Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma.
Ribonucleotide reductase (RR)M2B is an enzyme belonging to the ribonucleotide reductase enzyme family, which is essential for DNA synthesis and repair. RRM2B plays an important role in tumor progression and metastasis; however, little is known about the expression and underlying molecular mechanisms of RRM2B in hepatocellular carcinoma (HCC). In the present study, we report that down-regulation of RRM2B in HCC is negatively associated with intrahepatic metastasis, regardless of p53 status. Moreover, the ectopic overexpression of RRM2B decreased HCC cell migration and invasion in vitro, whereas silencing RRM2B expression resulted in increased migration and invasion in vitro and intrahepatic and lung metastasis in vivo. Additionally, knockdown of RRM2B by short hairpin RNA (shRNA) in HCC cells was associated with epithelial-mesenchymal transition (EMT), including the down-regulation of E-cadherin, and the concomitant up-regulation of N-cadherin and slug. A further experiment showed that RRM2B inhibited cell migration and spreading through regulation of the early growth response protein 1 (Egr-1)/phosphatase and tensin homolog (PTEN)/Akt1 pathway. Consistently, we also detected a significant correlation between RRM2B and E-cadherin protein expression in HCC tissues. Furthermore, Egr-1 also directly bound to the RRM2B promoter and repressed RRM2B transcription, thereby establishing a negative regulatory feedback loop.


CONCLUSIONS
These findings indicate that RRM2B suppresses cell migration and spreading by way of modulation of the Egr-1/PTEN/Akt1 pathway.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Hua
H
Tian
Chao
C
Ge
Hong
H
Li
Fangyu
F
Zhao
Helei
H
Hou
Taoyang
T
Chen
Guoping
G
Jiang
Haiyang
H
Xie
Ying
Y
Cui
Ming
M
Yao
Jinjun
J
Li
D015820:Cadherins / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology
D015820:Cadherins; D018797:Cell Cycle Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human