Department of Molecular and Tumor Pathology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Int J Oncol. 2011 Nov;39(5):1311-20. doi: 10.3892/ijo.2011.1114. Epub 2011 Jul 4.
Hyaluronan (HA) is synthesized by HA synthase (HAS) 1, HAS2 and HAS3, and degraded by hyaluronidase (HYAL) 1 and HYAL2 in a CD44-dependent manner. HA and HYALs are intricately involved in tumor growth and metastasis. Random cell movement is generally described as chemokinesis, and represents an important step at the beginning of tumor cell liberation from the primary site. To investigate the roles of HAS2 and HYAL2/CD44 in cell motility, we examined HeLa-S3 cells showing spontaneous chemokinesis. HeLa-S3 cells expressed HAS2 and HAS3. siRNA-mediated knockdown of HAS2 decreased spontaneous chemokinesis of HeLa-S3 cells. Although HeLa-S3 cells secreted 50 ng/ml of high molecular weight (HMW)-HA (peak: 990 kDa) into the culture supernatant after 6 h of culture, exogenously added HMW-HA did not enhance spontaneous chemokinesis of the cells. These observations suggested that HeLa-S3 cells may have a self-degrading system for HA to regulate their spontaneous chemokinesis. To examine this possibility, we investigated the effects of siRNA-mediated knockdown of HYAL2 or CD44 on the spontaneous chemokinesis of HeLa-S3 cells. Knockdown of either molecule decreased the spontaneous chemokinesis of the cells. Low molecular weight (LMW)-HA (23 kDa) reversed the HYAL2 siRNA-mediated reduction in spontaneous chemokinesis of HeLa-S3 cells to the level in control cells stimulated with the same HA. These findings indicate that the HAS2-HYAL2/CD44 system may support spontaneous chemokinesis of human cancer cells through self-degradation of HMW-HA to produce LMW-HA by an autocrine mechanism. Consequently, our study may further expand our understanding of HA functions in cancer.
透明质酸（HA）由透明质酸合酶（HAS）1、HAS2 和 HAS3 合成，并通过 CD44 依赖性方式被透明质酸酶（HYAL）1 和 HYAL2 降解。HA 和 HYALs 错综复杂地参与肿瘤生长和转移。随机细胞运动通常被描述为趋化运动，代表肿瘤细胞从原发部位释放的起始重要步骤。为了研究 HAS2 和 HYAL2/CD44 在细胞运动中的作用，我们研究了自发表现出趋化运动的 HeLa-S3 细胞。HeLa-S3 细胞表达 HAS2 和 HAS3。通过 siRNA 介导的 HAS2 敲低降低了 HeLa-S3 细胞的自发趋化运动。尽管 HeLa-S3 细胞在培养 6 小时后向培养上清液中分泌 50ng/ml 的高分子量（HMW）-HA（峰值：990kDa），但外源性添加 HMW-HA 并没有增强细胞的自发趋化运动。这些观察结果表明，HeLa-S3 细胞可能具有 HA 的自我降解系统来调节其自发趋化运动。为了检验这种可能性，我们研究了 siRNA 介导的 HYAL2 或 CD44 敲低对 HeLa-S3 细胞自发趋化运动的影响。两种分子的敲低均降低了细胞的自发趋化运动。低分子量（LMW）-HA（23kDa）逆转了 HYAL2 siRNA 介导的 HeLa-S3 细胞自发趋化运动的减少，使其恢复至与用相同 HA 刺激的对照细胞相当的水平。这些发现表明 HAS2-HYAL2/CD44 系统可能通过自分泌机制将 HMW-HA 自身降解为 LMW-HA，从而支持人类癌细胞的自发趋化运动。因此，我们的研究可能进一步扩展我们对 HA 在癌症中的功能的理解。
