Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma

Abstract

BACKGROUND Inactivation of the tumor suppressor gene PTEN/MMAC1/TEP1, located on chromosome 10q23, is a common event in advanced stages of diverse human malignancies. However, the prognostic role of PTEN expression in patients with hepatocellular carcinoma (HCC) has not been characterized. METHODS One hundred five resected specimens were collected from patients with HCC. Expression levels of PTEN and p53 in clinical samples were analyzed by immunohistochemistry. RESULTS Immunohistochemical analysis of 105 HCC tissue specimens revealed that decreased or absence of PTEN immunostaining was found in 43 specimens (40.9%). Reduced PTEN expression levels were correlated with increased tumor grade (P = 0.017), advanced disease stage (P = 0.016), and elevated serum α‐fetoprotein (αFP) levels (P = 0.001). Kaplan–Meier analysis indicated that patients with reduced PTEN levels had shorter overall survival (P = 0.001) and higher recurrence rates (P = 0.0007) compared with patients who had intact PTEN expression. Examining p53 expression unveiled an inverse correlation between p53 overexpression and reduced PTEN expression in patients with HCC (P = 0.004). In addition, patients with p53 overexpression had shorter overall survival compared with patients who were without p53 overexpression (P = 0.0014). Univariate and multivariate analyses revealed that reduced PTEN expression was an independent prognostic factor for survival in patients with HCC. CONCLUSIONS The current study demonstrated that reduced PTEN expression levels are involved in the pathogenesis of HCC. Moreover, decreased PTEN expression was correlated with tumor progression, high αFP levels, p53 overexpression, and poor prognosis in patients with HCC. Cancer 2003;97:1929–40. © 2003 American Cancer Society. DOI 10.1002/cncr.11266

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

“…Receptor tyrosine kinase activation rather than somatic mutations of PTEN or PI3KCA, which are rare in HCC, is likely to be responsible for activation of mTOR in HCC. Consistent with this notion, activation of AKT has been found in 40%-60% of human HCC samples (12) and is a risk factor for early recurrence and poor prognosis (13). More importantly, recent studies using knockout mice showed that mTOR activation was sufficient to cause HCC in rodent models (14), indicating the pivotal role of mTOR signaling in HCC.…”

MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer

“…22 Moreover, decreased PTEN correlates with tumor progression and poor prognosis in HCC. 20,23 Loss of functional PTEN leads to increased activity of AKT and the mammalian target of rapamycin (mTOR) kinase pathways, which can promote both cell survival and proliferation through phosphorylation and inactivation of several downstream mediators. 24 Activation of FAK has been observed in human HCC, and an increase in FAK activity correlates with more aggressive tumor behavior.…”

Increased endostatin/collagen XVIII expression correlates with elevated VEGF level and poor prognosis in hepatocellular carcinoma

“…18 The closing date of follow-up was December 31, 2002. All the HCC specimens consisted of paired tumor and adjacent nontumor parts.…”

“…The stages of HCC were classified according to the staging system by the International Union against Cancer with slight modification as described previously. 18 The hepatic fibrosis stages in nontumor tissues were determined by masson trichrome staining and divided into three groups for comparison: group 1 (fibrosis 0-1), group 2 (fibrosis 2-3), and group 3 (fibrosis 4: cirrhosis).…”

“…It was reported that endostatin and the proteolytic fragments of C18 could be extracted using various extraction agents. 18 We evaluated the specificity of endostatin antibodies by Western blot analysis using various extracts of hepatoma cells. In EDTA extract, endostatin antibodies specifically detected a 20-kDa protein (Figure 1c), which had a molecular weight approximate to that of endostatin.…”