The Function Mechanism And Clinical Significance Of GDF15in Oral Squamous Cell Carcinoma

Purpose: In our previous studies, we established an in vitro cellularcarcinogenesis model of oral squamous epithelia cell. The difference of geneexpression was then investigated by microarray analysis, and growthdifferentiation factor15(GDF15) was the most significantly up-regulatedgene. GDF15play an important role in the carcinogenesis and progression ofmany types of cancers, was rarely reported in oral squamous cell carcinoma(OSCC). In this study, the relationship between the expression of GDF15andthe carcinogenesis, progession and prognosis of OSCC was investigated.Methods: Western blotting and real-time PCR methods were applicatedto confirm the expression of GDF15mRNA and protein levels in HIOEC, HB96and several other OSCC cells. ELISA was performed to measure theconcentration of GDF15in serum from healthy persons, patients with oralleukoplakia and OSCC respectively, to find the role of serum GDF15concentration detection for potential diagnositic value in OSCC patients.Immunohistochemistry was used to detect the expression of GDF15protein in biopsy samples from230OSCC patients, as well as paired adjacentnon-malignant epithelia samples, to explore the potential role of GDF15as aprognostic biomarker or predictive biomarker for response to TPF inductionchemotherapy in OSCC patients. Functional studies of GDF15gene, such asin the HIOEC, HB96and HN30cells were performed using RNAi andoverexpression technologies by tranfecting cells with lentivirus.Results: GDF15mRNA and protein levels in the HB96and other fourkinds of OSCC cell lines were higher than those in HIOEC cells.The serum GDF15concentration in the OSCC patients was significantlyhigher than that in the patients with oral leukoplakia and healthy personsrespectively. A ROC curve was constructed to determine the cutoff value of346.9ng/L for both patients with oral leukoplakia and OSCC. The OSCCpatients with serum GDF15concentration below the cut off value had aslightly better clinical response to TPF induction chemotherapy and survival.The expression of GDF15protein in the tissue of tumor was higher thanthat in the adjacent normal tissues. Patients with lower GDF15expressionhad a better clinical response to TPF induction chemotherapy and survival.And GDF15expression was an independent risk factor on poor prognosis.Decreasing GDF15expression in OSCC cell lines significantly inhibited cellproliferation, migration, invasion, colony formation, and tumorigenesis through decreased phosphorylation of AKT and ERK1/2. Likewise,overexpression of GDF15significantly promoted cell proliferation, migration,invasion, and colony formation through increased phosphorylation of AKTand ERK1/2.Conclusions: The expression of GDF15was up-regulated in OSCC and canbe used as a potential diagnostic and prognostic biomarker for OSCC. A lowGDF15expression level predicts a high clinical response rate to TPF inductionchemotherapy in OSCC patients. GDF15promotes tumorigenesis andprogression through phosphorylation of AKT and ERK1/2in OSCC cell lines.