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Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells

BACKGROUND: Despite the important role of radiotherapy in cancer treatment, a subset of patients responds poorly to treatment majorly due to radioresistance. Particularly the role of radiotherapy has not been established in gastric cancer (GC). Herein, we aimed to identify a radiosensitivity gene si...

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Autores principales: Kim, Kyung Hwan, Kim, Han Sang, Kim, Sang Cheol, Kim, DooA, Kim, Yong Bae, Chung, Hyun Cheol, Rha, Sun Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517358/
https://www.ncbi.nlm.nih.gov/pubmed/33042843
http://dx.doi.org/10.3389/fonc.2020.562284
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author Kim, Kyung Hwan
Kim, Han Sang
Kim, Sang Cheol
Kim, DooA
Kim, Yong Bae
Chung, Hyun Cheol
Rha, Sun Young
author_facet Kim, Kyung Hwan
Kim, Han Sang
Kim, Sang Cheol
Kim, DooA
Kim, Yong Bae
Chung, Hyun Cheol
Rha, Sun Young
author_sort Kim, Kyung Hwan
collection PubMed
description BACKGROUND: Despite the important role of radiotherapy in cancer treatment, a subset of patients responds poorly to treatment majorly due to radioresistance. Particularly the role of radiotherapy has not been established in gastric cancer (GC). Herein, we aimed to identify a radiosensitivity gene signature and to discover relevant targets to enhance radiosensitivity in GC cells. METHODS: An oligonucleotide microarray (containing 22,740 probes) was performed in 12 GC cell lines prior to radiation. A clonogenic assay was performed to evaluate the survival fraction at 2 Gy (SF2) as a surrogate marker for radiosensitivity. Genes differentially expressed (fold change > 6, q-value < 0.025) were identified between radiosensitive and radioresistant cell lines, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for validation. Gene set and pathway analyses were performed using Ingenuity Pathway Analysis (IPA). RESULTS: Radiosensitive (SF2 < 0.4) and radioresistant cell lines (SF2 ≥ 0.6) exhibited a marked difference in gene expression. We identified 68 genes that are differentially expressed between radiosensitive and radioresistant cell lines. The identified genes showed interactions via AKT, HIF1A, TGFB1, and TP53, and their functions were associated with the genetic networks associated with cellular growth and proliferation, cellular movement, and cell cycle. The Akt signaling pathway exhibited the highest association with radiosensitivity. Combinatorial treatment with MK-2206, an allosteric Akt inhibitor, and radiotherapy significantly increased cell death compared with radiotherapy alone in two radioresistant cell lines (YCC-2 and YCC-16). CONCLUSION: We identified a GC-specific radiosensitivity gene signature and suggest that the Akt signaling pathway could serve as a therapeutic target for GC radiosensitization.
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spelling pubmed-75173582020-10-09 Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells Kim, Kyung Hwan Kim, Han Sang Kim, Sang Cheol Kim, DooA Kim, Yong Bae Chung, Hyun Cheol Rha, Sun Young Front Oncol Oncology BACKGROUND: Despite the important role of radiotherapy in cancer treatment, a subset of patients responds poorly to treatment majorly due to radioresistance. Particularly the role of radiotherapy has not been established in gastric cancer (GC). Herein, we aimed to identify a radiosensitivity gene signature and to discover relevant targets to enhance radiosensitivity in GC cells. METHODS: An oligonucleotide microarray (containing 22,740 probes) was performed in 12 GC cell lines prior to radiation. A clonogenic assay was performed to evaluate the survival fraction at 2 Gy (SF2) as a surrogate marker for radiosensitivity. Genes differentially expressed (fold change > 6, q-value < 0.025) were identified between radiosensitive and radioresistant cell lines, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for validation. Gene set and pathway analyses were performed using Ingenuity Pathway Analysis (IPA). RESULTS: Radiosensitive (SF2 < 0.4) and radioresistant cell lines (SF2 ≥ 0.6) exhibited a marked difference in gene expression. We identified 68 genes that are differentially expressed between radiosensitive and radioresistant cell lines. The identified genes showed interactions via AKT, HIF1A, TGFB1, and TP53, and their functions were associated with the genetic networks associated with cellular growth and proliferation, cellular movement, and cell cycle. The Akt signaling pathway exhibited the highest association with radiosensitivity. Combinatorial treatment with MK-2206, an allosteric Akt inhibitor, and radiotherapy significantly increased cell death compared with radiotherapy alone in two radioresistant cell lines (YCC-2 and YCC-16). CONCLUSION: We identified a GC-specific radiosensitivity gene signature and suggest that the Akt signaling pathway could serve as a therapeutic target for GC radiosensitization. Frontiers Media S.A. 2020-09-11 /pmc/articles/PMC7517358/ /pubmed/33042843 http://dx.doi.org/10.3389/fonc.2020.562284 Text en Copyright © 2020 Kim, Kim, Kim, Kim, Kim, Chung and Rha. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Kim, Kyung Hwan
Kim, Han Sang
Kim, Sang Cheol
Kim, DooA
Kim, Yong Bae
Chung, Hyun Cheol
Rha, Sun Young
Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells
title Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells
title_full Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells
title_fullStr Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells
title_full_unstemmed Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells
title_short Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells
title_sort gene expression profiling identifies akt as a target for radiosensitization in gastric cancer cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517358/
https://www.ncbi.nlm.nih.gov/pubmed/33042843
http://dx.doi.org/10.3389/fonc.2020.562284
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