Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer
"> Figure 1
<p>Gene expression level data transformation. Raw data set values (<b>A</b>,<b>B</b>). Log2 transformation (<b>C</b>,<b>D</b>); rlog transformation (<b>E</b>,<b>F</b>). RNA-seq: RNA-sequencing.</p> "> Figure 2
<p>Gene expression level filtering. Histograms of data before (<b>A</b>) and after (<b>B</b>) the data set filtration process. Filtering was carried out by removing genes with a profile expression lower than 0.125 Reads per Kilobase per Millions of mapped reads (RPKM). Data are shown as rlog transformed.</p> "> Figure 3
<p>Heatmap Hierarchical Cluster of samples with healthy phenotype (<b>A</b>–<b>D</b>) and tumor phenotype (<b>E</b>–<b>H</b>). Pseudocolor scale shows hierarchical distance from minimum (0, blue) to maximum (6, red).</p> "> Figure 4
<p>Hierarchical clustering of genes. Genes have been divided into six different groups according to their Euclidean distances relative to their expression values (in RPKM).</p> "> Figure 5
<p>Correlation or co-regulation between couples of genes. The larger the circle and the darker the color, the higher the correlation (either positive in blue or negative in red) between each pair of genes.</p> "> Figure 6
<p>Principal Component Analysis (PCA), where genes are variables and samples are observations. The proportion of variance explained by PC1 is equal to 59.82%, and 16.19% for PC2. (<b>A</b>) PC2 vs. PC1; (<b>B</b>) Decay Variance Explained graph; (<b>C</b>) Correlation coefficients.</p> "> Figure 7
<p>Expression of voltage-gated Ca<sup>2+</sup> channels in normal and colon cancer cells. Expression levels of Cav1s (<b>A</b>), Cav2s (<b>B</b>) and Cav3s (<b>C</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 8
<p>Expression of genes involved in store-operated Ca<sup>2+</sup> entry in normal and colon cancer cells. Expression levels of <span class="html-italic">Orais</span> (<b>A</b>), <span class="html-italic">STIMs</span> (<b>B</b>), <span class="html-italic">MSA412</span> (<b>C</b>) and CRACR2A (<b>D</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 9
<p>Expression of transient receptor potential (TRP) channels in normal and colon cancer cells. Expression levels of canonical transient receptor potential channels <span class="html-italic">TRPCs</span> (<b>A</b>), canonical Transient Receptor Potential channels <span class="html-italic">(TRPVs</span>) (<b>B</b>), Melastatin Transient Receptor Potential channels (<span class="html-italic">TRPMs</span>) (<b>C</b>), Mucolipin Transient Receptor Potential channels (<span class="html-italic">TRPMLs</span>) (<b>D</b>), Polycystin Transient Receptor Potential channels (<span class="html-italic">TRPPs</span>) (<b>E</b>) and Transient Receptor Potential channel member A, subfamily 1 <span class="html-italic">(TRPA1</span>) (<b>F</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 10
