SOX9 in chemoresistance of intracellular cholangiocarcinoma (iCCA)

SOX9 在细胞内胆管癌 (iCCA) 化疗耐药中的作用

• 批准号: 512448110
• 负责人: Professor Dr. Steven Dooley, Ph.D.
• 金额: --
• 依托单位: II. Medizinische Klinik: Gastroenterologie, Hepatologie, Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/512448110?language=en
• 关键词: SOX9; chemoresistance; intracellular; cholangiocarcinoma; iCCA

In most patients of intrahepatic cholangiocarcinoma (iCCA), systemic chemotherapy such as receiving gemcitabine remains the only approach to render them eligible for surgery and palliative treatment, given that tumors are too advanced at the time of diagnosis. However, the response of iCCA to current treatments is very weak. Our recent study found that sex-determining region Y-box (SRY-box) containing gene 9 (SOX9), the master transcription factor of cholangiocytes, plays a crucial role in chemoresistance of CCA cells to gemcitabine therapy through impacting on cell cycle check points and downstream p53 signaling. We further observed that SOX9 expression in iCCA is regulated by the retinoic acid – retinoic acid receptor (RAR) axis. Retinoic acid is largely produced during activation of hepatic stellate cells, the key event leading to fibrogenesis and induced by inflammation. Based on these findings, we propose two hypotheses in this project: (I) During chemotherapy, iCCA cells undergo cell cycle arrest to avoid cell death through SOX9-dependent activation of cell cycle checkpoint proteins, and (II) chronic inflammation plays a crucial role in upregulating SOX9 expression in iCCA cells through activated HSC, which release retinoic acid. To prove the proposed hypotheses, we will address five key questions: (1) How does RA-RAR regulate expression of SOX9 in iCCA? (2) What are the mechanisms of the disease environment (inflammation and fibrosis) that modulate SOX9 expression? (3) Does SOX9 contribute to activation of CHK1 transcription through upstream modulation of ATR? (4) Whether, and if yes, how SOX9 influences the ATM-CHK2-p53 pathway? (5) How does SOX9 mediate chemoresistance of iCCA? These experiments will clarify detailed molecular mechanisms of how SOX9 contribute to chemoresistance in iCCA and provide a novel approach to overcome SOX9-dependent chemoresistance in clinical practice.

在大多数肝内胆管癌（iCCA）患者中，考虑到肿瘤在诊断时过于晚期，全身化疗（如接受吉西他滨）仍然是使他们符合手术和姑息治疗条件的唯一方法。然而，iCCA对目前治疗的反应非常弱。我们最近的研究发现，含有基因9 （SOX9）的性别决定区Y-box （SRY-box）是胆管细胞的主转录因子，通过影响细胞周期检查点和下游p53信号传导，在CCA细胞对吉西他滨化疗耐药中起着至关重要的作用。我们进一步观察到SOX9在iCCA中的表达受视黄酸-视黄酸受体（RAR）轴的调控。视黄酸主要是在肝星状细胞的激活过程中产生的，这是导致纤维化和炎症诱导的关键事件。基于这些发现，本项目提出两种假设：(1)化疗期间，iCCA细胞通过SOX9依赖性的细胞周期检查点蛋白激活而发生细胞周期阻滞，避免细胞死亡；(2)慢性炎症通过激活HSC而上调iCCA细胞中SOX9的表达，从而释放维甲酸。为了证明提出的假设，我们将解决五个关键问题：(1)RA-RAR如何调节iCCA中SOX9的表达？(2)疾病环境（炎症和纤维化）调节SOX9表达的机制是什么？(3) SOX9是否通过ATR的上游调控参与了CHK1转录的激活？(4) SOX9是否影响ATM-CHK2-p53通路？如果是，SOX9如何影响ATM-CHK2-p53通路？(5) SOX9如何介导iCCA的化疗耐药？这些实验将阐明SOX9如何促进iCCA化疗耐药的详细分子机制，并为在临床实践中克服SOX9依赖性化疗耐药提供一种新的方法。