PRSS3 promotes tumour growth and metastasis of human pancreatic cancer.
OBJECTIVE
Metastasis 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.


METHODS
PRSS3 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.


RESULTS
PRSS3 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).


CONCLUSIONS
PRSS3 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.
Jiang
Guozhong
G
The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Cao
Fengyu
F
Ren
Guoping
G
Gao
Dongling
D
Bhakta
Vipul
V
Zhang
Yunhan
Y
Cao
Hua
H
Dong
Ziming
Z
Zang
Weidong
W
Zhang
Shuijun
S
Wong
Han Hsi
HH
Hiley
Crispin
C
Crnogorac-Jurcevic
Tatjana
T
Lemoine
Nick R
NR
Wang
Yaohe
Y
D000328:Adult; D000368:Aged; D000818:Animals; D002070:Butadienes / Q000627:therapeutic use; D049109:Cell Proliferation; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D014357:Trypsin / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D002070:Butadienes; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009570:Nitriles; C113580:U 0126; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases; C040749:PRSS3 protein, human; D014357:Trypsin