<p>Expression of Ca<sup>2+</sup> release channels in normal and colon cancer cells. Expression levels of inositol trisphosphate receptors (IP<sub>3</sub>Rs) (<b>A</b>) and ryanodine receptors (RyRs) (<b>B</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 11
<p>Expression of Ca<sup>2+</sup> pumps in normal and colon cancer cells. Expression levels of plasma membrane Ca<sup>2+</sup> ATPases (PMCAs) (<b>A</b>), sarcoplasmic and/or endoplasmic reticulum Ca<sup>2+</sup> ATPases (SERCAs) (<b>B</b>) and secretory pathway Ca<sup>2+</sup> ATPases (SPCAs) (<b>C</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 12
<p>Expression of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger isoforms in normal and colon cancer cells. Expression levels of NCXs in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 13
<p>Expression of genes involved in mitochondrial Ca<sup>2+</sup> transport in normal and colon cancer cells. Expression levels of Mitochondrial Calcium Uniporter (MCU) (<b>A</b>), Mitochondrial Calcium Uptake (MICU) isoforms (<b>B</b>), Mitochondrial Calcium Uptake Regulator 1 (MICUR1) (<b>C</b>), Mitochondrial Calcium Uniporter Dominant Negative Beta Subunit (MCUb) (<b>D</b>), Essential MCU regulator (EMRE) (<b>E</b>) and voltage-dependent anion channels (VDACs) (<b>F</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 14
<p>Expression of selected genes coding for other selected proteins. Expression levels of <span class="html-italic">BCL2</span>, (<b>A</b>) calsequestrins <span class="html-italic">CASQ1</span> and <span class="html-italic">CASQ2</span> (<b>B</b>), <span class="html-italic">PICALM</span> (<b>C</b>) and <span class="html-italic">PLN</span> (Phospholamban) (<b>D</b>) in normal colonic cells (grey bars) and colon cancer cells (red bars). * <span class="html-italic">p</span> statistically significant by three independent methods.</p> "> Figure 15
<p>Molecular players differentially expressed in NCM460 normal colonic and HT29 colorectal cancer cells. Genes significantly upregulated (↑) and downregulated (↓) in colorectal cancer cells vs. normal colonic cells are shown in specific locations in the plasma membrane, the endoplasmic reticulum (ER) and mitochondria (<b>A</b>). To best appreciate the differences, molecular players downregulated in cancer cells have been removed in the prototypical, normal colonic cell (<b>B</b>), whereas only genes upregulated in CRC are shown in the prototypic CRC cell (<b>C</b>). Molecular players in red are those with the largest fold changes in expression from the normal to the tumor phenotype. PMCAs, plasma membrane calcium ATPases; VOCCS, voltage-operated calcium channels; SOCE, store-operated calcium entry; TRPs, Transient Receptor Potential channels.</p> ">
Abstract
:1. Introduction
2. Results and Discussion
2.1. Data Set Transformation and Filtering
2.2. Exploratory Data Analysis: Hierarchical Clustering
2.3. Gene Correlations
