Bmi1 essentially mediates podocalyxin-enhanced Cisplatin chemoresistance in oral tongue squamous cell carcinoma.
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.
Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
Yueying
Y
Zhou
Department of Minimal Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
Leiyi
L
Zhang
Department of Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, China.
Hao
H
Pan
Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
Baisheng
B
Wang
Department of Prosthodontics, Xiangya Stomatological Hospital, Central South University, Changsha, China.
Fei
F
Yan
Department of Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, China.
Xiaodan
X
Fang
Department of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
Krishna
K
Munnee
Department of Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, China.
Zhangui
Z
Tang
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics*; D014062:Tongue Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C001643:podocalyxin; D063150:Polycomb Repressive Complex 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D002945:Cisplatin