Intermedin调控Rac1/CDC42通路及Lamin蛋白在肝细胞癌侵袭和转移中的机制研究

Our group found that Intermedin (IMD) was significantly over-expressed in the serum and hepatocellular carcinoma (HCC) tissues, and the level of IMD might be correlated with HCC invasion and metastasis. IMD-induced filopodia and migration of HCC cells were significantly decreased by depressing Rac1 and CDC42 activity. The Lamin protein was the most important molecule that determined the stiffness of nucleus. IMD significantly decreased the mRNA level of Lamin protein in HCC cells, and anti-IMD might increase Lamin protein transcription. According to literature reports and our previous work, we proposed that IMD might promote the formation of filopodiain in HCC cells through Rac1/CDC42 pathway, enhancing its migration ablitiy. Meanwhile, IMD could decrease stiffness of nucleus to enhance penetration ability in HCC cells by regulating Lamin protein. IMD significantly enhanced invasion and metastasis of HCC cells by these two ways. Combined with IMD, Rac1/CDC42 pathway and Lamin protein in HCC cells for the first time, the study aimed to investigate the IMD molecular mechanism of promotion on HCC invasion and metastasis from the cell level and the overall level comprehensively, which would be conducive to provide new insight into screening biomarkers for diagnosis and treatment on HCC invasion and metastasis.

课题组前期发现Intermedin(IMD)在肝癌患者的外周血和肿瘤组织中表达显著增高，与肿瘤侵袭和转移密切相关。抑制Rac1和CDC42活性可显著降低IMD诱导肝癌细胞丝状伪足形成；IMD可显著降低肝癌细胞Lamin蛋白mRNA水平，anti-IMD可增加Lamin蛋白转录，而Lamin蛋白是决定肿瘤细胞核刚性最重要的分子。基于文献和前期研究，我们推测“IMD可能通过Rac1/CDC42通路促进肝癌细胞丝状伪足的形成能力，从而提高其运动能力；同时，IMD还通过对Lamin蛋白的调控，降低肿瘤细胞核的刚性来提高肝癌细胞穿过狭窄孔隙的能力；IMD通过提升这两种能力，显著增强了肝癌细胞的侵袭和转移能力。”本研究首次结合IMD、Rac1/CDC42通路及Lamin蛋白，从细胞和整体水平探讨IMD在肝癌侵袭和转移过程中的分子机制，为筛选肝癌侵袭和转移的分子标志物提供理论基础和实验依据。

作为恶性度最高的癌症之一，肝细胞癌（HCC）具有高度侵袭性并且能够转移到远处器官。Intermedin (IMD) 是一种属于降钙素家族的内源性肽，已被认为在癌细胞存活和侵袭中发挥重要作用，包括在 HCC 中。然而，IMD 如何影响 HCC 细胞的行为及其潜在机制尚未完全阐明。在本项目中，我们发现IMD通过激活 ERK1/2-EGR1（早期生长反应蛋白 1）信号通路来维持重要的稳态；通过该通路，HCC 细胞生成更多的丝状伪足并获得更高的侵袭能力。 阻断IMD 抑制了下游 ERK1/2 的磷酸化，导致 EGR1 下调和内质网应激 (ER) 应激，表现为ER 应激标记物 DDIT3（DNA 损伤诱导转录物 3）的上调。高水平的 DDIT3 可诱导 HCC 细胞进入 ER 应激相关的凋亡途径。本研究首次从细胞和动物模型整体水平探讨IMD在HCC侵袭和转移过程中的分子机制，为筛选肝癌侵袭和转 移的分子标志物提供理论基础和实验依据。