Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Abstract

Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. In this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor b1 (TGFb1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGFb1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGFb1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGFb1-reluctant cells. The TGFb1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGFb1 activity during liver fibrosis. ß

Implications of pleiotrophin in human PC3 prostate cancer cell growth in vivo

“…Interestingly, AS‐PC3 cells in vitro and AS‐PC3 tumors present with increased apoptosis compared with PC‐PC3 cells and tumors, respectively, suggesting that PTN may have an antiapoptotic role. This is in line with data showing that PTN prevents apoptosis of SW‐13 epithelial cells, spermatocytes, and human embryonic stem cells, and inhibits transforming growth factor beta 1‐induced apoptosis in hepatoma cell lines . However, PTN potentiates cardiomyocyte apoptosis .…”

Pleiotrophin regulates the ductular reaction by controlling the migration of cells in liver progenitor niches

“…[7][8][9][10][11][12] PTN expression has been demonstrated in two conditions associated with accumulation of liver progenitors; partial hepatectomy (PH) and hepatocellular carcinoma (HCC). [13][14][15][16] Bile duct ligation (BDL), a well-established stimulus for the DR, also induces PTN. 17 PTN appears to promote liver growth because regeneration after PH is inhibited in PTN-deficient mice.…”

Loss of Receptor Protein Tyrosine Phosphatase β/ζ (RPTPβ/ζ) Promotes Prostate Cancer Metastasis

“…Concomitantly, pleiotrophin is a proto-oncogene that functions as a mitogenic, anti-apoptotic, and tumor-transforming factor (4,(12)(13)(14)(15)(16)(17)(18). Furthermore, pleiotrophin stimulates epithelial-to-mesenchymal transition (EMT) (19), extensive remodeling of the malignant cell microenvironment (20), tumor angiogenesis (21,22), and metastasis (7).…”