KIAA1199 is induced by inflammation and enhances malignant phenotype in pancreatic cancer.
BACKGROUND
Recent evidence suggests a critical role of hyaluronan (HA), especially low-molecular-weight HA (LMW-HA), in the aggressive tumor phenotype. Increased expression of KIAA1199, a newly identified protein involved in HA degradation, has been reported in various cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the functional significance of KIAA1199 in PDAC.


METHODS
Using siRNA knockdown and forced expression models, we investigated the effects of KIAA1199 expression on malignant behaviors (proliferation, migration, and invasion) of PDAC cells. We also examined the effect of inflammation on the transcriptional regulation of KIAA1199 using a pro-inflammatory cytokine and anti-inflammatory agent.


RESULTS
Knockdown of KIAA1199 expression using siRNA resulted in decreased cell migration and proliferation. On the other hand, forced expression of KIAA1199 using gene transduction significantly enhanced the migration and invasion. Importantly, increased KIAA1199 expression was associated with an increased level of LMW-HA in the conditioned medium. Exposure to a pro-inflammatory cytokine, interleukin-1ß, increased the KIAA1199 transcription and enhanced the migration. In contrast, treatment with NS-398, a cyclooxygenase-2 inhibitor, decreased the KIAA1199 expression and inhibited the migration.


CONCLUSIONS
These findings suggest that increased KIAA1199 expression may contribute to the aggressive phenotype partly through increasing the LMW-HA concentration. Our present results also suggest a possible link between inflammation, induced KIAA1199 expression, and enhanced migration during PDAC progression.
Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Shiro
S
Kohi
Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Norihiro
N
Sato
Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Atsuhiro
A
Koga
Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Nobutaka
N
Matayoshi
Department of Surgery 1, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Keiji
K
Hirata
D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D006821:Hyaluronoglucosaminidase; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008970:Molecular Weight; D009578:Nitrobenzenes / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D053583:Interleukin-1beta; D009578:Nitrobenzenes; D011506:Proteins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D006820:Hyaluronic Acid; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase
KIAA1199; hyaluronan; inflammation; migration; pancreatic cancer