Li Ting, Wang Zhen, Hou Yi-Feng, Li Ying-Yi
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
J Cancer. 2017 Jun 2;8(9):1530-1541. doi: 10.7150/jca.18628. eCollection 2017.
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.
由于其侵袭性以及对传统疗法的异常抗性，胰腺癌是一种预后很差的高致死性胃肠道恶性肿瘤。根据癌症干细胞假说，存在一部分癌细胞，即癌症干细胞，它们负责肿瘤维持和治疗失败。在此，我们研究了原癌基因Pim-3在驱动胰腺癌干性特征中的作用。检测了几种胰腺癌细胞系中几种干性相关标志物的表达水平。从PANC-1和L3.6pl中分离出双阳性（CD24+ESA+）和双阴性（CD24-ESA-）的胰腺癌细胞，然后评估它们的自我更新能力、致瘤性以及对吉西他滨的敏感性。结果显示，胰腺癌细胞系中干性相关表面标志物的表达水平存在异质性。与CD24-ESA-细胞相比，CD24+ESA+胰腺癌细胞表现出更高的致瘤性和对吉西他滨更低的化学敏感性。此外，与双阴性（CD24-ESA-）亚群相比，双阳性（CD24+ESA+）亚群的Pim-3表达水平也更高。此外，胰腺癌细胞中Pim-3的沉默导致单阳性（CD24+和ESA+）和双阳性（CD24+ESA+）胰腺癌细胞的比例均下降。Pim-3的过表达与一些干性相关转录因子（如STAT3等）水平的升高有关。此外，Pim-3沉默的胰腺癌细胞中STAT3的磷酸化水平和转录活性降低，其活性的恢复导致干细胞样表型的恢复。因此，Pim-3通过激活STAT3信号通路维持胰腺癌细胞的干性，可能作为胰腺癌的一个新的治疗靶点。
