Objectives: 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.
Methods: 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.
Results: 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.
Conclusions: 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.