Galectin-3激活ezrin蛋白促宫颈癌转移的作用及其信号机制研究

Cervical cancer metastasis is the leading cause for death. Our previous work have indicated that vascular endothelial growth factor C (VEGF-C) potently promotes cervical cancer invasion through the upregulation of Galectin-3 (Gal-3) protein. However, the undelying mechanism remain obscure. The initital step for tumor cell invasion is the actin cytoskeleton remodeling and the formation of lamillipodia or filopodia, which is controlled by ezrin protein. The preliminary result of this project found that Gal-3 increased ezrin phosphorylation. On the basis of this, the present project plans to investigate the signaling mechanism responsible for ezrin activation induced by Gal-3 and the role of this signaling pathway in cervical cancer metastasis. To achieve this aim, we will investigate the role of α3β1 integrin and its downstream signaling in ezrin activation and in the formation of lamillipodia and fillopodia, as well as invasive ability of cervical cancer cells. In addition, the cervical cancer cell line overexpressing Gal-3 or silencing Gal-3 will be constructed and implanted into Zebrafish in oder to verify the role of Gal-3 in cervical cancer metastasis in vivo. Furthermore, we will collect the clinical cervical cancer samples in different pathological stage and dectect the expression level of Gal-3, α3β1 integrin and ezrin in these samples, thus verfiy the correlation between these molecules and cervical cancer malignant progression and predicate the prognostic value of this protein. The present project will provide new insight into the molecular mechanisms of cervical cancer metastasis and may possibly provide novel target for clinial therapy of cervical cancer patients.

宫颈癌转移是患者死亡的主要原因。我们的前期工作发现，VEGF-C通过上调半乳糖凝素3（Gal-3）蛋白表达，促进宫颈癌细胞侵袭。Gal-3通过何种分子机制调控宫颈癌的侵袭能力？目前尚不清楚。侵袭的首要步骤为肌动蛋白骨架重构，伪足和突起形成，该过程受ezrin蛋白调控；预实验已表明：Gal-3可增强ezrin蛋白磷酸化。由此，本项目拟探讨Gal-3激活ezrin蛋白的信号机制及其在宫颈癌转移中的作用。包括：1、研究α3β1 integrin及其下游信号分子在ezrin蛋白激活中的作用；2、探讨此信号通路促进宫颈癌细胞伪足和突起形成、增强侵袭能力的作用；3、在斑马鱼模型中证实Gal-3促宫颈癌转移的效应；4、收集宫颈癌临床标本，确认Gal-3、α3β1 integrin、ezrin与肿瘤恶性程度相关性，判断其预后价值。本项目有助于揭示宫颈癌恶性进展的新机制，为宫颈癌的临床治疗提供新的干预靶点。

宫颈癌转移是患者死亡的主要原因。肌动蛋白骨架重构，伪足和突起形成是癌细胞发生侵袭转移的首要步骤，该过程受ezrin蛋白调控。我们的前期工作发现，VEGF-C通过上调半乳糖凝素3（Gal-3）蛋白表达，促进宫颈癌细胞侵袭。同时，Gal-3可以增强ezrin蛋白磷酸化。但是，Gal-3调控宫颈癌的侵袭转移的具体机制尚不清楚。本项目对Gal-3在宫颈癌转移过程中的作用和促进宫颈癌细胞转移的机制进行了探究。研究结果显示：1、Gal3和ezrin蛋白在宫颈癌组织中高表达，并且提示不良生存预后；2、Gal3在细胞模型和动物模型中可以促进宫颈癌转移；3、Gal-3可交联α3β1 integrin并激活c-Src/ PI3K/Akt信号通路；4、Gal-3通过c-Src/PI3K/Akt信号通路促ezrin蛋白磷酸化；5、Gal-3通过促ezrin蛋白磷酸化，调节肌动蛋白骨架重构和伪足形成，促进宫颈癌细胞的转移能力。本项目有助于揭示宫颈癌恶性进展的新机制，为宫颈癌的临床治疗提供新的干预靶点