Ferritin heavy chain is a negative regulator of ovarian cancer stem cell expansion and epithelial to mesenchymal transition

Maria Elena Pisanu,Nadia Lobello,Emanuela Chiarella,Gennaro Ciliberto,Francesco Costanzo,Emilia Dora Giovannone,Žiga Jakopin,Rita Mancini,Maria Concetta Faniello,Flavia Biamonte,Giovanni Cuda

doi:10.18632/oncotarget.11495

Abstract

ObjectivesFerritin is the major intracellular iron storage protein essential for maintaining the cellular redox status. In recent years ferritin heavy chain (FHC) has been shown to be involved also in the control of cancer cell growth. Analysis of public microarray databases in ovarian cancer revealed a correlation between low FHC expression levels and shorter survival. To better understand the role of FHC in cancer, we have silenced the FHC gene in SKOV3 cells.ResultsFHC-KO significantly enhanced cell viability and induced a more aggressive behaviour. FHC-silenced cells showed increased ability to form 3D spheroids and enhanced expression of NANOG, OCT4, ALDH and Vimentin. These features were accompanied by augmented expression of SCD1, a major lipid metabolism enzyme. FHC apparently orchestrates part of these changes by regulating a network of miRNAs.MethodsFHC-silenced and control shScr SKOV3 cells were monitored for changes in proliferation, migration, ability to propagate as 3D spheroids and for the expression of stem cell and epithelial-to-mesenchymal-transition (EMT) markers. The expression of three miRNAs relevant to spheroid formation or EMT was assessed by q-PCR.ConclusionsIn this paper we uncover a new function of FHC in the control of cancer stem cells.

Highlights

Iron uptake, storage and utilization are among the most highly regulated biochemical pathways in the cell
In this paper we uncover a new function of ferritin heavy chain (FHC) in the control of cancer stem cells
We have recently demonstrated that FHC down-modulation by shRNA interference strongly reduces, both in vivo and in vitro, melanoma cell proliferation [20], while, in the erythroleukemia K562 cell line, it modulates the expression of a specific set of onco-miRNAs [21]

Summary

Introduction

Storage and utilization are among the most highly regulated biochemical pathways in the cell. The L subunit is absent in nuclear form and www.impactjournals.com/oncotarget mitochondrial ferritin; in the latter, the shell is composed by a single subunit with a 75% sequence identity to the H ferritin [8, 9]. Two different genes, both belonging to complex multigene families and subjected to different transcriptional control mechanisms, code the heavy- and light-subunits, while an intronless H-type gene codes the mitochondrial form [10, 11]. The CXCR4 receptor is highly expressed in a variety of human tumors: the ability of FHC to modulate the CXCR4 pathway might partly explain the complex role that FHC plays in the process of neoplastic transformation [12]

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