title: Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog.
abstract: A major obstacle to successful treatment of hepatocellular carcinoma (HCC) is its high resistance to cytotoxic chemotherapy due to overexpression of multidrug resistance genes. Activation of the AKT pathway is known to be involved in chemoresistance in HCC; however, the underlying mechanisms modulating the AKT pathway by chemopreventive agents remain unclear. In the present study, we found that indole-3-carbinol (I3C) treatment for tumor cells repressed the AKT pathway by increasing the expression of phosphatase and tensin homolog (PTEN) in HCC xenograft tumor and HCC cell lines. qRT-PCR data showed that the expression of miR-21 and miR-221&222 was significantly reduced by I3C in HCC cells in vitro and in vivo. Reactivation of the AKT pathway via restoration of miR-21 was reversed by I3C. Ectopic expression of miR-21 mediated-accelerated wound healing was abrogated by I3C. Moreover, reducing the expression of miR-21 by anti-miR decreased the resistance of HCC cells to I3C. These results provide experimental evidences that I3C could function as a miR-21 regulator, leading to repression of the PTEN/AKT pathway and opening a new avenue for eradication of drug-resistant cells, thus potentially helping to improve the therapeutic outcome in patients diagnosed with HCC.
authors.affiliation: NSF Nanoscale Science and Engineering Center (NSEC), The Ohio State University, Columbus, OH, USA.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Wang
authors.affiliation: NSF Nanoscale Science and Engineering Center (NSEC), The Ohio State University, Columbus, OH, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Yuanzhi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Ren
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Kun-Yu
authors.initials: KY
authors.lastname: Teng
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Chi-Ling
authors.initials: CL
authors.lastname: Chiang
authors.affiliation: NSF Nanoscale Science and Engineering Center (NSEC), The Ohio State University, Columbus, OH, USA.
authors.forename: Zhaogang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: NSF Nanoscale Science and Engineering Center (NSEC), The Ohio State University, Columbus, OH, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: Shuhao
authors.initials: S
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Samson T
authors.initials: ST
authors.lastname: Jacob
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
authors.affiliation: NSF Nanoscale Science and Engineering Center (NSEC), The Ohio State University, Columbus, OH, USA; Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA. Electronic address: lee.31@osu.edu.
authors.forename: L James
authors.initials: LJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000502:physiology; D008840:Microfilament Proteins / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000070876:Tensins
chemical_list: D016588:Anticarcinogenic Agents; D007211:Indoles; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D000070876:Tensins; C016517:indole-3-carbinol; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Hepatocellular carcinoma; Indole-3-carbinol; PTEN; miR-21; miR-221&222