近日來自第四軍醫(yī)大學(xué)、沈陽軍區(qū)總醫(yī)院和比利時(shí)根特大學(xué)的研究人員在新研究中揭示了肝癌細(xì)胞運(yùn)動(dòng)和遷移的分子機(jī)制，這一研究成果于8月1日在線發(fā)表在在國際肝臟病研究權(quán)威期刊《肝臟病學(xué)》（Hepatology）上,。
原發(fā)性肝癌是世界五大常見癌癥之一,，全球每年有超過50萬新患者,。中國新病例占了全球所有肝癌病例的一半以上（55%）,。手術(shù)切除仍是目前首選的治療方式，但術(shù)后的高復(fù)發(fā)和轉(zhuǎn)移率明顯影響患者的長(zhǎng)期生存,，因此,，探索肝癌侵襲和轉(zhuǎn)移分子機(jī)制對(duì)于改善肝癌患者的生存具有重要意義。
與單細(xì)胞相似,，腫瘤細(xì)胞主要是通過在間充質(zhì)遷移和阿米巴運(yùn)動(dòng)樣遷移兩種遷移模式間不斷轉(zhuǎn)換從而實(shí)現(xiàn)細(xì)胞運(yùn)動(dòng)的,。在這一過程中，細(xì)胞骨架重排發(fā)揮了極其重要的作用,。此前,，這一研究小組證實(shí)HAb18G/CD147和annexin II是一對(duì)與細(xì)胞骨架重排相關(guān)的互作蛋白，然而對(duì)于HAb18G/CD147和annexin II相互作用對(duì)癌細(xì)胞運(yùn)動(dòng)的影響及相關(guān)機(jī)制卻并不清楚,。
在這篇文章中,，研究人員發(fā)現(xiàn)當(dāng)他們?cè)诟伟┘?xì)胞中抑制HAb18G/CD147時(shí)，細(xì)胞顯示出阿米巴樣近圓形運(yùn)動(dòng)模式的主要特征：細(xì)胞變形呈近圓形,。而當(dāng)他們?cè)诩?xì)胞中抑制annexin II時(shí),，細(xì)胞顯示出間充質(zhì)樣梭性運(yùn)動(dòng)特征：細(xì)胞伸長(zhǎng)變性為長(zhǎng)梭形。
在更進(jìn)一步的分析中,，研究人員發(fā)現(xiàn)HAb18G/CD147可通過胞外部分與annexin II互作抑制annexin II磷酸化,，從而阻斷細(xì)胞內(nèi)Rho信號(hào)傳導(dǎo)，防止細(xì)胞出現(xiàn)阿米巴樣運(yùn)動(dòng),。此外,，通過integrin-FAK-PI3K/PIP3信號(hào)通路，HAb18G/CD147還可促使細(xì)胞膜上的WAVE2和Rac1激活,，從而促使細(xì)胞形成板狀偽足,，發(fā)生間充質(zhì)遷移。
這些研究結(jié)果表明HAb18G/CD147與 annexin II之間的相互作用在肝癌細(xì)胞的間充質(zhì)遷移及阿米巴運(yùn)動(dòng)樣遷移兩種遷移模式轉(zhuǎn)換過程中發(fā)揮關(guān)鍵性的作用,。
第四軍醫(yī)大學(xué)腫瘤生物學(xué)國家重點(diǎn)實(shí)驗(yàn)室的張思河,、蔣建利教授和陳志南院士為這篇文章的共同通訊作者。這一研究項(xiàng)目得到了國家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃（973計(jì)劃）,、國家科技重大專項(xiàng)以及國家自然科學(xué)基金的資金資助,。
doi:10.1002/hep.24592
PMC:
PMID:
HAb18G/CD147 promotes cell motility by regulating annexin II‐activated RhoA and Rac1 signaling pathways in HCC cells
Zhao, Pu; Zhang, Wei; Wang, Shi‐Jie; Yu, Xiao‐Ling; Tang, Juan; Huang, Wan; Li, Yong; Cui, Hong‐Yong; Guo, Yun‐Shan; Tavernier, Jan; Zhang, Si‐He; Jiang, Jian‐Li; Chen, Zhi‐Nan
Keywords:mesenchymal movement;amoeboid movement;metastasis;WAVE2;MLC2AbstractTumor cells can move as individual cells in two interconvertible modes: mesenchymal mode and amoeboid mode. Cytoskeleton rearrangement plays important roles in the interconversion. Previously, we reported that HAb18G/CD147 and annexin II are interacting proteins involved in cytoskeleton rearrangement, yet the role of their interaction is unclear. In this study, we found that the depletion of HAb18G/CD147 produced a rounded morphology, which is associated with amoeboid movement, while the depletion of annexin II resulted in an elongated morphology, which is associated with mesenchymal movement. The extracellular portion of HAb18G/CD147 can interact with a phosphorylation‐inactive mutant of annexin II and inhibit its phosphorylation. HAb18G/CD147 inhibits Rho signaling pathways and amoeboid movement by inhibiting annexin II phosphorylation, promotes membrane localization of WAVE2 and Rac1 activation via the integrin‐FAK‐PI3K/PIP3 signaling pathway, and promotes the formation of lamellipodia and mesenchymal movement. These results suggest that the interaction of HAb18G/CD147 with annexin II is involved in the interconversion between mesenchymal and amoeboid movement of HCC cells.
