Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90.
We investigated the production of matrix metalloproteinase (MMP) by hyaluronan(HA) stimulation in a human cancer cell line, QG90, that expresses a large amount of CD44s, a HA receptor. Treatment of QG90 with HA strongly activated MMP-2 secretion in a time- and dose-dependent manner. We found that expression of antisense CD44s in QG90 cells substantially inhibited the HA-dependent secretion of MMP-2, whereas overexpression of full-length CD44s augmented the HA-dependent secretion of MMP-2. In addition, pretreatment of cells with the neutralizing anti-CD44 antibody significantly inhibited both the HA-dependent MMP-2 secretion and the HA-dependent activation of mitogen-activated protein kinase in a dose-dependent manner. Similarly, treatment of cells with a Ras farnesyltransferase inhibitor, manumycin A, strongly inhibited the HA-dependent MMP-2 secretion. Moreover, in vitro invasiveness of QG90 and its activation by HA were clearly suppressed by the expression of antisense CD44s. In addition, treatment of cells with anti-CD44, a mitogen-activated protein/extracellular signal-regulated kinase kinase 1 inhibitor, PD98059, or phosphatidylinositol 3'-kinase inhibitors, wortmannin and LY294002, effectively blocked the HA-dependent activation of the invasiveness. In contrast, overexpression of full-length CD44 substantially activated the invasiveness of QG90. Taken together, HA-CD44s signaling plays a key role in the HA-dependent secretion of MMP-2 and, hence, in the invasiveness of QG90 cells.
Department of Molecular Pathogenesis, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Yanying
Y
Zhang
Aye Aye
AA
Thant
Kazuya
K
Machida
Yasukatsu
Y
Ichigotani
Yuko
Y
Naito
Yukiko
Y
Hiraiwa
Takeshi
T
Senga
Yasuyoshi
Y
Sohara
Satoru
S
Matsuda
Michinari
M
Hamaguchi
D018288:Carcinoma, Small Cell / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D016373:DNA, Antisense / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D016373:DNA, Antisense; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D020778:Matrix Metalloproteinase 2