title: 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.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|Department of Health Statistics, Second Military Medical University, Shanghai, China.|National Innovation Alliance for Hepatitis & Liver Cancer, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Ling-Hao
authors.initials: LH
authors.lastname: Zhao
authors.affiliation: Suzhou Municipal Hospital, Jiangsu Province, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Sheng-Xian
authors.initials: SX
authors.lastname: Yuan
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Qi-Fei
authors.initials: QF
authors.lastname: Tao
authors.affiliation: Shanghai Dingdian Biotechnology Limited Company, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Han-Yong
authors.initials: HY
authors.lastname: Sun
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Lin
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.|National Innovation Alliance for Hepatitis & Liver Cancer, Shanghai, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C000593871:AGER protein, human; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: RAGE; growth; hepatocellular carcinoma; invasion; pioglitazone