Non-hepatic tumors change the activity of genes encoding copper trafficking proteins in the liver

Polina S. Babich, Alexey N. Skvortsov, Paolo Rusconi, Nadezhda V. Tsymbalenko, Marja Mutanen, Ludmila V. Puchkova, Massimo Broggini

Research output: Contribution to journalArticlepeer-review

Abstract

To assess the statistical relationship between tumor growth and copper metabolism, we performed a meta-analysis of studies in which patients with neoplasms were characterized according to any of the copper status indexes (atomic copper serum concentration, serum oxidase activity, ceruloplasmin protein content). Our meta-analysis shows that in the majority of cases (more than 3,100 patients), tumor growth positively correlates with the copper status indexes. Nude athymic CD-1 nu/nu mice with subcutaneous tumors of human origin, C57Bl/6J mice with murine melanoma and ApcMin mice with spontaneously developing adenomas throughout the intestinal tract were studied to experimentally determine the relationship between tumor progression, liver copper metabolism, and copper status indexes. We showed that the copper status indexes increased significantly during tumor growth. In the liver tissue of tumor-bearing mice, ceruloplasmin gene expression, as well as the expression of genes related to ceruloplasmin metallation (CTR1 and ATP7B), increased significantly. Moreover, the presence of an mRNA splice variant encoding a form of ceruloplasmin anchored to the plasma membrane by glycosylphosphatidyl inositol, which is atypical for hepatocytes, was also detected. The ATP7A copper transporter gene, which is normally expressed in the liver only during embryonic copper metabolism, was also activated. Depletion of holo-ceruloplasmin resulted in retardation of human HCT116 colon carcinoma cell growth in nude mice and induced DNA fragmentation in tumor cells. In addition, the concentration of cytochrome c increased significantly in the cytosol, while decreasing in the mitochondria. We discuss a possible trans-effect of developing tumors on copper metabolism in the liver.

Original languageEnglish
Pages (from-to)614-624
Number of pages11
JournalCancer Biology and Therapy
Volume14
Issue number7
DOIs
Publication statusPublished - Jul 2013

Keywords

  • Animal models
  • Copper deficiency
  • Copper status indexes
  • Gene expression
  • Liver copper metabolism
  • Metaanalysis
  • Tumor progression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

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