Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma.

Hui-Tzu Hsu,Hsin-Chen Lee,Cheng-Yuan Hsia,Yin-Ju Kuo,Chih-Chun Lee,Chin-Wen Chi,Ming-Ta Sung

doi:10.3390/ijms17081226

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients.

Highlights

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide [1], in Asia and Africa
We examined the relationship between Peroxisome proliferator-activated receptor γ (PPARγ) protein expression and various clinicopathological variables such as age, tumor number, macroscopic vascular invasion (MVI), TNM stage, and survival rate in 83 HCC patients, who have underwent surgical resection
MVI was independently associated with PPARγ expression based on the results of the multiple logistic regression analysis, indicating that low PPARγ expression is independently predictive of more MVI in HCC patients

Summary

Introduction

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide [1], in Asia and Africa. Accumulating evidence indicates that PPARγ plays a critical role in cancer cell growth [7], migration [8], invasion [9], and apoptosis [10]. Krüppel-like factor 4 (KLF4), a tumor suppressor in HCC [14,15,16], has been reported to be up-regulated by the PPARγ agonist troglitazone and promotes cell cycle arrest in colorectal cancer cells [17]. These findings indicate that PPARγ collaborates with KLF4 to regulate HCC tumorigenesis and cancer progression

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Methods

Results