Pioglitazone, a PPARγ agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling.

Abstract

Pioglitazone (PGZ), a synthetic PPARγ ligand, is known to have anti-tumor activity. However, it is unclear how it acts against hepatocellular carcinoma (HCC). We hypothesized that the pathological receptor for advanced glycation end products (RAGE) is involved in the PGZ anti-tumor process. To test this notion, human primary HCC tissues and corresponding adjacent non-cancerous tissues (ANCT) from 75 consecutive cases were analyzed. The expression and clinical significance of RAGE was assessed by immunohistochemical assay through tissue microarray. After HCC cells were pretreated with different concentrations of PGZ, cell proliferation, apoptosis, cell invasion, and cell cycle distribution were evaluated by multiple assays. The results showed that, the positive expression of RAGE was significantly higher in HCC tissues than in ANCT (66.7% vs. 36.0%, P < 0.001), and was closely associated with pathological staging (P = 0.014) and lymph-vascular space invasion (P = 0.003). Moreover, PGZ inhibited proliferative activity and invasive potential, and induced apoptosis and cell cycle arrest in HCC cells resulting in increased expression of PPARγ and decreased expression of RAGE, NF-κB, HMGB1, p38MAPK, Ki-67, MMP-2, and CyclinD1. Furthermore, knockdown of RAGE or NF-κB by siRNA effectively suppressed cell proliferation and invasion, and mediated the inhibitory effects of PGZ in HCC cells. Taken together, our findings suggest that, RAGE is overexpressed in human HCC tissues, and is closely associated with the pathological staging and tumor invasion of HCC. In addition, PGZ as a PPARγ agonist may inhibit growth and invasion of HCC cells via blockade of the RAGE signaling.

• Authors: Yuan Yang, Ling-Hao Zhao, Bo Huang, Ruo-Yu Wang, Sheng-Xian Yuan, Qi-Fei Tao, Yong Xu, Han-Yong Sun, Chuan Lin, Wei-Ping Zhou
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 54 Issue 12 Pg. 1584-95 (Dec 2015) ISSN: 1098-2744 [Electronic] United States
• PMID: 25307746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• AGER protein, human
• PPAR gamma
• Receptor for Advanced Glycation End Products
• Thiazolidinediones
• Pioglitazone

Topics

• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Neoplasm Invasiveness (prevention & control)
• PPAR gamma (agonists)
• Pioglitazone
• Receptor for Advanced Glycation End Products (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Thiazolidinediones (pharmacology)