Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma.
A high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients; however, the underlying molecular mechanisms are largely unknown. In the present study a novel metastasis-related gene, eukaryotic initiation factor 5A2 (EIF5A2), was characterized for its role in HCC metastasis and underlying molecular mechanisms. Overexpression of EIF5A2 messenger RNA (mRNA) was detected in 50/81 (61.7%) of HCCs, which was significantly higher than those in nontumorous liver tissues. Compared with matched primary HCC, higher expression of EIF5A2 protein was observed in 25/47 (53.2%) of metastatic tumors. Functional studies found that ectopic expression of EIF5A2 could enhance cancer cell migration and invasion in vitro and tumor metastasis in vivo in an experimental mouse model. Moreover, inhibition of EIF5A by small interfering RNA (siRNA) or deoxyhypusine synthase (DHPS) inhibitor GC7, which inhibits EIF5A2 maturation, could effectively decrease cell motility. Further study found that EIF5A2 was able to induce epithelial-mesenchymal transition (EMT), a key event in tumor invasion and metastasis, characterized by down-regulation of epithelial markers (E-cadherin and beta-catenin) and up-regulation of mesenchymal markers (fibronectin, N-cadherin, alpha-SMA, and vimentin). In addition, EIF5A2 could also activate RhoA/Rac1 to stimulate the formation of stress fiber and lamellipodia.


CONCLUSIONS
EIF5A2 plays an important role in HCC invasion and metastasis by inducing EMT, as well as stimulating cytoskeleton rearrangement through activation of RhoA and Rac1.
Tang
Dong-Jiang
DJ
Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China.
Dong
Sui-Sui
SS
Ma
Ning-Fang
NF
Xie
Dan
D
Chen
Leilei
L
Fu
Li
L
Lau
Sze Hang
SH
Li
Yan
Y
Li
Yan
Y
Guan
Xin-Yuan
XY
D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000556:secondary*; D002465:Cell Movement; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C100667:N(1)-guanyl-1,7-diaminoheptane; D010448:Peptide Initiation Factors; D034741:RNA, Small Interfering; C425967:eIF-5A2; D006147:Guanine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase; D020741:rho GTP-Binding Proteins