title: The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells.
abstract: Hepatocellular carcinoma (HCC) is complicated by aggressive migration and invasion, which contribute to the increased mortality of HCC patients. The NKD1 protein is abnormally expressed in many neoplasms and plays an important role in tumor progression. However, the regulation and underlying molecular mechanisms of NKD1 in HCC cell invasion and migration remain poorly understood. In the present study, ectopic expression of NKD1 in HCC cells attenuated migration and invasion in vitro and in vivo by down-regulating Rac1 expression level and activity, which affected the HCC cell cytoskeleton and E-cadherin expression. Mechanistic studies showed that NKD1 interacted with Rac1 in the cytoplasm and promoted its degradation by the ubiquitin-proteasome pathway. Over-expression of Rac1 enhanced the transcription of the NKD1 gene and protein expression conversely owing to its negative regulation of EZH2. Analysis of clinical samples showed that abnormal expression of NKD1 and Rac1 was associated with the poor prognosis of HCC patients. In summary, our data indicate a new role for NKD1 as a regulator of HCC cell invasion and migration via a feedback loop involving Rac1.
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Xuqing
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.|Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007279:Injections, Subcutaneous; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C449091:NKD1 protein, human; C107953:RAC1 protein, human; D025801:Ubiquitin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D046988:Proteasome Endopeptidase Complex; D020830:rac1 GTP-Binding Protein