Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib
<p>Identification of homeodomain finger protein 14 (PHF14) mutations in neurocytomas by whole exome sequencing. (<b>A</b>) Neurocytoma formalin-fixed, paraffin-embedded (FFPE) and frozen tissues (<span class="html-italic">n</span> = 54 total) were retrospectively collected from 11 centers across United States and Canada. Genomic DNA was extracted from 38 neurocytoma tissues with tumor area >95% and diameter >5 mm and was of suitable quality for whole exome sequencing in 21 neurocytoma tumors (FFPE samples <span class="html-italic">n</span> = 17, frozen samples <span class="html-italic">n</span> = 4). (<b>B</b>) Demographics and subtypes of 21 sequenced neurocytoma samples and 5 normal cerebellar controls. (<b>C</b>) Summary of the six PHF14 mutations detected by WES in three neurocytoma samples compared.</p> "> Figure 2
<p>PHF14 Depletion Enhances Cell Proliferation and Anchorage Independent Cell Growth. (<b>A</b>) A conserved 19-bp region in the human, mouse and rat PHF14 gene in Exon 10 (CGC ATG ATT CAA ATT CAG GAA) was selected as shRNA target to knockdown PHF14 expression. Five cell lines originating from human, mouse and rat were used to evaluate the biological effect of PHF14 depletion. PHF14 knockdown stable transfectants were established by puromycin selection, and the knockdown efficiency was determined by Western Blot using anti-PHF14 antibody. The densitometric analyses of the protein bands vs. the individual loading controls were shown under individual blot using the ImageQuant 5.2 software (GE Healthcare, Pittsburgh, PA). (<b>B</b>) Cell proliferation rate was enhanced in shRNA PHF4 knockdown transfectants compared to Nonsense controls as measured by CellTiter-Glo<sup>®</sup> luminescent cell viability assay in a variety of cell lines. (<b>C</b>) Soft agar assay demonstrated that PHF14 knockdown induced an increase in colony size in human neuroblastoma SHSY-5Y cells. (<b>D</b>) A single guiding RNA (sgRNA) targeting a 20-bp region (TGG ATC GCA GCT CCA AGA GG) in PHF14 Exon 1 was designed for CRISPR-Cas9 mediated genetic editing. The knockout efficiency was confirmed by Western Blot. PHF14 knockout in human neuroblastoma SHSY-5Y cells promoted cell proliferation as measured by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. PHF14 knockout increased colony formation in soft agar assay. The results shown were representative of three independent experiments. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 2 Cont.
<p>PHF14 Depletion Enhances Cell Proliferation and Anchorage Independent Cell Growth. (<b>A</b>) A conserved 19-bp region in the human, mouse and rat PHF14 gene in Exon 10 (CGC ATG ATT CAA ATT CAG GAA) was selected as shRNA target to knockdown PHF14 expression. Five cell lines originating from human, mouse and rat were used to evaluate the biological effect of PHF14 depletion. PHF14 knockdown stable transfectants were established by puromycin selection, and the knockdown efficiency was determined by Western Blot using anti-PHF14 antibody. The densitometric analyses of the protein bands vs. the individual loading controls were shown under individual blot using the ImageQuant 5.2 software (GE Healthcare, Pittsburgh, PA). (<b>B</b>) Cell proliferation rate was enhanced in shRNA PHF4 knockdown transfectants compared to Nonsense controls as measured by CellTiter-Glo<sup>®</sup> luminescent cell viability assay in a variety of cell lines. (<b>C</b>) Soft agar assay demonstrated that PHF14 knockdown induced an increase in colony size in human neuroblastoma SHSY-5Y cells. (<b>D</b>) A single guiding RNA (sgRNA) targeting a 20-bp region (TGG ATC GCA GCT CCA AGA GG) in PHF14 Exon 1 was designed for CRISPR-Cas9 mediated genetic editing. The knockout efficiency was confirmed by Western Blot. PHF14 knockout in human neuroblastoma SHSY-5Y cells promoted cell proliferation as measured by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. PHF14 knockout increased colony formation in soft agar assay. The results shown were representative of three independent experiments. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 3
