Mg2+ Transporters in Digestive Cancers

Abstract

Despite magnesium (Mg²⁺) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg²⁺ homeostasis is regulated by Mg²⁺ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg²⁺ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg²⁺ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg²⁺ transporters' expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg²⁺ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.

Keywords: TCGA; digestive cancers; magnesium transporters; overall survival.

Figure 1

Summary of Mg²⁺ homeostasis.

Figure 2

General distribution and localization of Mg²⁺ transporters in cells. Mg²⁺, magnesium; Na⁺, sodium; CNNM2/3/4, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator2/3/4; MAGT1, Magnesium Transporter 1; SLC41A1, Solute Carrier Family 41, Member 1; TRPM7, Transient Receptor Potential Cation Channel Subfamily M Member 7; TRPM6, Transient Receptor Potential Cation Channel Subfamily M Member 6; CNNM1, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator1; MRS2, Mitochondrial RNA Splicing Protein 2.

Figure 3

Relative mRNA expression of magnesium transporters in digestive cancers and normal tissues. Whiskers boxplots for Mg²⁺ transporters mRNA (TRPM6, TRPM7, MAGT1, SLC41A1, MRS2, CNNM1, CNNM2, CNNM3, CNNM4) were generated using GEPIA2 from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) samples. TCGA datasets were (A) Esophageal carcinoma (ESCA), (B) Stomach Adenocarcinoma (STAD), (C) Pancreatic Adenocarcinoma (PAAD), (D) Colon Adenocarcinoma (COAD) and (E). Rectum Adenocarcinoma (READ). TRPM7, Transient Receptor Potential Cation Channel Subfamily M, Member 7; MAGT1, Magnesium Transporter 1; SLC41A1, Solute Carrier Family 41, Member 1; MRS2, Mitochondrial RNA Splicing Protein 2; CNNM4, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4; n = number of samples; N, normal; T, tumoral. Relative mRNA levels are expressed as log2 transcripts per million bases (TPM). Only significative results (* p < 0.01) are presented. The whole dataset analysis is provided as supplementary data (Supplementary Figure S1).

Figure 4

Analysis of patient survival in digestive cancers. Survival heatmaps were generated using GEPIA2 with TCGA data for overall survival (A) and disease-free survival (B) for Esophageal Cancer (ESCA), Stomach Adenocarcinoma (STAD), Pancreatic Adenocarcinoma (PAAD), Colon Adenocarcinoma (COAD) and Rectum Adenocarcinoma (READ) datasets. Survival is expressed as hazard ratio (HR). Framed squares represent significative statistical values (p < 0.05). Kaplan–Meier curves for overall survival (C) and disease-free survival (D) were analyzed using GEPIA2. TRPM6, Transient Receptor Potential Cation Channel Subfamily M, Member 6. TRPM7, Transient Receptor Potential Cation Channel Subfamily M, Member 7; MAGT1, Magnesium Transporter 1; SLC41A1, Solute Carrier Family 41, Member 1; MRS2, Mitochondrial RNA Splicing Protein 2; CNNM4, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4. Only statistically significant curves (p < 0.05) are presented.

Figure 5

Correlation analysis of relative magnesium transporters mRNA levels in digestive cancers TCGA cohorts. Pearson cor-relation R values were calculated for each magnesium transporter mRNA using RStudio. All queries for TRPM6, TRPM7, MAGT1, SLC41A1, MRS2, CNNM1, CNNM2, CNNM3 and CNNM4 genes were realized in ESCA (A), STAD (B), PAAD (C) and COAD-READ (D) datasets from TCGA using the cBioPortal website. mRNA expression values were retrieved as RNA-Seq by Expectation Maximization RSEM (Batch normalized from Illumina HiSeq_RNASeqV2). Only significative correlations values (p < 0.05) are presented. Principal component analysis (PCA) of Mg²⁺ transporters mRNA relative expression in TCGA datasets are also represented. Grouped variables are positively correlated whereas opposed variables are negatively correlated. Independency of the variables is formed by a 90° angle formed by two arrows. The quality of the variables on the Principal Component Analysis (PCA) are designated by Cos2 (square cosine, squared coordinates) values.

Figure 6

Summary of signaling pathways associated with Mg²⁺ transporters. Mg²⁺ transporter, channels and Mg²⁺-dependent proteins are underlined. These proteins activate kinases, signaling proteins and/or transcription factors (framed in ovals). As a result, some processes, such as protein redistribution to the plasma membrane, control of effector proteins and transcriptional regulation can occur. Rec. Endo-mb. Comp^t.: recycling endomembrane compartment. Mg²⁺, Magnesium; EGFR, Epidermal Growth Factor Receptor; TRPM6, Transient Receptor Potential Cation Channel Subfamily M, Member 6; TRPM7, Transient Receptor Potential Cation Channel Subfamily M, Member 7; SLC41A1, Solute Carrier Family 41, Member 1; CNNM4, Cyclin and CBS Domain Divalent Metal Cation Transport Mediator 4; Jak, Janus Kinase; Src, Src Proto-Oncogene; PI3K, Phosphatidylinositol-4,5-Biphosphate 3-Kinase; AKT, AKT Serine/Threonine Kinase; Rac1, Rac-Family Small GTPase 1; mTor, Mechanistic Target of Rapamycin Kinase; BCl2, BCL2 Apoptosis Regulator; Bax, BCL2 Associated X Apoptosis Regulator; ATP, Adenosine Tri-Phosphate; AMPK, AMP-Activated Protein Kinase, STAT3, Signal Transducer And Activator Of Transcription 3; MDP-1, Magnesium-Dependent Phosphatase-1; JNK, c-Jun N-terminal Kinase.

Figure 7

Analysis of overall survival of the TRPM7/MAGT1/CNNM4 signature in pancreatic cancer datasets using SurvExpress. PAAD patients were stratified using a gene signature combining TRPM7, MAGT1, and CNNM4. Kaplan–Meier curves were analyzed using the optimized SurvExpress Maximize algorithm. The number of analyzed patients across time (days) is indicated below the horizontal axis for both conditions, as previously described [86].