title: NFκB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. It is a heterogeneous disorder and >80 % of the tumors develop in patients with liver cirrhosis, resulting from chronic inflammation and/or fibrosis. Here, we set out to identify novel targets for HCC therapy and to define a subgroup of patients that might benefit most from it.
  
  
  METHODS
  Cellular pathway activation profiling of 45 transcription factors in a HCC-derived cell line (HEP3B), in vitro analysis of NFκB reporter activity in additional HCC-derived cell lines and pathway-focused integrative analyses of publicly available primary HCC-derived expression profiling data (GSE6764, GSE9843, E-TABM-36 and E-TABM-292) were employed to reveal a role of NFκB in HCC development. In order to identify potential targeting agents, a luciferase-based NFκB reporter screening assay was established in HEP3B cells. After screening of a drug library through this assay, a potent NFκB pathway inhibitor was identified and characterized using an array of additional in vitro assays.
  
  
  RESULTS
  Using cellular pathway activation profiling, we found a high activation of NFκB-mediated signaling in HCC-derived cell lines and in primary HCC tumors. Through NFκB inhibitor screening we observed a highly efficacious NFκB pathway inhibitory potential of ornithogalum in HCC-derived HEP3B cells. Although its active component still remains to be defined, ornithogalum has been found to inhibit endoplasmic reticulum (ER) and oxidative stress responses. ER stress, oxidative stress and NFκB signaling were found to be enhanced in a subset of HCCs, as well as in (precancerous) liver cirrhosis tissues.
  
  
  CONCLUSIONS
  From our data we conclude that NFκB signaling is activated in precancerous cirrhosis tissues and in a subset of HCCs. We found that ornithogalum exhibits NFκB targeting and stress relieving activities. NFκB inhibitors, including the active component of ornithogalum, may serve as putative preventive and targeted therapeutic agents for at least a subset of HCCs in which the NFκB pathway is activated. These latter notions require further investigation in a translational context.
authors: Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India.
authors: Vignesh
authors: V
authors: Ramesh
authors: Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India.
authors: Karthikeyan
authors: K
authors: Selvarasu
authors: Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India.
authors: Jaishree
authors: J
authors: Pandian
authors: Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India.
authors: Soundarajan
authors: S
authors: Myilsamy
authors: Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India.
authors: Chidambaranathan
authors: C
authors: Shanmugasundaram
authors: Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625 021, India. kumar@oncocellomics.org.
authors: Kumaresan
authors: K
authors: Ganesan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy / Q000379:methods*; D016328:NF-kappa B / Q000378:metabolism*; D031442:Ornithogalum; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B
keywords: Anti-inflammatory; ER stress; Hepatocellular carcinoma; NFkB pathway; Ornithogalum; Oxidative stress; Targeted therapy