<p>PHF14 Depletion Elevates platelet derived growth factor receptor-alpha (PDGFRα) Expression and Increases Responsivity to the PDGFR Inhibitor Sunitinib. (<b>A</b>–<b>B</b>) ShRNA-directed PHF14 knockdown increased PDGFRα expression at both mRNA (<b>A</b>) and protein (<b>B</b>) levels by Real Time PCR (<b>A</b>) and Western Blot (<b>B</b>) in human neuroblastoma SHSY-5Y cells and mouse embryonic fibroblasts NIH3T3 cells. (<b>C</b>) Increased PDGFRα expression at both protein and mRNA levels was confirmed in PHF14 knockout human neuroblastoma SHSY-5Y cells. (<b>D</b>) The anti-proliferation effects of PDGFR inhibitors, Imatinib and Sunitinib, were evaluated in SHSY-5Y cells by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. (<b>E</b> and <b>F</b>) PHF4 knockdown sensitized the anti-proliferation effect of PDGFR inhibitor Sunitinib (<b>F</b>), but not Imatinib (<b>E</b>) in human neuroblastoma SHSY-5Y cells as analyzed by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. (<b>G</b>) The sensitization to Sunitinib treatment was reproduced in PHF14 knockout SHSY-5Y cells. The results shown were representative of three independent experiments. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.005, compared with media control. # <span class="html-italic">p</span> < 0.05; ## <span class="html-italic">p</span> < 0.01 compared with Nonsense control.</p> "> Figure 4
<p>PHF14 Inhibits Cell Growth in Neurocytoma Primary Culture. (<b>A</b>) Typical morphologic appearance of neurocytoma primary cultures in serum free, insulin, transferrin, selenium and fibronectin (ITSFn) media (Top Panel) and serum supplemented ITFSn media (Bottom Panel) for 3 weeks to compare cell morphology changes. (<b>B</b>) Detection of four splicing loss mutations of PHF14 in the neurocytoma primary cultures by whole exome sequencing (WES). (<b>C</b>) Comparison of the transfection efficiency of Lipofectamine 2000 and transduction efficiency of lentivirus by introducing GFP-expressing vector. Wild type PHF14 was introduced into neurocytoma primary culture using lentivirus. The transduction efficiency was evaluated by Real Time PCR to detect PHF14 overexpression. Cell viability was detected by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. (<b>D</b>) Neurocytoma primary culture was treated with Sunitinib, MEK-162 and Metformin. Cell viability was detected by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. Data shown are representative of at least three independently conducted experiments. Bars indicate the mean ± standard error of the mean of triplicate tests. * <span class="html-italic">p</span> < 0.05; *** <span class="html-italic">p</span> < 0.005.</p> "> Figure 4 Cont.
<p>PHF14 Inhibits Cell Growth in Neurocytoma Primary Culture. (<b>A</b>) Typical morphologic appearance of neurocytoma primary cultures in serum free, insulin, transferrin, selenium and fibronectin (ITSFn) media (Top Panel) and serum supplemented ITFSn media (Bottom Panel) for 3 weeks to compare cell morphology changes. (<b>B</b>) Detection of four splicing loss mutations of PHF14 in the neurocytoma primary cultures by whole exome sequencing (WES). (<b>C</b>) Comparison of the transfection efficiency of Lipofectamine 2000 and transduction efficiency of lentivirus by introducing GFP-expressing vector. Wild type PHF14 was introduced into neurocytoma primary culture using lentivirus. The transduction efficiency was evaluated by Real Time PCR to detect PHF14 overexpression. Cell viability was detected by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. (<b>D</b>) Neurocytoma primary culture was treated with Sunitinib, MEK-162 and Metformin. Cell viability was detected by CellTiter-Glo<sup>®</sup> luminescent cell viability assay. Data shown are representative of at least three independently conducted experiments. Bars indicate the mean ± standard error of the mean of triplicate tests. * <span class="html-italic">p</span> < 0.05; *** <span class="html-italic">p</span> < 0.005.</p> "> Figure 5
<p>Evaluation of the Tumor Inhibitory Effect of PHF14 and Sunitinib Using in vivo Xenograft Animal Model. (<b>A</b>,<b>B</b>) Comparison of tumor development in PHF14 knockout cells (<span class="html-italic">n</span> = 10) and control neuroblastoma cells (<span class="html-italic">n</span> = 10) in an in vivo xenograft model of neuroblastoma. (<b>C</b>,<b>D</b>) To determine the effects of Sunitinib treatment on tumor growth in vivo, we administrated Sunitinib (dissolved in 0.5% CMC) by oral gavage following SHSY-5Y cells inoculation. The tumor growth was monitored and measured daily, and the animals were euthanized on day 21 after drug treatment due to deteriorating animal health condition. Tumors were excised, and weighed. Data were analyzed by two-tailed unpaired <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.005; **** <span class="html-italic">p</span> < 0.0001.</p> "> Figure 5 Cont.
