ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway
Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. D...
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| Veröffentlicht in: | Cancers 2022-11, Vol.14 (22), p.5704 |
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| creator | Shan, Wulin Dai, Chunyang Zhang, Huanhuan Han, Dan Yi, Qiyi Xia, Bairong |
| description | Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/β-catenin pathway in CRC. We validated that radiotherapy first reduced β-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in β-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/β-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC. |
| doi_str_mv | 10.3390/cancers14225704 |
| format | Article |
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This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/β-catenin pathway in CRC. We validated that radiotherapy first reduced β-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in β-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/β-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers14225704</identifier><identifier>PMID: 36428796</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Amino acids ; Cancer ; Cancer therapies ; Care and treatment ; Cell proliferation ; Cellular signal transduction ; Colorectal cancer ; Colorectal carcinoma ; Datasets ; E-cadherin ; Enzymes ; Health aspects ; Immunohistochemistry ; Lymph nodes ; Metastases ; Metastasis ; Next-generation sequencing ; Patients ; Radiation therapy ; Radiosensitivity ; Signal transduction ; Tumors ; Wnt protein ; Wnt proteins ; β-Catenin</subject><ispartof>Cancers, 2022-11, Vol.14 (22), p.5704</ispartof><rights>COPYRIGHT 2022 MDPI AG</rights><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c372t-6c947307a4c9bdd9e86a632dc6bd5cca08462a623aeb15b354a54307727aca633</cites><orcidid>0000-0002-0729-3315 ; 0000-0001-5143-8828</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688869/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9688869/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27907,27908,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36428796$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shan, Wulin</creatorcontrib><creatorcontrib>Dai, Chunyang</creatorcontrib><creatorcontrib>Zhang, Huanhuan</creatorcontrib><creatorcontrib>Han, Dan</creatorcontrib><creatorcontrib>Yi, Qiyi</creatorcontrib><creatorcontrib>Xia, Bairong</creatorcontrib><title>ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/β-catenin pathway in CRC. We validated that radiotherapy first reduced β-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in β-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/β-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC.</description><subject>Amino acids</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Cell proliferation</subject><subject>Cellular signal transduction</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Datasets</subject><subject>E-cadherin</subject><subject>Enzymes</subject><subject>Health aspects</subject><subject>Immunohistochemistry</subject><subject>Lymph nodes</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Next-generation sequencing</subject><subject>Patients</subject><subject>Radiation therapy</subject><subject>Radiosensitivity</subject><subject>Signal transduction</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Wnt proteins</subject><subject>β-Catenin</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptksFu1DAQQCMEolXpmRuyxIVLuo7t2MkFaZWWUqkSqIAQJ2viOFlXWbvYTst-Rf-FD-GbcLZL1VbYB1v2m-cZa7LsdYGPKK3xQoFV2oeCEVIKzJ5l-wQLknNes-cP9nvZYQiXOA1KC8HFy2yPckYqUfP97HbZ_CjQsbuxXg_TCNE4i07salYHFFcaXUBnXNA2mGiuTdwg16NGx-mXWUObX-hgQgQbUeNG57WKMKJmmxhqN-jMgkphSWuHre27jYs_v_MGorbGoi9msDDOl58hrm5g8yp70cMY9OFuPci-fTj52nzMzz-dnjXL81xRQWLOVc0ExQKYqtuuq3XFgVPSKd52pVKAK8YJcEJBt0XZ0pJByRIviACVSHqQvb_zXk3tWndK2-hhlFc-VeU30oGRj2-sWcnBXcuaV1XF6yR4txN493PSIcq1CUqPI1jtpiCJYLjErCxwQt8-QS_d5FPdM0VrVlRiK9xRA4xaGtu79K6apXIpWElS6rRK1NF_qDQ7vTbKWd2bdP4oYHEXoLwLwev-vsYCy7mN5JM2ShFvHn7NPf-vaehfRMvGfA</recordid><startdate>20221121</startdate><enddate>20221121</enddate><creator>Shan, Wulin</creator><creator>Dai, Chunyang</creator><creator>Zhang, Huanhuan</creator><creator>Han, Dan</creator><creator>Yi, Qiyi</creator><creator>Xia, Bairong</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0729-3315</orcidid><orcidid>https://orcid.org/0000-0001-5143-8828</orcidid></search><sort><creationdate>20221121</creationdate><title>ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway</title><author>Shan, Wulin ; Dai, Chunyang ; Zhang, Huanhuan ; Han, Dan ; Yi, Qiyi ; Xia, Bairong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-6c947307a4c9bdd9e86a632dc6bd5cca08462a623aeb15b354a54307727aca633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Amino acids</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Care and treatment</topic><topic>Cell proliferation</topic><topic>Cellular signal transduction</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Datasets</topic><topic>E-cadherin</topic><topic>Enzymes</topic><topic>Health aspects</topic><topic>Immunohistochemistry</topic><topic>Lymph nodes</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Next-generation sequencing</topic><topic>Patients</topic><topic>Radiation therapy</topic><topic>Radiosensitivity</topic><topic>Signal transduction</topic><topic>Tumors</topic><topic>Wnt protein</topic><topic>Wnt proteins</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shan, Wulin</creatorcontrib><creatorcontrib>Dai, Chunyang</creatorcontrib><creatorcontrib>Zhang, Huanhuan</creatorcontrib><creatorcontrib>Han, Dan</creatorcontrib><creatorcontrib>Yi, Qiyi</creatorcontrib><creatorcontrib>Xia, Bairong</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shan, Wulin</au><au>Dai, Chunyang</au><au>Zhang, Huanhuan</au><au>Han, Dan</au><au>Yi, Qiyi</au><au>Xia, Bairong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2022-11-21</date><risdate>2022</risdate><volume>14</volume><issue>22</issue><spage>5704</spage><pages>5704-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Treatment of cetuximab-resistant colorectal cancer (CRC) is a global healthcare problem. This study aimed to assess the effects of radiotherapy on cetuximab-resistant CRC and explore the underlying mechanism. We established a cetuximab-resistant HCT116 cell line (HCT116-R) by extracorporeal shock. Differentially expressed mRNAs were screened from cells treated with different radiation doses using second-generation high-throughput sequencing. Sequence data showed that ACY1 was significantly downregulated in HCT116-R cells after irradiation. Analysis of the GEO and TCGA datasets revealed that high ACY1 expression was associated with lymph node metastasis and a poor prognosis in CRC patients. In addition, immunohistochemistry results from CRC patients revealed that ACY1 protein expression was related to cetuximab resistance and lymph node metastasis. These findings suggested that ACY1 may function as an oncogene to promote CRC progression and regulate the radiosensitivity of cetuximab-resistant CRC. As expected, ACY1 silencing weakened the proliferation, migration, and invasion abilities of HCT116-R cells after radiotherapy. Mechanistically, TCGA data demonstrated that ACY1 expression was closely related to the Wnt/β-catenin pathway in CRC. We validated that radiotherapy first reduced β-catenin levels, followed by decreased expression of the metastasis-related protein E-cadherin. Silencing ACY1 dramatically enhanced these changes in β-catenin and E-cadherin after radiotherapy. In conclusion, ACY1 downregulation could enhance the radiosensitivity of cetuximab-resistant CRC by inactivating Wnt/β-catenin signaling, implying that ACY1 may serve as a radiotherapy target for cetuximab-resistant CRC.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36428796</pmid><doi>10.3390/cancers14225704</doi><orcidid>https://orcid.org/0000-0002-0729-3315</orcidid><orcidid>https://orcid.org/0000-0001-5143-8828</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Cancer Cancer therapies Care and treatment Cell proliferation Cellular signal transduction Colorectal cancer Colorectal carcinoma Datasets E-cadherin Enzymes Health aspects Immunohistochemistry Lymph nodes Metastases Metastasis Next-generation sequencing Patients Radiation therapy Radiosensitivity Signal transduction Tumors Wnt protein Wnt proteins β-Catenin |
| title | ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway |
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