2.4. Principal Component Analysis
2.5. Differential Expression Analysis
3. Materials and Methods
3.1. Materials
3.2. Cell Culture
3.3. mRNA Isolation and Ion Torrent Reading
3.4. Transformation and Filtration of Raw Data Set
3.5. Exploratory Data Analysis
3.6. Differential Expression Analysis
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
CRC | Colorectal cancer |
VOCC | Voltage-operated Ca2+ channels |
SOCE | Store-operated Ca2+ entry |
TRP | Transient receptor potential channels |
IP3R | Inositol trisphosphate receptor |
RyR | Ryanodine receptor |
PMCA | Plasma membrane Ca2+/ATPase |
SERCA | Sarcoplasmic and endoplasmic reticulum Ca2+/ATPase |
SPCA | Secretory pathway Ca2+/ATPase |
MCU | Mitochondrial calcium uniporter |
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Gene Group | Protein Name (Gene Name) |
---|---|
Voltage Operated Calcium Channels | Cav1.1 (CACNA1S); Cav1.2 (CACNA1C); Cav1.3 (CACNA1D); Cav1.4 (CACNA1F); Cav2.1 (CACNA1A); Cav2.2 (CACNA1B); Cav2.3 (CACNA1E); Cav3.1 (CACNA1G); Cav3.2 (CACNA1H); Cav3.3 (CACNA1I) |
Store-Operated Calcium Entry Player | Orai1; Orai2; Orai3; STIM1; STIM2; CRACR2A (EFCAB4B); MS4A12 |
TRP Channels | TRPC1; TRPC3; TRPC4; TRPC5; TRPC6; TRPC7; TRPV1; TRPV2; TRPV3; TRPV4; TRPV5; TRPV6; TRPM1; TRPM2; TRPM3; TRPM4; TRPM5; TRPM6; TRPM7; TRPM8; TRPA1; TRPML1 (MCOLN1); TRPML2 (MCOLN2); TRPML3 (MCOLN3); TRPP1 (PKD2); TRPP2 (PKD2L1); TRPP3 (PKD2L2) |
Calcium Release Channels | IP3R1 (ITPR1); IP3R3 (ITPR2); IP3R3 (ITPR3); RYR1; RYR2; RYR3 |
Calcium Pumps | PMCA1 (ATP2B1); PMCA2 (ATP2B2); PMCA3 (ATP2B3); PMCA4 (ATP2B4); SERCA1 (ATP2A1); SERCA2 (ATP2A2); SERCA3 (ATP2A3); SPCA1 (ATP2C1); SPCA2 (ATP2C2) |
Sodium Calcium Exchangers | NCX1 (SLC8A1); NCX2 (SLC8A2); NCX3 (SLC8A3) |
Mitochondrial Calcium Transport Proteins | MCU; MICU1; MICU2 (EFHA1); MICU3 (EFHA2); MCUR1 (CCDC90A); EMRE (C22orf32); MCUb (CCDC109B); VDAC1; VDAC2; VDAC3 |
Other Proteins | Bcl-2 (BCL2); Calsequestrin 1 (CASQ1); Calsequestrin 2 (CASQ2); PICALM; Phospholamban (PLN) |
Gene | Expression | Gene | Expression | Gene | Expression | Gene | Expression | Gene | Expression |
---|---|---|---|---|---|---|---|---|---|
ATP2A1 | −0.166 | CACNA1C | −0.174 | ITPR1 | 0.143 | ORAI3 | 0.090 | TRPA1 | −0.147 |
ATP2A2 | 0.148 | CACNA1D | 0.162 | ITPR2 | −0.173 | PICALM | −0.089 | TRPM3 | −0.070 |
ATP2A3 | −0.088 | CACNA1G | 0.072 | ITPR3 | 0.152 | PKD2 | 0.020 | TRPM4 | −0.113 |
ATP2B1 | 0.172 | CACNA1H | −0.173 | MCOLN1 | −0.175 | PKD2L1 | −0.169 | TRPM5 | −0.168 |
ATP2B4 | −0.173 | CACNA1I | −0.084 | MCOLN2 | −0.174 | RYR1 | 0.103 | TRPM7 | 0.105 |
ATP2C1 | −0.121 | CASQ1 | 0.093 | MCOLN3 | −0.148 | RYR2 | −0.174 | TRPV1 | −0.141 |
ATP2C2 | 0.142 | CCDC109B | −0.167 | MCU | 0.149 | SLC8A1 | −0.010 | TRPV2 | 0.096 |
BCL2 | −0.141 | CCDC90A | 0.140 | MICU1 | 0.131 | SLC8A2 | 0.165 | TRPV3 | −0.060 |
C22orf32 | 0.131 | EFCAB4B | −0.169 | ORAI1 | 0.061 | STIM1 | 0.174 | TRPV4 | 0.026 |
