Molecular Mechanism Of GDF15 On TPF Induction Chemotherapy In Patients With Locally Advanced Oral Squamous Cell Carcinoma

Objective: The role of induction chemotherapy in oral squamous cell carcinoma(OSCC)remains controversial.While TPF(docetaxel,cisplatin and 5-fluorouracil)induction chemotherapy might improve outcomes in specific patient populations defined by clinical and/or molecular criteria,and a potential correlation between growth differentiation factor 15(GDF15)expression and response to TPF induction chemotherapy in OSCC patients was found.The aim of the current study was to explore the clinical usefulness of GDF15 as a potential predictive biomarker for TPF induction chemotherapy in patients with locally advanced OSCC.Patients and Methods: 256 patients with locally advanced OSCC from a prospective,randomized trial were enrolled into this study,and the long-term follow up data of the initial prospective clinical trial were collected.The relationship between GDF15 expression and chemotherapeutics sensitivity in OSCC lines was analyzed in a cellular and molecular study using cytotoxicity assay and western blotting assay.Results: The entire OSCC patients did not benefit from adding TPF induction chemotherapy before surgery and radiotherapy compared to surgery and radiotherapy alone,the subgroup of cT3/4N0M0 patients with high GDF15 expression could benefit from TPF induction chemotherapy,with regard to overall survival(HR=0.238,95%CI: 0.082-0.694,P=0.009),disease-free survival(HR=0.300,95%CI: 0.122-0.736,P=0.009),locoregional recurrence-free survival(HR=0.334,95%CI: 0.136-0.820,P=0.017)and distant metastasis-free survival(HR=0.231,95%CI: 0.079-0.673,P=0.007).Overexpression of GDF15 in OSCC cell lines leads to an increase of chemotherapeutics sensitivity on apoptosis effects induced by docetaxel,cisplatin and 5-fluorouracil,through a caspase activation-dependent pathway.Downregulation of GDF15 expression in OSCC cell lines decreased their chemotherapeutics sensitivity on apoptosis effects induced by docetaxel,cisplatin and 5-fluorouracil in vitro,as decreasing activation of caspase 9,caspase 3 add PARP.Conclusion: Our findings suggested that cT3/4N0M0 OSCC patients with high GDF15 expression could benefit from TPF induction chemotherapy before surgery and radiotherapy,and GDF15 overexpression could be used as a potential predictive biomarker for TPF induction chemotherapy in OSCC patients.