Interleukin-1alpha enhances the aggressive behavior of pancreatic cancer cells by regulating the alpha6beta1-integrin and urokinase plasminogen activator receptor expression.
BACKGROUND
In human pancreatic cancer progression, the alpha6beta1-integrin is expressed on cancer cell surface during invasion and metastasis formation. In this study, we investigated whether interleukin (IL)-1alpha induces the alterations of integrin subunits and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) expression in pancreatic cancer cells. We hypothesize that the alterations of integrin subunits and uPA/uPAR expression make an important role in signaling pathways responsible for biological behavior of pancreatic cancer cells.


RESULTS
IL-1alpha upregulated the expression of alpha6 and beta1 integrins without any alterations of alpha5 and alphav integrins expression. IL-1alpha also induced enhancement in the expression of uPA/uPAR in pancreatic cancer cells. IL-1alpha enhanced the proliferation, adhesion, and migration in pancreatic cancer cells, and IL-1alpha-induced alterations of uPA/uPAR expression correlated with the increased the migration of pancreatic cancer cells. Upregulation of alpha6 integrin subunit and uPA/uPAR correlated with the activation of Ras and downstream extracellular signal-regulated kinase (ERK) pathways. IL-1alpha-induced activation of Ras and downstream ERK can be inhibited by using inhibitory antibodies against alpha6 and beta1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and migration of pancreatic cancer cells. Immunohistochemical analysis demonstrated a significant association between strong expressions of alpha6 integrin with uPAR in pancreatic cancer specimens. Furthermore, the strong expression of alpha6 integrin and uPAR was found to be independent prognosticator in pancreatic cancer patients.


CONCLUSIONS
Based on these findings, we conclude that IL-1alpha can induce selective upregulation of alpha6beta1-integrin and uPA/uPAR in pancreatic cancer cells and these changes may modulate the aggressive functions of pancreatic cancer.
Sawai
Hirozumi
H
Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya 4678601, Japan. cb8h-swi@asahi-net.or.jp
Okada
Yuji
Y
Funahashi
Hitoshi
H
Matsuo
Yoichi
Y
Takahashi
Hiroki
H
Takeyama
Hiromitsu
H
Manabe
Tadao
T
D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D039482:Integrin alpha5 / Q000032:analysis; D039121:Integrin alpha6beta1 / Q000096:biosynthesis* / Q000235:genetics; D039564:Integrin alphaV / Q000032:analysis; D039663:Integrin beta4 / Q000032:analysis; D007375:Interleukin-1 / Q000494:pharmacology*; D007797:Laminin / Q000378:metabolism; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics
D039482:Integrin alpha5; D039121:Integrin alpha6beta1; D039564:Integrin alphaV; D039663:Integrin beta4; D007375:Interleukin-1; D007797:Laminin; D009363:Neoplasm Proteins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator; D016283:Proto-Oncogene Proteins p21(ras)