National Research Laboratory, Department of Biological Science, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Oncogene. 2010 Jan 7;29(1):56-67. doi: 10.1038/onc.2009.298. Epub 2009 Sep 28.
Pancreatic cancer is characterized by early metastatic spread, but the process of tumor cell dissemination is largely unknown. In this study we show that the soluble protein pancreatic adenocarcinoma upregulated factor (PAUF) has an important role in the metastasis and progression of the disease. Variations in the level of PAUF, either by overexpression or knockdown, resulted in altered migration, invasion and proliferation capacity of pancreatic cancer cells. Moreover, depletion of PAUF in metastatic cells dramatically abrogated the spread of the cells to distant organs in an orthotopic xenograft mouse model. PAUF elicited the activation of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT intracellular signaling cascades and consequently their downstream transcription factors in an autocrine manner. Genome-wide expression analysis revealed that C-X-C chemokine receptor type 4 (CXCR4) expression was induced by PAUF overexpression but was repressed by PAUF knockdown. The PAUF-mediated increase in cancer cell motility was attenuated by the CXCR4 inhibitor, AMD3100, or by anti-CXCR4 antibody. Furthermore, immunohistochemical analysis of pancreatic tumor tissues clearly showed a significant positive correlation between PAUF and CXCR4 expression. Collectively, these findings indicate that PAUF enhances the metastatic potential of pancreatic cancer cells, at least in part, by upregulating CXCR4 expression.
胰腺癌的特点是早期转移扩散，但肿瘤细胞扩散的过程在很大程度上是未知的。在这项研究中，我们表明可溶性蛋白胰腺腺癌上调因子（PAUF）在疾病的转移和进展中具有重要作用。PAUF 水平的变化，无论是通过过表达还是敲低，都会导致胰腺癌细胞迁移、侵袭和增殖能力的改变。此外，在原位异种移植小鼠模型中，耗竭转移性细胞中的 PAUF 会显著阻止细胞向远处器官的扩散。PAUF 以自分泌的方式引发细胞外信号调节激酶 (ERK)、c-Jun N 末端激酶 (JNK) 和 AKT 细胞内信号通路及其下游转录因子的激活。全基因组表达分析显示，PAUF 过表达诱导 C-X-C 趋化因子受体 4 (CXCR4) 的表达，但 PAUF 敲低抑制 CXCR4 的表达。CXCR4 抑制剂 AMD3100 或抗 CXCR4 抗体可减弱 PAUF 介导的癌细胞迁移增加。此外，胰腺肿瘤组织的免疫组织化学分析清楚地表明，PAUF 与 CXCR4 的表达呈显著正相关。综上所述，这些发现表明，PAUF 通过上调 CXCR4 的表达增强了胰腺癌细胞的转移潜能。