CACNA1B | −0.141 | EFHA1 | −0.149 | ORAI2 | 0.168 | STIM2 | 0.057 | TRPV6 | 0.133 |
VDAC1 | −0.175 | VDAC2 | 0.147 | VDAC3 | −0.170 | TRPC1 | 0.041 |
p-Value Adjusted by BH Method | ||||
---|---|---|---|---|
ID | Fold Change | BH.DESeq2 | BH.edgeR | BH.limma |
ATP2A1 | 1.02810479 | 9.71 × 10−8 | 0.0027235 | 0.00160014 |
ATP2A2 | 0.83492287 | 0.00142512 | 0.00029452 | 0.02416078 |
ATP2B1 | 1.66289207 | 1.32 × 10−29 | 1.69 × 10−13 | 1.58 × 10−5 |
ATP2B4 | 2.75628322 | 5.53 × 10-18 | 7.86 × 10−22 | 3.01 × 10−6 |
BCL2 | 2.34849379 | 0.00307301 | 0.00070215 | 0.00754796 |
CACNA1B | 2.19132122 | 0.00190951 | 0.00050421 | 0.00207432 |
CACNA1C | −11.408836 | 1.05 × 10−24 | 1.40 × 10−53 | 1.24 × 10−9 |
CACNA1D | 1.55721384 | 1.97 × 10−08 | 9.80 × 10−06 | 0.00077412 |
CACNA1H | −4.7419621 | 2.25 × 10−29 | 1.04 × 10−17 | 3.37 × 10−6 |
CCDC109B | 2.08593613 | 4.67 × 10−8 | 2.73 × 10−09 | 0.00018476 |
EFCAB4B | 2.03186213 | 4.66 × 10−11 | 1.96 × 10−14 | 4.98 × 10−5 |
EFHA1 | 0.74675824 | 0.00147429 | 0.00014479 | 0.00278932 |
ITPR1 | 0.83887283 | 3.72 × 10−5 | 0.00927132 | 0.00956689 |
ITPR2 | 1.76953569 | 4.12 × 10−46 | 5.79 × 10−21 | 3.01 × 10−6 |
ITPR3 | 0.52236077 | 3.25 × 10−5 | 0.0068986 | 0.01284295 |
MCOLN1 | 1.79737402 | 8.88 × 10−82 | 2.08 × 10−17 | 8.54 × 10−7 |
MCU | 0.73588616 | 6.87 × 10−8 | 0.00151019 | 0.00278932 |
MICU1 | 0.50129943 | 0.00011815 | 0.02325149 | 0.01284295 |
ORAI2 | 2.15394804 | 4.74 × 10−15 | 3.48 × 10−14 | 0.00018476 |
PKD2L1 | 5.34354792 | 1.49 × 10−8 | 2.43 × 10−10 | 3.01 × 10−6 |
RYR2 | 12.5085599 | 1.17 × 10−30 | 1.39 × 10−77 | 2.95 × 10−10 |
SLC8A2 | 4.76101144 | 2.08 × 10−15 | 1.17 × 10−14 | 0.00010438 |
STIM1 | 1.92340546 | 5.41 × 10−70 | 1.20 × 10−23 | 1.80 × 10−6 |
TRPA1 | −7.2445088 | 9.71 × 10−8 | 4.32 × 10−10 | 3.59 × 10−6 |
TRPM5 | 1.57085974 | 7.99 × 10−6 | 0.00121578 | 0.00097882 |
TRPV6 | 3.55456363 | 7.99 × 10−6 | 1.29 × 10−6 | 0.02627047 |
VDAC1 | 1.70533848 | 1.03 × 10−75 | 1.02 × 10−39 | 1.03 × 10−8 |
VDAC2 | 0.32791712 | 0.00017495 | 0.035753 | 0.00617185 |
VDAC3 | 1.50237461 | 6.80 × 10−10 | 1.07 × 10−14 | 5.86 × 10−6 |
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Pérez-Riesgo, E.; Gutiérrez, L.G.; Ubierna, D.; Acedo, A.; Moyer, M.P.; Núñez, L.; Villalobos, C. Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer. Int. J. Mol. Sci. 2017, 18, 922. https://doi.org/10.3390/ijms18050922
Pérez-Riesgo E, Gutiérrez LG, Ubierna D, Acedo A, Moyer MP, Núñez L, Villalobos C. Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer. International Journal of Molecular Sciences. 2017; 18(5):922. https://doi.org/10.3390/ijms18050922
Chicago/Turabian StylePérez-Riesgo, Enrique, Lucía G. Gutiérrez, Daniel Ubierna, Alberto Acedo, Mary P. Moyer, Lucía Núñez, and Carlos Villalobos. 2017. "Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer" International Journal of Molecular Sciences 18, no. 5: 922. https://doi.org/10.3390/ijms18050922