Combined Phosphatase and Tensin Homolog (PTEN) Loss and Fatty Acid Synthase (FAS) Overexpression Worsens the Prognosis of Chinese Patients with Hepatocellular Carcinoma

Xuehua Zhu,Maogui Fei,Crystal Ying Qin,Richard Wooster,Wenmin Hou,Joel Greshock,Jiuhong Kang,Kurtis E Bachman,Xia Qin

doi:10.3390/ijms13089980

Abstract

We aimed to investigate the expression pattern of phosphatase and tensin homolog (PTEN), to evaluate the relationship between PTEN expression and clinicopathological characteristics, including fatty acid synthase (FAS) expression, and to determine the correlations of PTEN and FAS expression with survival in Chinese patients with hepatocellular carcinoma (HCC). The expression patterns of PTEN and FAS were determined using tissue microarrays and immunohistochemistry. The expression of PTEN was compared with the clinicopathological characteristics of HCC, including FAS expression. Receiver operator characteristic curves were used to calculate the clinical sensitivity and specificity of PTEN expression. Kaplan-Meier survival curves were constructed to evaluate the correlations of PTEN loss and FAS overexpression with overall survival. We found that the loss of PTEN expression occurred predominantly in the cytoplasm, while FAS was mainly localized to the cytoplasm. Cytoplasmic and total PTEN expression levels were significantly decreased in HCC compared with adjacent non-neoplastic tissue (both, p < 0.0001). Decreased cytoplasmic and total PTEN expression showed significant clinical sensitivity and specificity for HCC (both, p < 0.0001). Downregulation of PTEN in HCC relative to non-neoplastic tissue was significantly correlated with histological grade (p = 0.043 for histological grades I–II versus grade III). Loss of total PTEN was significantly correlated with FAS overexpression (p = 0.014). Loss of PTEN was also associated with poor prognosis of patients with poorly differentiated HCC (p = 0.049). Moreover, loss of PTEN combined with FAS overexpression was associated with significantly worse prognosis compared with other HCC cases (p = 0.011). Our data indicate that PTEN may serve as a potential diagnostic and prognostic marker of HCC. Upregulating PTEN expression and inhibiting FAS expression may offer a novel therapeutic approach for HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide [1], with very high incidences in China and Africa [2]
We found that the loss of Phosphatase and tensin homolog (PTEN) mainly occurred in the cytoplasm in HCC tissues relative to adjacent non-neoplastic tissues, and that PTEN expression was markedly downregulated in HCC tissues compared with paired adjacent non-neoplastic tissues
We suggest that PTEN may serve as a molecular prognostic marker for poorly differentiated HCC, and that PTEN loss in combination with Fatty acid synthase (FAS) overexpression is associated with even worse prognosis of HCC patients

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide [1], with very high incidences in China and Africa [2]. Phosphatase and tensin homolog (PTEN) [4] is a plasma membrane lipid phosphatase that acts as a tumor suppressor [5] and regulates several key cellular functions, including proliferation, apoptosis and migration [6]. The PI3K/Akt pathway is important in terms of regulating growth, survival and proliferation of cells [7]. Overexpression of FAS occurs in many types of cancer and is frequently correlated with poor prognosis [10]. The loss of PTEN function plays an important role in the overexpression of FAS [10]. The correlation between PTEN loss and FAS overexpression in Chinese patients with HCC is still unclear and awaits further investigation

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