J Cancer 2017; 8(9):1530-1541. doi:10.7150/jca.18628 This issue
1. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China;
2. Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Due to its aggressiveness and unusual resistance to conventional therapies, pancreatic cancer is a highly lethal gastrointestinal malignancy with poor prognosis. According to the cancer stem cell hypothesis, there exists a fraction of cancer cells, that is, cancer stem cells, responsible for tumor maintenance and therapeutic failure. Herein we investigated the involvement of proto-oncogene Pim-3 in driving the stemness properties in pancreatic cancer. Expression levels of several stemness-associated markers were examined in several pancreatic cancer cell lines. The double positive (CD24+ESA+) and double negative (CD24-ESA-) pancreatic cancer cells were isolated from PANC-1 and L3.6pl, and their self-renewal ability, tumorigenicity as well as sensitivity to gemcitabine were then evaluated. Results showed that there existed heterogeneity in expression levels of stemness-associated surface markers among pancreatic cancer cell lines. CD24+ESA+ pancreatic cancer cells exhibited increased tumorigenicity and decreased chemosensitivity to gemcitabine as compared to CD24-ESA- cells. Besides, the double positive (CD24+ESA+) subpopulation also exhibited greater expression level of Pim-3 when compared with the double negative (CD24-ESA-) ones. Furthermore, silencing of Pim-3 in pancreatic cancer cells leads to decreased proportions of both single positive (CD24+ and ESA+) and double positive (CD24+ESA+) pancreatic cancer cells. Overexpression of Pim-3 was associated with increased levels of some stemness-associated transcription factors (STAT3, etc.). Moreover, the phosphorylation level and transcriptional activity of STAT3 were decreased in Pim-3 silenced pancreatic cancer cells and restoration of its activity results in restitution of stem cell-like phenotypes. Therefore, Pim-3 maintains stemness of pancreatic cancer cells via activating STAT3 signaling pathway and might be used as a novel therapeutic target in pancreatic cancer.
Keywords: Pim-3, stemness, chemoresistance, STAT3, pancreatic cancer.