PRSS3 promotes tumour growth and metastasis of human pancreatic cancer

• Published in: Gut Vol. 59; no. 11; pp. 1535 - 1544
• Main Authors: Jiang, Guozhong, Cao, Fengyu, Ren, Guoping, Gao, Dongling, Bhakta, Vipul, Zhang, Yunhan, Cao, Hua, Dong, Ziming, Zang, Weidong, Zhang, Shuijun, Wong, Han Hsi, Hiley, Crispin, Crnogorac-Jurcevic, Tatjana, Lemoine, Nick R, Wang, Yaohe
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.11.2010; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Animals; Biological and medical sciences; Butadienes - therapeutic use; Cancer therapies; Cell growth; Cell Proliferation; Disease Progression; Enzyme Inhibitors - therapeutic use; ERK; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - physiology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; gene targeting; Humans; Kinases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphatic system; Male; Medical prognosis; Medical sciences; Metastasis; Mice; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins - physiology; Neoplasm Transplantation; Nitriles - therapeutic use; Pancreatic cancer; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - pathology; pancreatic tumours; Prognosis; Proteins; PRSS3; Survival Analysis; Trypsin - pharmacology; Trypsin - physiology; Tumor Cells, Cultured; Tumors; Up-Regulation - drug effects; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; VEGF; Xenograft Model Antitumor Assays; Human; Growth; Pancreas cancer; Gastroenterology; Digestive diseases; Malignant tumor; Metastasis; Cancer; Pancreatic disease
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2009.200105

Background and aimsMetastasis accounts for the poor outcome of patients with pancreatic cancer. We recently discovered PRSS3 to be over-expressed in metastatic human pancreatic cancer cells. This study aimed to elucidate the role of PRSS3 in the growth and metastasis of human pancreatic cancer.MethodsPRSS3 expression in human pancreatic cancer cell lines was detected by qPCR and immunoblotting. The effect of PRSS3 on cancer cell proliferation, migration and invasion in vitro, tumour growth and metastasis in vivo were investigated by manipulation of PRSS3 expression in human pancreatic cancer cell lines. VEGF expression was detected by ELISA, and the pathway through which PRSS3 regulates VEGF expression was investigated. The therapeutic effect of targeting this pathway on metastasis was assessed in vivo. Immunohistochemistry was employed to detect PRSS3 expression in human pancreatic cancer tissues.ResultsPRSS3 was over-expressed in the metastatic PaTu8988s cell line, but not in the non-metastatic PaTu8988t cell line. Over-expression of PRSS3 promoted pancreatic cancer cell proliferation as well as invasion in vitro, and tumour progression and metastasis in vivo. Stepwise investigations demonstrated that PRSS3 upregulates VEGF expression via the PAR1-mediated ERK pathway. ERK inhibitor significantly delayed the progression of metastases of pancreatic cancer and prolonged the survival of animals bearing metastatic pancreatic cancer (p<0.05). 40.54% of human pancreatic cancers (n=74) were positive for PRSS3 protein. A significant correlation was observed between PRSS3 expression and metastasis (p<0.01). Multivariate Cox regression analysis indicated that patients with PRSS3 expression in their tumours had a shorter survival time compared to those without PRSS3 expression (p<0.05).ConclusionPRSS3 plays an important role in the progression, metastasis and prognosis of human pancreatic cancer. Targeting the PRSS3 signalling pathway may be an effective and feasible approach for treatment of this lethal cancer.