Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma

• Published in: Oncogene Vol. 25; no. 45; pp. 6101 - 6112
• Main Authors: ZHANG, H, OZAKI, I, MIZUTA, T, HAMAJIMA, H, YASUTAKE, T, EGUCHI, Y, IDEGUCHI, H, YAMAMOTO, K, MATSUHASHI, S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 05-10-2006; Nature Publishing Group
• Subjects: Ageing, cell death; Apoptosis; Biological and medical sciences; Caspase; Cell death; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; DNA fragmentation; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Growth factors; Hepatocellular carcinoma; Liver cancer; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mitochondria; Molecular and cellular biology; Smad7 protein; Transfection; Transforming growth factor-b1; Tumor suppressor genes; Tumors; Western blotting; Human; Smad protein; Hepatic disease; Hepatocellular carcinoma; HCC; tumor suppressor; Malignant tumor; Carcinogenesis; PDCD4 gene; Cell death; Digestive diseases; TGF-β1; Smad; Transforming growth factor β1; Apoptosis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209634

The programmed cell death 4 (PDCD4) gene was originally identified as a tumor-related gene in humans and acts as a tumor-suppressor in mouse epidermal carcinoma cells. However, its function and regulatory mechanisms of expression in human cancer remain to be elucidated. We therefore investigated the expression of PDCD4 in human hepatocellular carcinoma (HCC) and the role of PDCD4 in human HCC cells. Downregulation of PDCD4 protein was observed in all HCC tissues tested compared with corresponding noncancerous liver, as revealed by Western blotting or immunohistochemical staining. Human HCC cell line, Huh7, transfected with PDCD4 cDNA showed nuclear fragmentation and DNA laddering characteristic of apoptotic cells associated with mitochondrial changes and caspase activation. Transforming growth factor-β1 (TGF-β1) treatment of Huh7 cells resulted in increased PDCD4 expression and occurrence of apoptosis, also concomitant with mitochondrial events and caspase activation. Transfection of Smad7, a known antagonist to TGF-β1 signaling, protected cells from TGF-β1-mediated apoptosis and suppressed TGF-β1-induced PDCD4 expression. Moreover, antisense PDCD4 transfectants were resistant to apoptosis induced by TGF-β1. In conclusion, these data suggest that PDCD4 is a proapoptotic molecule involved in TGF-β1-induced apoptosis in human HCC cells, and a possible tumor suppressor in hepatocarcinogenesis.