Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
Pancreas. 2010 May;39(4):473-85. doi: 10.1097/MPA.0b013e3181c0decc.
Gemcitabine is the standard chemotherapeutic agent for pancreatic cancer. Nevertheless, the prognosis of pancreatic cancer patients is still poor. Evaluating the mechanisms of chemoresistance to gemcitabine will be helpful for the improvement of the therapeutic outcome.
Using 11 pancreatic cancer cell lines and global gene expression profiling, molecular markers were detected for acquired and intrinsic gemcitabine sensitivity. Acquired gemcitabine resistance in vitro was obtained by continual exposure to gradually increased concentrations of gemcitabine; however, intrinsic sensitivity is originally provided and differs between cell lines.
Microarray analysis of intrinsic sensitivity showed no correlation to that of acquired resistance. Fifteen overexpressed and 49 downexpressed genes in accordance with intrinsic gemcitabine resistance were identified, and we selected those highly expressed in resected pancreatic cancer tissue. Interferon-stimulated gene 15 (ISG15), which plays a role in cellular defense from infection and carcinogenesis, was identified as the gene related to gemcitabine chemosensitivity. By inhibition of ISG15 in gemcitabine-resistant cell lines using siRNA, gemcitabine resistance was reversed.
It was demonstrated that ISG15 is one of the genes associated with intrinsic gemcitabine sensitivity, having a possibility to be a candidate of molecular targeting for the improvement of chemotherapy against pancreatic cancer.
吉西他滨是胰腺癌的标准化疗药物。然而，胰腺癌患者的预后仍然很差。评估对吉西他滨的化疗耐药机制将有助于改善治疗效果。
使用 11 种胰腺癌细胞系和全基因表达谱，检测获得性和内在吉西他滨敏感性的分子标志物。通过持续暴露于逐渐增加的吉西他滨浓度来获得体外获得性吉西他滨耐药性；然而，内在敏感性是最初提供的，并且在细胞系之间存在差异。
内在敏感性的微阵列分析与获得性耐药性无关。鉴定出与内在吉西他滨耐药性一致的 15 个过表达和 49 个下调基因，我们选择了在切除的胰腺癌组织中高表达的基因。干扰素刺激基因 15（ISG15）在细胞防御感染和致癌作用中起作用，被鉴定为与吉西他滨化疗敏感性相关的基因。通过使用 siRNA 抑制吉西他滨耐药细胞系中的 ISG15，逆转了吉西他滨耐药性。
研究表明，ISG15 是与内在吉西他滨敏感性相关的基因之一，有可能成为改善针对胰腺癌化疗的分子靶向候选药物。
