Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells.
Hyaluronic acid (HA) binds to cell-surface receptors such as CD44, and seems to be involved in cell adhesion, motility, and tumor progression in brain. To identify gene expression changes that are initiated by HA, we explored human cytokine arrays in U87MG glioma cells and identified osteopontin, a secreted matrix protein, as a transcriptional target of HA. Interestingly, expression of osteopontin was induced by HA in glioma cells lacking functional PTEN, a tumor suppressor gene (U87MG, U251MG, and U373MG), but not in wild-type (wt)-PTEN-harboring cells (LN18 and LN428). To confirm the role of PTEN, adenoviral (Ad)-wt-PTEN was used to induce ectopic expression of wt-PTEN in U87MG cells, leading to reduced HA-mediated osteopontin induction. Reciprocally, transfection with dominant-negative Akt repressed HA-induced osteopontin expression. Furthermore, HA promoted the motility of glioma cells, and down-regulation of induced osteopontin activity via a neutralizing anti-osteopontin antibody repressed HA-induced motility in vitro. Together, these results strongly suggest that induction of osteopontin expression by HA is dependent on activation of the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, our data indicate that PTEN can effectively modulate the expression of osteopontin, and HA-induced osteopontin plays an important role in the motility response induced by HA in human glioma cells.
Kim
Mi-Suk
MS
Research Institute and Hospital, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi 411-764, Korea.
Park
Myung-Jin
MJ
Moon
Eui-Jung
EJ
Kim
So-Jeong
SJ
Lee
Chang-Hun
CH
Yoo
Heon
H
Shin
Sang-Hoon
SH
Song
Eun-Sook
ES
Lee
Seung-Hoon
SH
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D006820:Hyaluronic Acid; D053495:Osteopontin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012795:Sialoglycoproteins; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C506895:SPP1 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human; C494929:PTEN protein, human