Iron elevates mesenchymal and metastatic biomarkers in HepG2 cells

Kosha J Mehta,Paul A Sharp

doi:10.1038/s41598-020-78348-5

Kosha J Mehta, Paul A Sharp

Open Access

https://doi.org/10.1038/s41598-020-78348-5

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Journal: Scientific Reports	Publication Date: Dec 1, 2020
Citations: 16	License type: open-access

Affiliation: King's College London

Abstract

Liver iron excess is observed in several chronic liver diseases and is associated with the development of hepatocellular carcinoma (HCC). However, apart from oxidative stress, other cellular mechanisms by which excess iron may mediate/increase HCC predisposition/progression are not known. HCC pathology involves epithelial to mesenchymal transition (EMT), the basis of cancer phenotype acquisition. Here, the effect of excess iron (holo-transferrin 0–2 g/L for 24 and 48 h) on EMT biomarkers in the liver-derived HepG2 cells was investigated. Holo-transferrin substantially increased intracellular iron. Unexpectedly, mRNA and protein expression of the epithelial marker E-cadherin either remained unaltered or increased. The mRNA and protein levels of metastasis marker N-cadherin and mesenchymal marker vimentin increased significantly. While the mRNA expression of EMT transcription factors SNAI1 and SNAI2 increased and decreased, respectively after 24 h, both factors increased after 48 h. The mRNA expression of TGF-β (EMT-inducer) showed no significant alterations. In conclusion, data showed direct link between iron and EMT. Iron elevated mesenchymal and metastatic biomarkers in HepG2 cells without concomitant decrement in the epithelial marker E-cadherin and altered the expression of the key EMT-mediating transcription factors. Such studies can help identify molecular targets to devise iron-related adjunctive therapies to ameliorate HCC pathophysiology.

Highlights

Liver iron excess is observed in several chronic liver diseases and is associated with the development of hepatocellular carcinoma (HCC)
Since HCC can emerge from various liver aetiologies, it is of a wide clinical benefit to understand the molecular mechanisms that lead to HCC predisposition and/or mediate its pathological acceleration
To understand the mechanistic aspects of the observed holo-Tf induced-alterations, we examined the mRNA expression of epithelial to mesenchymal transition (EMT)-mediating transcription factors SNAI1 and SNAI2

Summary

Introduction

Liver iron excess is observed in several chronic liver diseases and is associated with the development of hepatocellular carcinoma (HCC). Iron elevated mesenchymal and metastatic biomarkers in HepG2 cells without concomitant decrement in the epithelial marker E-cadherin and altered the expression of the key EMT-mediating transcription factors. Such studies can help identify molecular targets to devise iron-related adjunctive therapies to ameliorate HCC pathophysiology. Mild-moderate iron-excess is common in other CLDs like alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, viral hepatitis and type 2 diabetes[6,7,8,9,10] In these conditions, the exact role of iron (whether excess iron acts as a marker or mediator or both) in the pathophysiology remains an enigma. Excess iron activates the TGF-β pathway and enhances fibrogenesis, which may contribute to the Scientific Reports | (2020) 10:21926

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