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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MDPI AG
2022-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/22/5704 |
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| author | Wulin Shan Chunyang Dai Huanhuan Zhang Dan Han Qiyi Yi Bairong Xia |
| author_facet | Wulin Shan Chunyang Dai Huanhuan Zhang Dan Han Qiyi Yi Bairong Xia |
| author_sort | Wulin Shan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T18:25:47Z |
| format | Article |
| id | doaj.art-d2f1ae4b56904615879bf9b0eb5749a2 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T18:25:47Z |
| publishDate | 2022-11-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d2f1ae4b56904615879bf9b0eb5749a22023-11-24T07:55:22ZengMDPI AGCancers2072-66942022-11-011422570410.3390/cancers14225704ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling PathwayWulin Shan0Chunyang Dai1Huanhuan Zhang2Dan Han3Qiyi Yi4Bairong Xia5Department of Laboratory Diagnostics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, ChinaDepartment of Laboratory Diagnostics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, ChinaDepartment of Cancer Epigenetics Program, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, ChinaDepartment of Cancer Epigenetics Program, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, ChinaSchool of Basic Medical Sciences, Anhui Medical University, Hefei 230032, ChinaDepartment of Gynecology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230031, ChinaTreatment 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.https://www.mdpi.com/2072-6694/14/22/5704colorectal cancercetuximab resistanceradiosensitivityACY1Wnt/β-catenin pathway |
| spellingShingle | Wulin Shan Chunyang Dai Huanhuan Zhang Dan Han Qiyi Yi Bairong Xia ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway Cancers colorectal cancer cetuximab resistance radiosensitivity ACY1 Wnt/β-catenin pathway |
| title | ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway |
| title_full | ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway |
| title_fullStr | ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway |
| title_full_unstemmed | ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway |
| title_short | ACY1 Downregulation Enhances the Radiosensitivity of Cetuximab-Resistant Colorectal Cancer by Inactivating the Wnt/β-Catenin Signaling Pathway |
| title_sort | acy1 downregulation enhances the radiosensitivity of cetuximab resistant colorectal cancer by inactivating the wnt β catenin signaling pathway |
| topic | colorectal cancer cetuximab resistance radiosensitivity ACY1 Wnt/β-catenin pathway |
| url | https://www.mdpi.com/2072-6694/14/22/5704 |
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