Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9
Article first published online: 28 OCT 2008
© 2008 The Japan Society of Hepatology
Volume 39, Issue 2, pages 177–186, February 2009
How to Cite
Chen, J.-s., Wang, Q., Fu, X.-h., Huang, X.-H., Chen, X.-l., Cao, L.-q., Chen, L.-z., Tan, H.-x., Li, W., Bi, J. and Zhang, L.-j. (2009), Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatology Research, 39: 177–186. doi: 10.1111/j.1872-034X.2008.00449.x
- Issue published online: 21 JAN 2009
- Article first published online: 28 OCT 2008
- Received 29 July 2008; revised 21 August 2008; accepted 21 August 2008.
- hepatocellular carcinoma;
- matrix metalloproteinase;
- phosphorylated AKT;
- phosphorylated mTOR;
- tissue microarray
Aim: To investigate the status of Phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mammalian target of rapamycin (mTOR) pathway and its correlation with clinicopathological features and matrix metalloproteinase-2, -9 (MMP-2, 9) in human hepatocellular carcinoma (HCC).
Methods: PTEN, Phosphorylated AKT (p-AKT), Phosphorylated mTOR (p-mTOR), MMP-2, MMP-9 and Ki-67 expression levels were evaluated by immunohistochemistry on tissue microarrays containing 200 HCCs with paired adjacent non-cancerous liver tissues. PTEN, MMP-2 and MMP-9 mRNA levels were determined by real-time RT-PCR in 36 HCCs. The relationships between PI3K/PTEN/AKT/mTOR pathway and clinicopathological factors and MMP-2, 9 were analyzed in HCC.
Results: In HCC, PTEN loss and overexpression of p-AKT and p-mTOR were associated with tumor grade, intrahepatic metastasis, vascular invasion, TNM stage and high Ki-67 labeling index (P < 0.05). PTEN loss was correlated with p-AKT, p-mTOR and MMP-9 overexpression. Furthermore, PTEN and MMP-2, 9 mRNA levels were down-regulated and up-regulated in HCC compared with paired non-cancerous liver tissues, respectively (P < 0.01). PTEN, MMP-2 and MMP-9 mRNA levels were correlated with tumor stage and metastasis. There was an inverse correlation between PTEN and MMP-9 mRNA expression. However, PI3K/PTEN/AKT/mTOR pathway was not correlated with MMP-2.
Conclusions: PI3K/PTEN/AKT/mTOR pathway, which is activated in HCC, is involved in invasion and metastasis through up-regulating MMP-9 in HCC.