Zhou Yueying, Zhang Leiyi, Pan Hao, Wang Baisheng, Yan Fei, Fang Xiaodan, Munnee Krishna, Tang Zhangui
Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
Department of Minimal Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
PLoS One. 2015 Apr 27;10(4):e0123208. doi: 10.1371/journal.pone.0123208. eCollection 2015.
Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance.
口腔舌鳞状细胞癌（OTSCC）是最常见的头颈癌之一。对于OTSCC患者而言，对顺铂这种OTSCC标准化疗药物产生先天性或获得性耐药很常见。了解OTSCC细胞中顺铂耐药的分子基础可为鉴定新的治疗靶点提供依据。足细胞外蛋白（PODXL）已被发现对多种癌症的恶性进展至关重要。最近发现Bmi1可诱导OTSCC细胞凋亡和顺铂化疗敏感性。在本研究中，我们探讨了OTSCC细胞中PODXL与Bmi1之间的相互作用，并评估了其对OTSCC细胞对顺铂耐药性的影响。在SCC - 4和Tca8113人OTSCC细胞中稳定过表达和敲低PODXL和/或Bmi1。两种细胞系中PODXL的过表达均显著提高了Bmi1的表达水平和顺铂的半数最大抑制浓度（IC50），并减少了顺铂诱导的细胞凋亡，而Bmi1的敲低或选择性粘着斑激酶（FAK）抑制剂可消除这种作用。另一方面，PODXL的敲低显著降低了Bmi1表达水平和顺铂IC50，并增加了顺铂诱导的细胞凋亡，而Bmi1的过表达可完全逆转这种情况。虽然PODXL的过表达和敲低分别增加和降低了FAK活性，但Bmi1对OTSCC细胞中的FAK活性没有显著影响。此外，PODXL的过表达显著提高了Bmi1 mRNA的稳定性，而选择性FAK抑制剂可消除这种作用。总之，本研究提供了首个证据，即PODXL通过FAK依赖性机制增加Bmi1 mRNA的稳定性，从而上调OTSCC细胞中Bmi1的表达水平；这种作用导致OTSCC细胞中顺铂耐药性增强。本研究为OTSCC耐药的分子机制增添了新的见解。
