基于Integrinα5β1/AKT调控力学-生物学信号传递探讨三石猫复方抑制高基质硬度致肝癌侵袭转移的机制

80%肝癌患者肝基质硬度增加。高基质硬度可促进肝癌侵袭转移，其机制与激活Integrins/AKT通路介导的力学-生物学信号传递有关。针对该病理进程，西医尚无有效手段。我们认为基质硬度增加属“瘀血”范畴，肝癌细胞属“癌毒”范畴，基质硬度增加促进肝癌细胞侵袭转移，属“瘀毒互结”。多中心临床研究证实解毒化瘀复方三石猫抑制肝癌复发转移的疗效。结合中医理论和预实验，我们推测三石猫可抑制高基质硬度致肝癌侵袭转移，其机制与下调高基质硬度环境下肝癌细胞和肝星状细胞Integrinα5β1/AKT通路有关。本研究拟建立高基质硬度体内、外模型，进一步确认三石猫抑制高基质硬度致肝癌侵袭转移疗效；并运用基因过表达、转基因小鼠等技术，基于Integrinα5β1/AKT通路，从降低力学-生物学信号传递角度揭示其机制。试图从物理（力学）微环境视角诠释解毒化瘀中药防治肝癌侵袭转移机制，为其临床应用提供理论支撑。

About 80% of patients with Hepatocellular carcinoma (HCC) had cirrhosis (high liver stiffness). Higher matrix stiffness promotes invasion and metastasis of HCC by Integrins/AKT，which plays an important role in the transmission of mechanical stimuli to biological signal in cells. Currently, Western medicine had no effective drugs for this pathological process in clinical. Increased matrix stiffness belongs to the category of blood stasis. HCC belong to cancer toxin. Higher matrix stiffness promotes invasion and metastasis of HCC belong to the syndrome of toxicity and blood stasisacute. A multi-center randomized blinded controlled trial demonstrated that Sanshimao formula for detoxify and dissipate blood stasis could prevent the recurrence and metastasis of HCC. Our preliminary data showed that Sanshimao might prevent the recurrence and metastasis of HCC with increased extracellular matrix stiffness via inhibiting Integrinα5β1/AKT of hepatic stellate cells (HSCs) and liver cancer cells. This project aims to validate the effect of Sanshimao on higher matrix stiffness promoted HCC recurrence and metastasis by using buffalo rat HCC models with high liver stiffness backgrounds and an in vitro Col I-coated cell culture system with high stiffness. Moreover, to explore if reducing mechanics-biological signal transmission by Integrinα5β1/AKT pathway is the potential mechanism of Sanshimao using gene overexpression technology and conditional gene overexpression mice. With the results of this project, we will have a better understanding of the effect of Jiedu Huayu formula on HCC from the perspective of liver mechanical microenvironment to support clinical therapy.