肿瘤源IL-35通过缓解ROS氧化应激介导胰腺癌化疗耐药的机制

Chemoresistance is one of the key reasons for poor clinical outcomes of patients with pancreatic cancer. Investigations have revealed that many chemotherapeutic drugs, such as gemcitabine (GEM) and 5-Fu cause the accumulation of reactive oxygen species (ROS) and intracellular lethal oxidative stress. To survive, tumor cells activate ROS scavenging system via complicated regulatory machineries. It is an important approach leading to chemoresistance. We recently reported on Gastroenterology and Nature Communications that turmor-derived interleukin 35 (IL-35) is widely overexpressed in human pancreatic ductal adenocarcinoma (PDAC) tissues. IL-35 directly facilitates tumor progression processes, such as metastasis and angiogenesis. Tumor-derived IL-35 scavenged the Gemcitabine or 5-Fu -induced ROS and protect PDAC cells from apoptosis. More importantly, these drugs significantly increased IL-35 expression level in PDAC cells, which lead to elevated ROS scavenging ability and acquired chemoresistance of PDAC cells. Based on our previous work, we plan to clarify the roles IL-35 in chemoresistance. We intend to investigate the molecular mechanisms how IL-35 scavenge ROS and how chemotherapeutic drugs activate IL-35 expression in PDAC. We also aim to evaluate the safety and effectiveness of IL-35 neutralizing antibodies in PDAC treatment. This study would provide scientific basis for developing novel treatment strategies for patients with pancreatic cancer.

化疗耐药是胰腺癌患者疗效不佳的关键原因之一。吉西他滨（GEM）、5‑Fu等多种药物可通过诱发活性氧（ROS）应激来杀伤癌细胞；而癌细胞异常激活ROS清除体系是导致化疗耐药的重要机制之一。我们近期在Nature Communications及Gastroenterology中报道了胰腺癌细胞过表达免疫因子IL-35，促进了胰腺癌转移及血管生成过程。我们进一步研究发现肿瘤源IL-35通过激活ROS清除体系，促使胰腺癌细胞对GEM及5-Fu的敏感性降低；另一方面，胰腺癌GEM耐药细胞株的IL-35表达显著升高，阻断IL-35后GEM对耐药株的半数抑制浓度显著下降，提示IL-35介导了胰腺癌的继发性耐药。本课题将通过临床资料分析、体外功能评价、分子机制探索及动物实验揭示IL-35介导胰腺癌化疗耐药的作用及分子机制，评价靶向IL-35疗法的安全性及有效性，进而为逆转化疗耐药策略的制定提供理论依据。

化疗后的快速耐药性是导致胰腺导管腺癌治疗失败的关键原因。在本项目的研究中我们发现肿瘤源性白介素35介导PDAC对吉西他滨的快速耐药性。在PDAC细胞和患者来源的异种肿瘤（PDX）模型中，通过分子和细胞生物学方法确定IL-35在GEM耐药性中的作用。我们使用全基因组RNA测序、分子克隆和其他分子生物学方法来研究IL-35介导的GEM抗性的分子机制。在小鼠模型中使用抗IL-35中和抗体，以研究IL-35作为胰腺癌耐药治疗靶点的可行性。我们发现，GEM抗性可以从GEM抗性PDAC细胞扩散到GEM敏感细胞。测序和实验结果证实，IL-35介导了耐药性的传播。与GEM敏感细胞相比，GEM抗性细胞中IL-35表达水平显著升高。PDAC中异常表达的IL-35通过GP130-STAT1信号转导激活SOD2表达，从而清除活性氧（ROS），然后导致GEM抗性。此外，GEM治疗通过激活NF-κB途径显著促进IL-35的表达，导致获得性耐药。在小鼠模型中，针对IL-35的中和抗体显著增强了GEM的肿瘤抑制作用。IL-35在胰腺癌中介导GEM抵抗中起关键作用。IL-35可能是对抗PDAC化疗耐药性的一个有前途的治疗靶点。