传导和G2/M期阻滞。NSC23766抑制辐射诱导的IκBα磷酸化（P<0.05）、Bcl-xL上调和细胞周期阻滞，减弱放射抗性。
RAC1过表达预示HCC预后不良，并通过抗凋亡通路的GTP依赖性激活和细胞周期调节介导放射抗性。靶向RAC1 GTP活性可能增强HCC的放射敏感性。
