Signal Transducers and Activators of Transcription 5b Activation Enhances Hepatocellular Carcinoma Aggressiveness through Induction of Epithelial-Mesenchymal Transition

Terence K Lee,Kevin T Ng,Chung Mau Lo,Irene O Ng,Anthony P Yuen,Ronnie T.P Poon,Warren Leonard,Kwan Man,Sheung Tat Fan

doi:10.1158/0008-5472.can-06-1092

Abstract

Poor prognosis of hepatocellular carcinoma (HCC) is associated with a high potential of vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. Recently, signal transducers and activators of transcription 5 (STAT5) has been linked to tumor progression by EMT induction. However, the precise roles of STAT5 genes (STAT5a and STAT5b) in human epithelial cancers have not been elucidated clearly. The aim of this study is to analyze the roles of STAT5 isoforms in HCC progression using HCC clinical samples. We showed that activation of STAT5b, but not STAT5a, was found in HCC clinical samples and its expression was significantly associated with younger age (P = 0.037), advanced tumor stages (P = 0.003), venous infiltration (P = 0.016), microsatellite formation (P = 0.024), multiple tumor nodules (P = 0.02), and poor patient survival. To specifically investigate the mechanism underlying constitutive activation of STAT5b in HCC, EGFP-HBX was introduced into Huh-7 cells. STAT5b activation in HCC is at least partially mediated by HBX activation. Ectopic STAT5b transfection conferred increased HCC cell motility and invasiveness by induction of EMT changes. In conclusion, STAT5b activation enhanced HCC aggressiveness by induction of EMT, which was possibly mediated by HBX activation. STAT5b could serve as a novel molecular target for HCC treatment.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and second most common cancer in Hong Kong [1, 2]
To determine signal transducers and activators of transcription 5 (STAT5) activation in HCC, we evaluated the intracellular protein expression of STAT5a and STAT5b in 50 HCC clinical samples by immunostaining
To further confirm the relative contribution of STAT5a and STAT5b to HCC, we did immunoblotting studies using antibody specific for each STAT5 isoform. These experiments showed down-regulation of STAT5a protein in HCC tumor when compared with nontumor liver (Fig. 1B)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and second most common cancer in Hong Kong [1, 2]. Poor prognosis of HCC is associated with a high potential of vascular invasion, metastasis, and recurrence even after curative surgical resection [3]. HCC invasiveness is the ability of tumor cells to invade the capsule and portal vein [4, 5]. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process whereby epithelial cell layers lose polarity together with cell-cell contacts and undergo a dramatic remodeling of the cytoskeleton [6]. The loss of E-cadherin expression is a hallmark of EMT [6]. E-cadherin plays a central role in cell-cell adhesion junctions in maintenance of cell polarity

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