The Study Of STAT3/HOTAIR Signaling Axis Regulating HNSCC Growth

PURPOSE: This study sought to explore the regulatory function of the STAT3-lnc RNA HOTAIR axis in head and neck squamous cell carcinoma(HNSCC)growth and sensitivity to cisplatin(DDP)and cetuximab.EXPERIMENTAL METHODS: Cell viability was examined by MTT assay.Cell proliferation ability was measured by Brd U and clone formation assay.STAT3(p STAT3),EZH2(p EZH2),MDR1,AKT(p AKT),cell cycle-related markers(p16,p21,cyclin-D1),apoptosis-related markers(Bcl2,Bax,cleaved caspase3)were used in Western blot(WB)assay and Immunohistochemistry staining(IHC)assay to detect protein expression levels.Lnc RNA HOTAIR expression level was examined by Real-time PCR and Fluorescence insitu hybridization(FISH)assay.Flow cytometric analysis was used to HNSCC cell cycle distribution of targeting STAT3/HOTAIR.Immunoprecipitation and luciferase reporter assays were performed to determine the interaction between STAT3 and HOTAIR or EZH2.An orthotopic mouse model of HNSCC was established to further confirm the anti-tumor effects of targeting HOTAIR on HNSCC in vivo.RESULTS: Our data revealed that STAT3 overexpression was correlated with HOTAIR level in human HNSCC tumor specimens and cell lines.Targeting STAT3/EZH2 signaling affected the cell cycle and proliferation of HNSCC cells.Luciferase report array showed that STAT3 regulated HOTAIR transcription through binding with the promoter.IP showed STAT3 interacted with phosphorylated EZH2 at Ser21.The overexpression of HOTAIR promoted UM-SCC1 derived HNSCC tumors growth in vivo.CONCLUSION: Overexpression of STAT3/HOTAIR and EZH2 is correlated with the sensitivity of HNSCC to cisplatin.IL-6/STAT3 signaling is positively associated with lnc RNA HOTAIR expression in HNSCC cells.Targeting STAT3/EZH2 could influence the cell cycle progression of HNSCC cells and its proliferation ability.STAT3 enhances HOTAIR transcription by interacting with p EZH2-S21.Suppression of IL-6/STAT3/HOTAIR signaling could enhance the sensitivity of HNSCC cells to cisplatin and cetuximab.Overexpression of HOTAIR promoted UM-SCC1 derived HNSCC tumors growth in vivo.Our findings suggest that IL-6/STAT3 signaling regulates HOTAIR transcription and interacting with EZH2 S21 and may serve as a target with therapeutic potential in HNSCC.