Biosystem Analysis of the Hypoxia Inducible Domain Family Member 2A: Implications in Cancer Biology.

Celia Salazar,William Tiznado,Lina María Ruiz,Osvaldo Yañez,Alvaro A Elorza,Olimpo García-Beltrán,Natalie Cortes

doi:10.3390/genes11020206

Abstract

The expression of HIGD2A is dependent on oxygen levels, glucose concentration, and cell cycle progression. This gene encodes for protein HIG2A, found in mitochondria and the nucleus, promoting cell survival in hypoxic conditions. The genomic location of HIGD2A is in chromosome 5q35.2, where several chromosomal abnormalities are related to numerous cancers. The analysis of high definition expression profiles of HIGD2A suggests a role for HIG2A in cancer biology. Accordingly, the research objective was to perform a molecular biosystem analysis of HIGD2A aiming to discover HIG2A implications in cancer biology. For this purpose, public databases such as SWISS-MODEL protein structure homology-modelling server, Catalogue of Somatic Mutations in Cancer (COSMIC), Gene Expression Omnibus (GEO), MethHC: a database of DNA methylation and gene expression in human cancer, and microRNA-target interactions database (miRTarBase) were accessed. We also evaluated, by using Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), the expression of Higd2a gene in healthy bone marrow-liver-spleen tissues of mice after quercetin (50 mg/kg) treatment. Thus, among the structural features of HIG2A protein that may participate in HIG2A translocation to the nucleus are an importin α-dependent nuclear localization signal (NLS), a motif of DNA binding residues and a probable SUMOylating residue. HIGD2A gene is not implicated in cancer via mutation. In addition, DNA methylation and mRNA expression of HIGD2A gene present significant alterations in several cancers; HIGD2A gene showed significant higher expression in Diffuse Large B-cell Lymphoma (DLBCL). Hypoxic tissues characterize the “bone marrow-liver-spleen” DLBCL type. The relative quantification, by using qRT-PCR, showed that Higd2a expression is higher in bone marrow than in the liver or spleen. In addition, it was observed that quercetin modulated the expression of Higd2a gene in mice. As an assembly factor of mitochondrial respirasomes, HIG2A might be unexpectedly involved in the change of cellular energetics happening in cancer. As a result, it is worth continuing to explore the role of HIGD2A in cancer biology.

Highlights

Mitochondria are crucial for virtually all aspects of malignant transformation and tumor progression, counting since the proliferation of transformed cells, the resistance of these cells to hostile environmental surroundings, the interaction of transformed cells with the tumor stroma, and their dissemination to remote anatomical sites [1]
We evaluated the correlation between DNA methylation and mRNA expression in the HIGD2A gene in cancer
Four miRNAs for HIGD2A gene show significant gene expression profile related to neoplasms, leukemia, carcinoma, and lymphoma

Summary

Introduction

Mitochondria are crucial for virtually all aspects of malignant transformation and tumor progression, counting since the proliferation of transformed cells, the resistance of these cells to hostile environmental surroundings, the interaction of transformed cells with the tumor stroma, and their dissemination to remote anatomical sites [1]. Besides being the leading supplier of ATP, mitochondria could provide building blocks for the proliferation of malignant cells, they produce reactive oxygen species (ROS), and they are critical players in regulated cell death signaling [1]. Among the main mechanisms used by mitochondria for the malignant transformation of cells, first, there is the production of ROS, which favors the accumulation of potential oncogenic defects in DNA, and the activation of probable oncogenic signaling pathways [2]. There are defects in the mitochondrial permeability transition (MPT), which allow the survival of malignant cells through the deregulation of regulated cell death processes [4]. Mitochondria influence the outcome of cancer cells to therapy through metabolic reprogramming between glycolysis and oxidative phosphorylation. The search for many anti-carcinogenic treatments is based on the identification of molecules that kill cancer cells or sensitize them to treatments by priming MPT [1]

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