Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration
Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration
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DOI：
10.1073/pnas.052026799
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发表时间：
2002-03-19
影响因子：
11.1
通讯作者：
Kimata, K
中科院分区：
文献类型：
--
作者：
Itano, N;Atsumi, F;Kimata, K
透明质酸生物合成和基质沉积升高与细胞增殖和迁移相关。我们在未转化的大鼠 3Y1 细胞中异位表达了透明质酸合酶的三种亚型（HAS1、HAS2 或 HAS3），并观察到透明质酸基质从头大量形成，导致接触介导的细胞生长和迁移抑制部分丧失。所有三种 HAS 转染子在划伤试验中均表现出增强的运动性，并且其汇合细胞密度显着增加。在高密度培养物中，HAS 转染子具有成纤维细胞形状，并明显形成重叠的细胞层。这种表型在 HAS2 转染子中比 HAS1 或 HAS3 转染子中更为明显，并且伴随微丝组织和细胞-细胞边界 N-钙粘蛋白分布的显着改变而发生。磷脂酰肌醇 3-激酶（P13-激酶）途径的抑制导致 HAS2 转染子重新获得正常表型，表明细胞内 P13-激酶信号传导调节由大量透明质酸基质形成引起的接触抑制的减弱。我们的观察表明透明质酸及其基质可以调节细胞生长和迁移的接触抑制，并为不同 HAS 蛋白合成的透明质酸之间的功能差异提供证据。
Elevated hyaluronan biosynthesis and matrix deposition correlates with cell proliferation and migration. We ectopically expressed three isoforms of hyaluronan synthase (HAS1, HAS2, or HAS3) in nontransformed rat 3Y1 cells and observed a de novo, massive formation of a hyaluronan matrix that resulted in a partial loss of contact-mediated inhibition of cell growth and migration. All three HAS transfectants showed an enhanced motility in scratch wound assays, and a significant increase in their confluent cell densities. In high-density cultures, the HAS transfectants had a fibroblastic cell shape and markedly formed overlapping cell layers. This phenotype was more pronounced in the HAS2 transfectants than HAS1 or HAS3 transfectants, and occurred with significant alterations in the microfilament organization and N-cadherin distribution at the cell-cell border. Inhibition of a phosphatidylinositol 3-kinase (P13-kinase) pathway resulted in reacquisition of the normal phenotype of HAS2 transfectants, suggesting that the intracellular P13-kinase signaling regulates diminution of contact inhibition induced by formation of the massive hyaluronan matrix. Our observations suggest that hyaluronan and its matrix can modulate contact inhibition of cell growth and migration, and provide evidence for functional differences between hyaluronan synthesized by the different HAS proteins.