Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Otsu, Japan.
Department of Urology, Shiga University of Medical Science, Otsu, Japan.
Cancer Med. 2024 Oct;13(19):e70276. doi: 10.1002/cam4.70276.
Tumor growth and progression are affected by interactions between tumor cells and stromal cells within the tumor microenvironment. We previously showed that the expression of an integral membrane protein, called stomatin, was increased in cancer cells following their association with stromal cells. Additionally, stomatin impaired the Akt signaling pathway to suppress tumor growth. However, it remains unclear how stomatin expression is regulated. To explore this, we examined the cell surface molecules that can transduce the intercellular communication signals between cancer cells and stromal cells.
Among these molecules, EphA3 and EphA7 receptors and their ligand ephrin-A5 were found to be expressed in prostate cancer cells, but not in prostate stromal cells. Cell-to-cell contact of prostate cancer cells through the EphA-ephrin-A interaction suppressed stomatin expression, while knockdown of EphA3/7 or ephrin-A5 increased stomatin expression. This increase contributed to an inhibition of prostate cancer cell proliferation. Intracellularly, the binding of ephrin-A to EphA attenuated extracellular signaling-regulated kinase (ERK) activation that promoted stomatin expression. Furthermore, ELK1 and ELK4, which are Ets family transcription factors phosphorylated by ERK, were involved in the induction of stomatin expression. We also found that higher Gleason score prostate cancer tissue samples had increased activation of EphA, while the stomatin expression and activated ERK and ELK levels were all low. In the mouse xenograft tumor samples generated by implantation of prostate cancer cells, EphA3 phosphorylation was attenuated and the ERK-ELK signaling and stomatin expression were enhanced in the area where stromal cells infiltrated the tumor.
The EphA-mediated signaling suppresses the ERK-ELK pathway, leading to the reduction of stomatin expression that affects prostate cancer malignancy.
肿瘤的生长和进展受到肿瘤微环境中肿瘤细胞与基质细胞相互作用的影响。我们之前的研究表明，一种称为 stomatin 的完整膜蛋白在肿瘤细胞与基质细胞发生关联后其表达增加。此外，stomatin 可破坏 Akt 信号通路以抑制肿瘤生长。然而，stomatin 的表达如何受到调控仍不清楚。为了探索这一点，我们研究了可以传递肿瘤细胞与基质细胞之间细胞间通讯信号的细胞表面分子。
在这些分子中，发现 EphA3 和 EphA7 受体及其配体 ephrin-A5 在前列腺癌细胞中表达，但在前列腺基质细胞中不表达。通过 EphA-ephrin-A 相互作用进行的前列腺癌细胞间接触抑制了 stomatin 的表达，而 EphA3/7 或 ephrin-A5 的敲低则增加了 stomatin 的表达。这种增加有助于抑制前列腺癌细胞的增殖。在细胞内，ephrin-A 与 EphA 的结合减弱了促进 stomatin 表达的细胞外信号调节激酶 (ERK) 激活。此外，ERK 磷酸化的 Ets 家族转录因子 ELK1 和 ELK4 参与了 stomatin 表达的诱导。我们还发现，Gleason 评分较高的前列腺癌组织样本中 EphA 的激活增加，而 stomatin 的表达以及激活的 ERK 和 ELK 水平均较低。在植入前列腺癌细胞的小鼠异种移植肿瘤样本中，EphA3 的磷酸化减弱，ERK-ELK 信号和 stomatin 表达在基质细胞浸润肿瘤的区域增强。
EphA 介导的信号抑制 ERK-ELK 通路，导致影响前列腺癌恶性程度的 stomatin 表达减少。
