Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.
Lab Invest. 2011 Mar;91(3):379-91. doi: 10.1038/labinvest.2010.176. Epub 2010 Oct 18.
We have previously established immortalized cells (HCF) from cementifying fibroma of the jaw bone. Here, we found that the receptor for hyaluronan (HA)-mediated motility (RHAMM) and epiregulin, a ligand for the epidermal growth factor receptor (EGFR), were highly expressed in HCF cells in comparison with osteoblasts by conducting a microarray analysis. The cell growth of HCF cells was significantly decreased by the knockdown of RHAMM using small interfering RNA (siRNA). RHAMM was associated with extracellular signal-regulated kinase (ERK) and essential for ERK phosphorylation. HCF cells had characteristic growth mechanisms in which epiregulin functions in an extracellular autocrine loop. Interestingly, exogenous HA induced the phosphorylation of EGFR, which was mainly dependent on CD44. The results raise the novel idea that the EGFR may activate Raf-MEK-ERK signaling in response to the binding of HA to CD44. Moreover, RHAMM was able to associate with TPX2 in the nucleus and was required for HA-induced activation of the Aurora A kinase. The results suggest that RHAMM has a predominant role in the cell cycle in HCF. Here, we report the new machinery by which RHAMM/ERK interaction induces the proliferative activity of cementifying fibroma cells via a specific signaling pathway through the CD44-EGFR axis.
我们之前已经从颌骨骨化性纤维瘤中建立了永生化细胞（HCF）。在这里，我们通过微阵列分析发现，与成骨细胞相比，透明质酸（HA）介导的运动受体（RHAMM）和表皮生长因子受体（EGFR）的配体表皮调节素在 HCF 细胞中高度表达。使用小干扰 RNA（siRNA）敲低 RHAMM 可显著降低 HCF 细胞的细胞生长。RHAMM 与细胞外信号调节激酶（ERK）相关，是 ERK 磷酸化所必需的。HCF 细胞具有特征性的生长机制，其中表皮调节素在细胞外自分泌环中发挥作用。有趣的是，外源性 HA 诱导 EGFR 的磷酸化，这主要依赖于 CD44。研究结果提出了一个新的观点，即 EGFR 可能通过与 CD44 结合来激活 Raf-MEK-ERK 信号通路。此外，RHAMM 能够在核内与 TPX2 结合，并且需要 HA 诱导的 Aurora A 激酶的激活。结果表明，RHAMM 在 HCF 中的细胞周期中起主要作用。在这里，我们报告了新的机制，即 RHAMM/ERK 相互作用通过 CD44-EGFR 轴通过特定的信号通路诱导骨化性纤维瘤细胞的增殖活性。
