Department of Oral and Maxillofacial Surgery, Program of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Public Oral Health, Program of Oral Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Eur J Oral Sci. 2021 Oct;129(5):e12812. doi: 10.1111/eos.12812. Epub 2021 Jul 8.
We previously found that microRNAs play major roles in the maintenance of amoeboid-like oral squamous cell carcinoma (OSCC) cells with high expression of CD44 (CD44 ). However, the roles of microRNAs in chemotherapeutic resistance exhibited by CD44 amoeboid-like OSCC cells are unclear. Here, docetaxel-induced apoptosis was examined in CD44 OSCC cells (CD44 OM-1 cells) cultured on laminin-coated silicone gel. Amoeboid-like CD44 OSCC cells exhibited robust resistance to docetaxel-induced apoptosis and significant upregulation of miR-224-5p expression compared with epithelial-like CD44 OSCC cells and mesenchymal-like CD44 OSCC cells. The expression of pannexin-1 (PANX1), a channel-forming protein that regulates the release of ATP, was significantly upregulated following transfection of amoeboid-like CD44 OSCC cells with an miR-224-5p inhibitor. These results suggest that miR-224-5p inhibits PANX1 expression. Furthermore, miR-224-5p inhibitor-transfected amoeboid-like CD44 OSCC cells exhibited significant enhancement of the proportion of apoptotic cells; however, this effect was significantly inhibited by knockdown of PANX1 with PANX1 small interfering RNA. Additionally, the miR-224-5p inhibitor-enhanced extracellular ATP levels were significantly reduced by PANX1 knockdown. These findings imply that miR-224-5p plays a vital role in the resistance to docetaxel-induced apoptosis by attenuating PANX1-induced ATP discharge. Moreover, amoeboid-like CD44 OSCC cells may be involved in chemotherapeutic resistance of OSCC.
我们之前发现 microRNAs 在维持高表达 CD44（CD44）的阿米巴样口腔鳞状细胞癌（OSCC）细胞中发挥重要作用。然而，CD44 阿米巴样 OSCC 细胞表现出的化疗耐药性中 microRNAs 的作用尚不清楚。在此，我们在层粘连蛋白包被的硅凝胶上培养 CD44 OSCC 细胞（CD44 OM-1 细胞），研究了多西紫杉醇诱导的细胞凋亡。与上皮样 CD44 OSCC 细胞和间充质样 CD44 OSCC 细胞相比，阿米巴样 CD44 OSCC 细胞对多西紫杉醇诱导的细胞凋亡表现出更强的耐药性，并且 miR-224-5p 的表达显著上调。在转染阿米巴样 CD44 OSCC 细胞的 miR-224-5p 抑制剂后，孔蛋白 1（PANX1）的表达显著上调，PANX1 是一种调节 ATP 释放的形成通道的蛋白。这些结果表明，miR-224-5p 抑制 PANX1 的表达。此外，转染 miR-224-5p 抑制剂的阿米巴样 CD44 OSCC 细胞中凋亡细胞的比例显著增加；然而，这种作用被 PANX1 小干扰 RNA 敲低显著抑制。此外，miR-224-5p 抑制剂增强的细胞外 ATP 水平通过 PANX1 敲低显著降低。这些发现表明，miR-224-5p 通过减弱 PANX1 诱导的 ATP 释放在多西紫杉醇诱导的细胞凋亡耐药中发挥重要作用。此外，CD44 样阿米巴样 OSCC 细胞可能参与 OSCC 的化疗耐药。
