Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP‐9

Abstract

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.