Life Sciences Institute, Guangxi Medical University, Nanning, 530021, China.
Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, 530021, China.
Clin Transl Oncol. 2023 Feb;25(2):482-490. doi: 10.1007/s12094-022-02961-1. Epub 2022 Oct 3.
Previous studies have shown that the ability of tumor cells to move and migrate is related to the molecular chain pathway mediated by actin. This study focused on the molecular mechanism of gelsolin (GSN) as an important actin-binding protein in promoting HCC invasion and metastasis.
The relationship between GSN expression and clinical characteristics was observed by immunohistochemistry (IHC). In vitro and in vivo experiments confirmed the role of GSN in HCC metastasis. Dual-immunoprecipitation (IP), immunofluorescence (IF), western blotting, and the gelatinase activity assay were used to investigate the mechanism of GSN-promoting metastasis. PEX fusion proteins were used to intervene in the transfer molecular chain.
Our study found that GSN promoted HCC invasion and metastasis through its synergistic effect with actin-related transfer molecular chain (actin-CD44-MMPs). Concretely, as an important binding molecule of actin, GSN activated MMP2 by interacting with MMP14. Furthermore, CD44 might be a key node in the above-mentioned mechanism. The use of MMP14 domain (PEX fusion protein) to competitively bind to CD44 helped to inhibit the activation of downstream MMP2.
GSN played crucial roles in HCC metastatic process. An improved understanding of the multiple effects of GSN in HCC might facilitate a deeper appreciation of GSN as an important HCC regulator. The study identified GSN and its regulated transfer molecular chain as potential therapeutic targets for HCC.
先前的研究表明，肿瘤细胞的运动和迁移能力与肌动蛋白介导的分子链途径有关。本研究聚焦于凝胶蛋白（GSN）作为一种重要的肌动蛋白结合蛋白在促进 HCC 侵袭和转移中的分子机制。
通过免疫组织化学（IHC）观察 GSN 表达与临床特征的关系。体外和体内实验证实了 GSN 在 HCC 转移中的作用。双免疫沉淀（IP）、免疫荧光（IF）、Western blot 和明胶酶活性测定用于研究 GSN 促进转移的机制。PEX 融合蛋白用于干预转移分子链。
我们的研究发现，GSN 通过与肌动蛋白相关的转移分子链（肌动蛋白-CD44-MMPs）的协同作用促进 HCC 的侵袭和转移。具体而言，作为肌动蛋白的重要结合分子，GSN 通过与 MMP14 相互作用激活 MMP2。此外，CD44 可能是上述机制中的关键节点。使用 MMP14 结构域（PEX 融合蛋白）竞争性结合 CD44 有助于抑制下游 MMP2 的激活。
GSN 在 HCC 转移过程中发挥着关键作用。对 GSN 在 HCC 中的多种作用的深入了解可能有助于更好地认识 GSN 作为 HCC 重要调节剂的作用。该研究确定 GSN 及其调节的转移分子链是 HCC 的潜在治疗靶点。
