The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value.

Paola Zacchi,Letizia Scola,Beatrice Belmonte,Alessandro Mangogna,Gaia Morello,Violetta Borelli,Anna Martorana

doi:10.3389/fonc.2021.638856

Abstract

Hephaestin (HEPH) belongs to a group of exocytoplasmic ferroxidases which contribute to cellular iron homeostasis by favouring its export. Down-regulation of HEPH expression, possibly by stimulating cell proliferation due to an increase in iron availability, has shown to correlate with poor survival in breast cancer. The lung is particularly sensitive to iron-induced oxidative stress, given the high oxygen tension present, however, HEPH distribution in lung cancer and its influence on prognosis have not been investigated yet. In this study we explored the prognostic value of HEPH and its expression pattern in the most prevalent histotypes of lung cancers, namely lung adenocarcinoma and lung squamous cell carcinoma. In silico analyses, based on UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter bioinformatics, revealed a significant correlation between higher levels of HEPH expression and favorable prognosis, in both cancer histotypes. Moreover, TIMER web platform showed a statistically significant association between HEPH expression and cell elements belonging to the tumor microenvironment identified as endothelial cells and a subpopulation of cancer-associated fibroblasts, further confirmed by double immunohistochemical labeling with cell type specific markers. Taken together, these data shed a light on the complex mechanisms of local iron handling lung cancer can exploit to support tumorigenesis.

Highlights

Lung cancer represents the most frequent malignant neoplasm in most countries and the leading cause of death worldwide in both sexes [1]
This analysis revealed that a significant down-regulation of HEPH mRNA expression levels is found in several other malignancies such as BLCA, BRCA, COAD, KICH, KIRP, LIHC, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), PRAD, READ, and UCEC compared to the corresponding normal tissues (Figure 1A)
Given our interest in better understanding the role iron dysregulation may exert in lung cancer development and prognosis, we evaluated HEPH mRNA expression levels in the most prevalent histological types, LUAD and LUSC, as compared to normal tissue, utilizing the Gene Expression Profiling Interactive Analysis (GEPIA) database

Summary

Introduction

Lung cancer represents the most frequent malignant neoplasm in most countries and the leading cause of death worldwide in both sexes [1]. The incidence of lung cancer is low in people aged below 40 years but it dramatically increases up to ages 60–65 years in most populations. Smoking status is certainly the most important causative link in lung cancer development even though air pollution represents another paramount source of risk factor [3]. Iron is found in cigarette smoke, the strongest causative link to pulmonary pathology [5, 6], and in asbestos fibers, which are the most frequent cause of occupational cancer [7]

Methods

Results

Conclusion