The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells

Jie Li; Sheng Zhang; Qing Hu; Kang Zhang; Jianbin Jin; Xuqing Zheng; Zhenyu Yin; Xiaomin Wang

doi:10.1038/srep26971

The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells

Sci Rep. 2016 May 27:6:26971. doi: 10.1038/srep26971.

Authors

Jie Li^{1

2}, Sheng Zhang^{1

2}, Qing Hu^{1

2}, Kang Zhang^{1

2}, Jianbin Jin^{1

2}, Xuqing Zheng^{1

2}, Zhenyu Yin^{1

2}, Xiaomin Wang^{1

2}

Affiliations

¹ Department of Hepatobiliary Surgery, ZhongShan Hospital Xiamen University, Xiamen, China.
² Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma (Xiamen University Affiliated ZhongShan Hospital), Xiamen, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Antigens, CD
Cadherins / genetics
Cadherins / metabolism
Calcium-Binding Proteins
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / mortality
Carcinoma, Hepatocellular / secondary
Carrier Proteins / genetics*
Carrier Proteins / metabolism
Cell Line, Tumor
Cell Movement
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism
Feedback, Physiological*
Gene Expression Regulation, Neoplastic*
Humans
Injections, Subcutaneous
Liver Neoplasms / genetics*
Liver Neoplasms / metabolism
Liver Neoplasms / mortality
Liver Neoplasms / pathology
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / mortality
Lung Neoplasms / secondary
Mice
Mice, Nude
Neoplasm Invasiveness
Neoplasm Transplantation
Prognosis
Proteasome Endopeptidase Complex / metabolism
Signal Transduction
Survival Analysis
Ubiquitin / genetics
Ubiquitin / metabolism
rac1 GTP-Binding Protein / genetics*
rac1 GTP-Binding Protein / metabolism

Substances

Adaptor Proteins, Signal Transducing
Antigens, CD
CDH1 protein, human
Cadherins
Calcium-Binding Proteins
Carrier Proteins
NKD1 protein, human
RAC1 protein, human
Ubiquitin
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Proteasome Endopeptidase Complex
rac1 GTP-Binding Protein