<p>Evaluation of the Tumor Inhibitory Effect of PHF14 and Sunitinib Using in vivo Xenograft Animal Model. (<b>A</b>,<b>B</b>) Comparison of tumor development in PHF14 knockout cells (<span class="html-italic">n</span> = 10) and control neuroblastoma cells (<span class="html-italic">n</span> = 10) in an in vivo xenograft model of neuroblastoma. (<b>C</b>,<b>D</b>) To determine the effects of Sunitinib treatment on tumor growth in vivo, we administrated Sunitinib (dissolved in 0.5% CMC) by oral gavage following SHSY-5Y cells inoculation. The tumor growth was monitored and measured daily, and the animals were euthanized on day 21 after drug treatment due to deteriorating animal health condition. Tumors were excised, and weighed. Data were analyzed by two-tailed unpaired <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.005; **** <span class="html-italic">p</span> < 0.0001.</p> ">
Abstract
:1. Introduction
2. Results
2.1. PHF14 Mutations in Human Neurocytoma
2.2. PHF14 Knockdown Enhances Cell Proliferation and Increases Anchorage Independent Cell Growth
2.3. PHF14 Depletion Increases PDGFRα Expression and Responsivity to Sunitinib
2.4. Overexpression of PHF14 Inhibits the Growth of Neurocytoma Primary Culture with PHF14 Defect
2.5. Confirmation of the Tumor Inhibitory Effect of PHF14 and Sunitinib In Vivo
3. Discussion
4. Materials and Methods
4.1. DNA Isolation and Whole Exome Sequencing
4.2. Bioinformatic Analysis of WES Data
4.3. Cell Culture and Reagents
4.4. RNA Microarray Processing and Bioinformatic Analysis
4.5. Human Neurocytoma Primary Cultures
4.6. Plasmid Constructs, Transfection and Viral Transduction
4.7. Cell Proliferation Assay
4.8. Anchorage-Independent Growth Assay
4.9. Real-Time PCR
4.10. Western Blotting
4.11. Tumor Xenograft Model
4.12. Statistics
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Zhang, D.; Yong, W.H.; Movassaghi, M.; Rodriguez, F.J.; Yang, I.; McKeever, P.; Qian, J.; Li, J.Y.; Mao, Q.; Newell, K.L.; et al. Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib. Biomedicines 2022, 10, 2842. https://doi.org/10.3390/biomedicines10112842
Zhang D, Yong WH, Movassaghi M, Rodriguez FJ, Yang I, McKeever P, Qian J, Li JY, Mao Q, Newell KL, et al. Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib. Biomedicines. 2022; 10(11):2842. https://doi.org/10.3390/biomedicines10112842
Chicago/Turabian StyleZhang, Dongyun, William H. Yong, Masoud Movassaghi, Fausto J. Rodriguez, Issac Yang, Paul McKeever, Jiang Qian, Jian Yi Li, Qinwen Mao, Kathy L. Newell, and et al. 2022. "Whole Exome Sequencing Identifies PHF14 Mutations in Neurocytoma and Predicts Responsivity to the PDGFR Inhibitor Sunitinib" Biomedicines 10, no. 11: 2842. https://doi.org/10.3390/biomedicines10112842