Inhibition of the proliferation and invasion of hepatocellular carcinoma cells by lipocalin 2 through blockade of JNK and PI3K/Akt signaling.
Lipocalin 2 (Lcn2) has been reported to induce cellular proliferation based on its expression in a variety of proliferative cells. Consistent with these findings, the present study demonstrates a significant increase in Lcn2 levels in human hepatocellular carcinoma (HCC) tissues compared with non-tumor liver tissues. However, the role of Lcn2 in hepatocarcinogenesis is far from clear. To investigate the effects of Lcn2 expression on hepatocarcinogenesis, Chang liver and SK-Hep1 HCC cell lines were genetically manipulated to express Lcn2, and the effects on the proliferation and invasion of HCC cells were analyzed. Ectopic expression of Lcn2 in HCC cells significantly inhibited the growth of HCC cells in vitro and in vivo, reduced the invasive potential of cells, and inhibited the expression of matrix metalloproteinase 2 (MMP-2). Lcn2 may exert its function partly through the inhibition of the c-Jun N-terminal kinase (JNK) and phospha-tidyl inositol 3'-kinase (PI3K)/Akt signaling pathways in HCC cells. The selective inhibition of these pathways using pharmacological inhibitors significantly inhibited proliferation, invasion and MMP-2 expression, whereas Lcn2 expression suppressed the JNK and PI3K/Akt pathways. Collectively, these results clearly indicate that Lcn2 may play a protective role against the progression of HCCs by suppressing cell proliferation and invasion. The clinical significance of the present findings should be evaluated further.
New Biologics Team, Mogam Biotechnology Research Institute, Yongin, Kyonggi-do 446-799, Republic of Korea.
Eun-Kyoung
EK
Lee
Hyun-Jun
HJ
Kim
Kong-Ju
KJ
Lee
Ho-Jeong
HJ
Lee
Ju-Seog
JS
Lee
Dae-Ghon
DG
Kim
Soon-Won
SW
Hong
Yeup
Y
Yoon
Jang-Seong
JS
Kim
D000209:Acute-Phase Proteins / Q000502:physiology*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D046888:Tissue Array Analysis
D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2