BACKGROUND Previous studies have demonstrated that the glycosaminoglycans (GAGs) heparan sulfate (HS) and hyaluronic acid (HA) are mechanosensors for interstitial flow on cancer cells. The proteins that link the GAGs to the cancer cell for mechanotransduction, however, are not known. OBJECTIVE To assess whether the HS proteoglycan core proteins, Glypican-1 and Syndecan-1, or the HA receptor, CD44, provides the mechanical linkage to the cell. METHODS The highly metastatic renal carcinoma cell line (SN12L1) and its companion low metastatic cell line (SN12C) were analyzed by Western blot, siRNA, and a 3-dimensional interstitial flow migration assay. RESULTS There was significant elevation of Glypican-1 protein expression in the SN12L1 cells relative to the SN12C cells while there were no significant differences in Syndecan-1 or CD44. Knock down of Glypican-1 by siRNA completely blocked flow induced migration in SN12L1 cells. MAPK inhibitors also blocked flow induced migration in SN12L1 cells. CONCLUSIONS Glypican-1 provides the mechanical linkage from HS (the flow sensor) to the SN12L1 cell where mechanotransduction leading to the enhancement of migration (metastasis) occurs. MAPKs downstream of Glypican-1 propagate the signal. The HS, Glypican-1, MAPK signaling axis suggests opportunities for pharmaceutical intervention.

中文翻译：

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癌细胞糖萼蛋白聚糖Glypican-1介导间质流机械转导，以增强细胞迁移和转移。

背景技术以前的研究表明，糖胺聚糖（GAGs）硫酸乙酰肝素（HS）和透明质酸（HA）是用于癌细胞间质流动的机械传感器。然而，将GAG连接至癌细胞进行机械转导的蛋白质尚不清楚。目的评估HS蛋白聚糖核心蛋白Glypican-1和Syndecan-1或HA受体CD44是否提供与细胞的机械连接。方法采用Western blot，siRNA和3维间质流迁移法分析高转移性肾癌细胞系（SN12L1）及其伴随的低转移性细胞系（SN12C）。结果SN12L1细胞中Glypican-1蛋白的表达相对于SN12C细胞显着升高，而Syndecan-1或CD44则没有显着差异。siRNA敲低Glypican-1完全阻断了流动诱导的SN12L1细胞迁移。MAPK抑制剂还阻断了SN12L1细胞中的水流诱导迁移。结论Glypican-1提供了从HS（流量传感器）到SN12L1细胞的机械连接，SN12L1细胞发生了机械迁移，从而导致迁移（转移）的增强。Glypican-1下游的MAPK传播信号。HS，Glypican-1，MAPK信号转导提示了药物干预的机会。Glypican-1下游的MAPK传播信号。HS，Glypican-1，MAPK信号转导提示了药物干预的机会。Glypican-1下游的MAPK传播信号。HS，Glypican-1，MAPK信号转导提示了药物干预的机会。