Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.

中文翻译：

---

GLI-SOX2信号轴对吉西他滨耐药在胰腺癌中的作用。

胰腺癌，主要是胰腺导管腺癌（PDAC），是最致命的癌症之一，其中位生存期约为8个月。众所周知，PDAC对化学疗法具有抗性。迄今为止，使用新型靶向疗法和免疫疗法的许多尝试对胰腺癌患者产生了有限的临床益处。希望在胰腺癌中描述耐药性的分子机制可能提供新颖的治疗选择。使用获得性吉西他滨抗性胰腺细胞系，我们揭示了GLI-SOX2信号转导轴在体外和动物模型中对吉西他滨敏感性调节的重要作用。下调GLI转录因子（GLI1或GLI2），但不抑制SMO信号传导，减少肿瘤球的形成，这是肿瘤起始细胞（TIC）的特征。GLI转录因子的下调也降低了TIC标记CD24的表达。同样，高SOX2表达与吉西他滨耐药相关，而SOX2的下调使胰腺癌细胞对吉西他滨治疗敏感。我们进一步揭示，升高的SOX2表达与GLI1或GLI2表达的增加有关。我们的ChIP分析表明，GLI蛋白与SOX2启动子中的一个假定的Gli结合位点相关，这表明GLI转录因子可以更直接地调节SOX2。在人类癌症样本中揭示了我们的发现与人类疾病的相关性。我们发现高SOX2蛋白表达与II期PDAC患者（均接受吉西他滨治疗）中频繁的肿瘤复发和不良的生存率相关，