Osteopontin splice variants differentially modulate the migratory activity of hepatocellular carcinoma cell lines.
Osteopontin (OPN, SPP1) is a secretory extracellular matrix protein that has been implicated in cancer-associated mechanisms such as metastasis, invasion and angiogenesis. Three OPN isoforms (OPN-a, -b and -c) derived from alternative splicing are known to exist, but their functional specificity remains unclear. Here, we found that the expression profile of OPN isoforms in hepatocellular carcinoma (HCC) cell lines and patient tissues were correlated with specific cellular phenotypes and tumorigenicity of HCC. Thus, SK-Hep1 cells with a robust migratory capacity dominantly expressed both OPN-a and -b, but non-migratory cell lines such as Hep3B and PLC/PRF/5 mainly expressed OPN-c. Moreover, tumor tissues predominantly expressed OPN-a and -b, whereas normal liver tissues mainly expressed OPN-c. Transwell infiltration and wound-induced migration assays revealed that both OPN-a and -b induced Hep3B cell migration, while OPN-c had no significant effects. By contrast, OPN-c suppressed the migratory activity of SK-Hep1 cells although no significant changes were induced by OPN-a. Consistently, OPN isoforms differentially activated migration-associated signaling pathways such that OPN-a and -b increased the expression of urokinase type plasminogen activator and the phosphorylation of p42/p44 MAP kinase, but these pathways were not activated by OPN-c. Thus, the findings of the present study suggest that OPN splice variants differentially couple to signaling pathways to modulate the migratory property of HCC cells and that this is one of the mechanisms underlying the pathological heterogeneity of HCC progression.
Chae
Sujin
S
Neurovascular Coordination Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Jun
Hyoung-Oh
HO
Lee
Eun Gyo
EG
Yang
Suk-Jin
SJ
Lee
Dong Chul
DC
Jung
Joon Ki
JK
Park
Kyung Chan
KC
Yeom
Young Il
YI
Kim
Kyu-Won
KW
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D020033:Protein Isoforms; D053495:Osteopontin