Insights into Overlapping of Fibrosis and Cancer: Exploring the  Tumor-related Cardinal Genes in Idiopathic Pulmonary Fibrosis

Marjan Taherian; Paria Bayati; Mohammad-Ali Assarehzadegan; Mansoureh Soleimani; Mehdi Shekarabi; Nazanin Mojtabavi

doi:10.18502/ijaai.v22i2.12680

Marjan Taherian Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Paria Bayati Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Mohammad-Ali Assarehzadegan Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Mansoureh Soleimani The Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
Mehdi Shekarabi Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Nazanin Mojtabavi Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

DOI: https://doi.org/10.18502/ijaai.v22i2.12680

Keywords: Cancer; Idiopathic pulmonary fibrosis; Lrp1; mTOR; Rheb1; Rptor; S6k1; Tsc1; Tsc2; Vegf; 4E-bp1

Abstract

The pathogenesis of idiopathic pulmonary fibrosis (IPF) is quite similar to that of cancer pathogenesis, and several pathways appear to be involved in both disorders. The mammalian
target of the rapamycin (mTOR) pathway harbors several established oncogenes and tumor suppressors. The same signaling molecules and growth factors, such as vascular endothelial growth
factor (VEGF), contributing to cancer development and progression play a part in fibroblast proliferation, myofibroblast differentiation, and the production of extracellular matrix in IPF development as well.

The expression of candidate genes acting upstream and downstream of mTORC1, as well as Vegf and low-density lipoprotein receptor related protein 1(Lrp1), was assessed using specific primers and quantitative polymerase chain reaction (qPCR) within the lung tissues of bleomycin (BLM)-induced IPF mouse models. Lung fibrosis was evaluated by histological examinations and hydroxyproline colorimetric assay.

BLM-exposed mice developed lung injuries characterized by inflammatory manifestations and fibrotic features, along with higher levels of collagen and hydroxyproline. Gene expression analyses indicated a significant elevation of regulatory associated protein of mTOR (Raptor), Ras homolog enriched in brain (Rheb), S6 kinase 1, and Eukaryotic translation initiation factor 4E-binding protein 1 (4Ebp1), as well as a significant reduction of Vegfa, Tuberous sclerosis complex (Tsc2), and Lrp1; no changes were observed in the Tsc1 mRNA level.

Our findings support the elevation of S6K1 and 4EBP1 in response to the TSC/RHEB/mTORC1 axis, which profoundly encourages the development and establishment of IPF and cancer. In addition, this study suggests a possible preventive role for VEGF-A and LRP1 in the development of IPF.