Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, China.
Department of Hepatobiliary, Pancreatic and Splenic Surgery, Jiangmen Central Hospital, Jiangmen, 529030, China.
J Exp Clin Cancer Res. 2022 Jul 22;41(1):230. doi: 10.1186/s13046-022-02441-y.
The extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear.
The expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models.
In the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice.
Our findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis.
肝细胞癌 (HCC) 细胞的外渗能力在远处转移中起着至关重要的作用。然而，HCC 肺转移中外渗的潜在机制在很大程度上仍不清楚。
通过定量 RT-PCR、western blot 和免疫组织化学 (IHC) 分析检测人 HCC 标本和 HCC 细胞系中 ARHGEF37 的表达。使用细胞系、患者样本、异种移植模型，在体外和体内研究 ARHGEF37/Cdc42 促进肺转移的生物学作用和机制。
在本研究中，我们发现 Rho 鸟苷酸交换因子 37 (ARHGEF37) 在人 HCC 样本中上调，并与肿瘤侵袭性、肺转移和预后不良相关。过表达 ARHGEF37 可通过促进肿瘤细胞与内皮细胞的黏附和跨内皮迁移，显著增强 HCC 细胞的外渗和转移能力。在机制上，ARHGEF37 直接与 Cdc42 相互作用并激活 Cdc42，以促进 HCC 细胞中侵袭小体的形成，从而破坏内皮细胞与周细胞之间的相互作用。重要的是，用 ZCL278（一种 Cdc42 的特异性抑制剂）处理可显著抑制 ARHGEF37 过表达 HCC 细胞与内皮细胞的黏附，以及在肺肺泡中的黏附和外渗，从而抑制小鼠的肺转移。
我们的研究结果为 ARHGEF37 过表达介导的 HCC 细胞外渗和肺转移的潜在机制提供了新的见解，并为预防和治疗 HCC 肺转移提供了潜在的治疗靶点。
