ROS激活IL6/JAK2/STAT3通路在索拉菲尼致手足皮肤反应中的分子机制研究

Sorafenib is the only targeted drug that has yet been proven to be effective for hepatocellular carcinoma patients so far. However, the adverse effect Hand-Foot Skin Reaction (HFSR) seriously affect the quality of life. At present, the study on mechanism of HFSR concentrate in the apotosis of keratinocyte. We found hyperkeratosis is another common pathological manifestation by clinical observations and the earlier animal model eatablishment. Multiple studies have confirmed that the inhibiton of mitogen-activated protein kinase (TAK1) led to the accumulation of Reactive Oxygen Species (ROS) in damaged keratinocyte, meanwhile the activity of TAK1 can be inhibited by Sorafenib, we also found HFSR could be induced by injury in the process of animal model establishment. Given that, we hypothesize Sorafenib result in the accumulation of ROS in keratinocyte then trigger the keratinocyte apotosis, meanwhile hyperkeratosis is also induced by JAK2/STAT3 pathway. Our project group will detect the related factors in the serum and tissue of patients to confirm the different expression between different clinical grading first, then explore the molecular mechanism of HFSR in vitro, at last we will verify the HFSR could be relieved by antioxidents in vivo. We will elaborate the molecular mechanism of HFSR from a new perspective and expect to provide a new target for the treatment of HFSR.

索拉菲尼（Sorafenib）是目前唯一被证实可以延长肝癌患者生存期的靶向药物。然而其所引起的手足皮肤反应（HFSR）严重影响患者生活质量。目前在对HFSR的机制研究多集中于角质细胞的凋亡，但我们通过临床观察及前期建立的动物模型发现角化过度也是常见的病理现象。研究证实损伤情况下角质细胞中促分裂原活化蛋白激酶(TAK1)的抑制可以导致活性氧簇(ROS)的蓄积，而Sorafenib能够抑制TAK1的活性，我们通过动物模型发现损伤可以诱导手足皮肤反应。故我们推测Sorafenib导致了损伤角质细胞的ROS蓄积，进而使得角质细胞凋亡的同时介导JAK2/STAT3通路致角质细胞分化过度。本课题拟首先检测患者血清组织相关因子证实不同临床分级间表达差异，然后体外实验探索分子调控机制，最后动物实验证实抗氧化剂抑制手足皮肤反应。本课题将从新的视觉阐明HFSR发生的分子机制，并为HFSR的防治提供新的靶点。

索拉菲尼（Sorafenib）是治疗肝癌的主力靶向药物，能够引起手足皮肤反应（HFSR）,该反应严重影响患者生活质量。对HFSR的研究多仅集中于角质细胞的凋亡，然而通过临床观察及新构建的动物模型发现，角化过度也是HFSR的重要特征。本研究聚焦角化过度这一生理过程，利用从大数据、临床样本、动物模型、细胞模型多个角度探索HFSR发生的分子机制。Meta分析发现HFSR是影响索拉菲尼患者生存期的预测因子，大数据及临床血清样品表明氧化应激可能为HFSR的使动因素；新构建小鼠摩擦力跑步机诱发灌胃索拉菲尼的昆明小鼠出现手足皮肤反应的模型，明确HFSR的发生由时间和外伤诱导，是损伤再修复的病理过程；角质细胞模型研究证实索拉菲尼能够诱导角质细胞ROS积累，通过JAK2/STAT3通路影响角质细胞的角化能力，短时间抑制、长时间促进角质细胞的增殖。NAC和STAT3抑制剂能够阻断这一调控过程，抗氧化剂和通路抑制剂是抑制手足皮肤反应发生的潜在治疗方向。在课题研究过程中，我们发现有关HFSR的特征K10，K14和JAK2/STAT3上下游相关分子P21，CyclinD1，SLC22A16对索拉菲尼的刺激变化明显，且以上基因与肿瘤密切相关。我们利用以上基因在多种数据库寻找与肿瘤的关系发现其在胰腺癌中与生存期密切相关，因此我们利用整合分析的方法进行了胰腺癌预后识别，得到了一些进展。