The Role Of DKK1 In Bone Metastasis Of Small Cell Lung Cancer

Lung cancer is an aggressive malignancy with high morbidity and mortality,and distant metastasis is the leading cause of cancer-related death.Bone is one of the major metastatic sites of lung cancer,over 30 to 40% of lung cancers can develop bone metastasis,which is accompanied by skeletal related events that negatively affect the overall survival and quality of life of lung cancer patients.Currently,the treatment on bone metastasis is limited.Therefore,figuring out the mechanism of bone metastasis is the premise and basis for the prevention and treatment on bone metastasis.Wnt/?-catenin signaling and its inhibitor Dickkopf1(DKK1)play important roles in the progression of lung cancer,which preferentially metastasizes to skeleton.However,the roles of DKK1 in osteotropism of SCLC remain to be elucidated.This study aimed to define the roles of DKK1 in SCLC bone metastasis and investigate the underlying mechanisms.Our results demonstrated that the expression level of DKK1 was dramatically higher in bone-metastatic SCLC cells(SBC-5 cell line)compared with that in cells without bone-metastatic ability(SBC-3 cell line).Therefore,we hypothesized that DKK1 was involved in bone metastasis of SCLC.And then we suppressed the DKK1 expression in SBC-5 cells by RNAi and unregulated DKK1 expression in SBC-3 cells,and subsequently we used the overexpression and interfering cell lines to investigate the relationship between DKK1 and tumor behavior(proliferation,migration,invasion and metastasis).The results demonstrated that down-regulation of DKK1 can inhibit the cell proliferation,colony formation,cell migration and invasion in vitro and bone metastasis in NOD-SCID mice in vivo while increase the apoptosis rate in vitro.In contrast,upregulation of DKK1 in SBC-3 cells enhanced cell proliferation,colony formation,cell migration and invasion in vitro,as well as bone metastasis in NOD-SCID mice in vivo.These results indicate that DKK1 may be an important regulator in the development of small cell lung cancer(SCLC),and targeting DKK1 may be an effective method for preventing and/or treating skeletal metastases in SCLC cases.