Hanning You1, Wei Ding, C Bart Rountree. 1. Department of Pediatrics and Pharmacology, Pennsylvania State University College of Medicine, Penn State Children's Hospital, Hershey, PA 17033, USA.
Abstract
UNLABELLED: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. CD133, a transmembrane glycoprotein, is an important cell surface marker for both stem cells and cancer stem cells in various tissues including liver. CD133 expression has been recently linked to poor prognosis in HCC patients. CD133+ liver cancer cells are characterized by resistance to chemotherapy, self-renewal, multilineage potential, increased colony formation, and in vivo cancer initiation at limited dilution. Recent studies demonstrate that CD133 expression is regulated by DNA methylation. In this study, we explored the role of transforming growth factor beta (TGFbeta), a multifunctional cytokine that plays a critical role in chronic liver injury, in the regulation of CD133 expression. TGFbeta1 is capable of up-regulating CD133 expression specifically within the Huh7 HCC cell line in a time- and dose-dependent manner. Most important, TGFbeta1-induced CD133+ Huh7 cells demonstrate increased tumor initiation in vivo. Forced expression of inhibitory Smads, including Smad6 and Smad7, attenuated TGFbeta1-induced CD133 expression. Within CD133- Huh7 cells, TGFbeta1 stimulation inhibited the expression of DNA methyltransferases (DNMT) 1 and DNMT3beta, which are critical in the maintenance of regional DNA methylation, and global DNMT activity in CD133- Huh7 cells was inhibited by TGFbeta1. DNMT3beta inhibition by TGFbeta1 was partially rescued with overexpression of inhibitory Smads. Lastly, TGFbeta1 treatment led to significant demethylation in CD133 promoter-1 in CD133- Huh7 cells. CONCLUSION: TGFbeta1 is able to regulate CD133 expression through inhibition of DNMT1 and DNMT3beta expression and subsequent demethylation of promoter-1. TGFbeta1-induced CD133+ Huh7 cells are tumorigenic. The mechanism by which TGFbeta induces CD133 expression is partially dependent on the Smads pathway.
UNLABELLED: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. CD133, a transmembrane glycoprotein, is an important cell surface marker for both stem cells and cancer stem cells in various tissues including liver. CD133 expression has been recently linked to poor prognosis in HCCpatients. CD133+ liver cancer cells are characterized by resistance to chemotherapy, self-renewal, multilineage potential, increased colony formation, and in vivo cancer initiation at limited dilution. Recent studies demonstrate that CD133 expression is regulated by DNA methylation. In this study, we explored the role of transforming growth factor beta (TGFbeta), a multifunctional cytokine that plays a critical role in chronic liver injury, in the regulation of CD133 expression. TGFbeta1 is capable of up-regulating CD133 expression specifically within the Huh7 HCC cell line in a time- and dose-dependent manner. Most important, TGFbeta1-induced CD133+ Huh7 cells demonstrate increased tumor initiation in vivo. Forced expression of inhibitory Smads, including Smad6 and Smad7, attenuated TGFbeta1-induced CD133 expression. Within CD133- Huh7 cells, TGFbeta1 stimulation inhibited the expression of DNA methyltransferases (DNMT) 1 and DNMT3beta, which are critical in the maintenance of regional DNA methylation, and global DNMT activity in CD133- Huh7 cells was inhibited by TGFbeta1. DNMT3beta inhibition by TGFbeta1 was partially rescued with overexpression of inhibitory Smads. Lastly, TGFbeta1 treatment led to significant demethylation in CD133 promoter-1 in CD133- Huh7 cells. CONCLUSION:TGFbeta1 is able to regulate CD133 expression through inhibition of DNMT1 and DNMT3beta expression and subsequent demethylation of promoter-1. TGFbeta1-induced CD133+ Huh7 cells are tumorigenic. The mechanism by which TGFbeta induces CD133 expression is partially dependent on the Smads pathway.
Authors: K Matsuzaki; M Date; F Furukawa; Y Tahashi; M Matsushita; K Sakitani; N Yamashiki; T Seki; H Saito; M Nishizawa; J Fujisawa; K Inoue Journal: Cancer Res Date: 2000-03-01 Impact factor: 12.701
Authors: Nadine Platet; Shi Yong Liu; Michèle El Atifi; Lisa Oliver; François M Vallette; François Berger; Didier Wion Journal: Cancer Lett Date: 2007-10-30 Impact factor: 8.679
Authors: Yi Tang; Krit Kitisin; Wilma Jogunoori; Cuiling Li; Chu-Xia Deng; Susette C Mueller; Habtom W Ressom; Asif Rashid; Aiwu Ruth He; Jonathan S Mendelson; John M Jessup; Kirti Shetty; Michael Zasloff; Bibhuti Mishra; E P Reddy; Lynt Johnson; Lopa Mishra Journal: Proc Natl Acad Sci U S A Date: 2008-02-08 Impact factor: 11.205
Authors: Sergey V Shmelkov; Jason M Butler; Andrea T Hooper; Adilia Hormigo; Jared Kushner; Till Milde; Ryan St Clair; Muhamed Baljevic; Ian White; David K Jin; Amy Chadburn; Andrew J Murphy; David M Valenzuela; Nicholas W Gale; Gavin Thurston; George D Yancopoulos; Michael D'Angelica; Nancy Kemeny; David Lyden; Shahin Rafii Journal: J Clin Invest Date: 2008-06 Impact factor: 14.808
Authors: Samuel W French; James Lee; Jim Zhong; Timothy R Morgan; Virgil Buslon; William Lungo; Barbara A French Journal: J Gastrointest Oncol Date: 2012-09
Authors: Chiara Raggi; Valentina M Factor; Daekwan Seo; Agnes Holczbauer; Matthew C Gillen; Jens U Marquardt; Jesper B Andersen; Marian Durkin; Snorri S Thorgeirsson Journal: Hepatology Date: 2014-05-01 Impact factor: 17.425