Leptin signaling enhances cell invasion and promotes the metastasis of human pancreatic cancer via increasing MMP-13 production

• Published in: Oncotarget 2015-06, Vol.6 (18), p.16120-16134
• Main Authors: Fan, Yingchao, Gan, Yu, Shen, Yuling, Cai, Xiaojin, Song, Yanfang, Zhao, Fangyu, Yao, Ming, Gu, Jianren, Tu, Hong
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Movement; Cell Proliferation; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Leptin - pharmacology; Lymphatic Metastasis; Male; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Prognosis; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3878

Emerging evidence has suggested that leptin, an adipokine related to energy homeostasis, plays a role in cancer growth and metastasis. However, its impact on pancreatic cancer is rarely studied. In this study, we found that leptin's functional receptor Ob-Rb was expressed in pancreatic cancer cell lines. Treatment with leptin enhanced the migration and invasion of pancreatic cancer cells but did not affect the proliferation of human pancreatic cancer cells. Leptin up-regulated the expression of matrix metalloproteinase-13 (MMP-13) via the JAK2/STAT3 signaling pathway. The overexpression of leptin was shown to significantly promote tumor growth and lymph node metastasis in a subcutaneous model and an orthotopic model of human pancreatic cancer, respectively. Furthermore, in human pancreatic cancer tissues, the expression of Ob-Rb was positively correlated with the MMP-13 level. The increased expression of either Ob-Rb or MMP-13 was significantly associated with lymph node metastasis and tended to be associated with the TNM stage in patients with pancreatic cancer. Our findings suggest that leptin enhances the invasion of pancreatic cancer through the increase in MMP-13 production, and targeting the leptin/MMP-13 axis could be an attractive therapeutic strategy for pancreatic cancer.