The Role Of HIC1 In Non-small Cell Lung Cancer Progression

Background:Lung cancer is the leading cause of cancer deaths throughout the world.More than 80% of which originates from non-small cell lung cancer(NSCLC);however,the mechanism underlying its progression still remains unclear,The aim of this study is to assay the methylation status and role of hypermethylatioted in cancer 1(HIC1)in NSCLC development.Methods:The methylation status of HIC1 promoter were assayed in cell lines and patient tissues of NSCLC patients by using MSP-PCR and bisulfate sequencing(BSP).The effect of HIC1 on apoptosis,migration and invasion of NSCLC cells was evaluated by in situ cell death detection,wound healing assay,and the extracellular matrices in porous culture chambers in vitro and metastasis assay in nude mice by using Xenogen IVIS with radiographic system in vivo.Protein expression of NSCLC patients and cells was assessed by Western blotting and immunohistochemistry.IL-6 promoter activity was determined by reporter assay.Results:The status within HIC1 promoter were abundantly methylated in cell lines and patient tissues of NSCLC compared with the respective controls.In vitro assays,the ability of migration,invasion and the induced apoptosis in NSCLC cells could be modulated by altering HIC1 expression.Moreover,mice bearing NSCLC-restoring HIC1 cells had a marked effect on reducing lung metastases.Notably,IL-6 is identified as the direct downstream target gene of HIC1.Restoring IL-6 expression in HIC1 infected cells could partially rescue HIC1-induced abolition of cell migration,invasion in vitro and metastasis in vivo.Mechanistic analyses show that autocrine secretion of IL-6 induced by loss of HIC1 could activate STAT3 through IL-6/JAK pathway,associated with NSCLC progression.Conclusions:We have identified that hypermethylation of HIC1 promoter results in loss of its repressive function,responsible for NSCLC progression.HIC1/IL-6/STAT3 axis may serve as the subtype-specific prognostic biomarker and provide an attractive therapeutic target for NSCLC.