LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway
Abstract Background Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However,...
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-022-03673-4 |
| _version_ | 1817984817300504576 |
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| author | Xiao-Ya Sun Hao-Zheng Li Da-Fei Xie Shan-Shan Gao Xin Huang Hua Guan Chen-Jun Bai Ping-Kun Zhou |
| author_facet | Xiao-Ya Sun Hao-Zheng Li Da-Fei Xie Shan-Shan Gao Xin Huang Hua Guan Chen-Jun Bai Ping-Kun Zhou |
| author_sort | Xiao-Ya Sun |
| collection | DOAJ |
| description | Abstract Background Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However, the upstream molecules driving the signaling pathways of radiation-induced EMT have not been fully delineated. Methods In this study, RNA-seq-based transcriptome analysis was performed to identify the early responsive genes of HeLa cells to γ-ray irradiation. EMT-associated genes were knocked down by siRNA technology or overexpressed in HeLa cells and A549 cells, and the resulting changes in phenotypes of EMT and radiosensitivity were assessed using qPCR and Western blotting analyses, migration assays, colony-forming ability and apoptosis of flow cytometer assays. Results Through RNA-seq-based transcriptome analysis, we found that LPAR5 is downregulated in the early response of HeLa cells to γ-ray irradiation. Radiation-induced alterations in LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., the early downregulating phase at 2 ~ 4 h and the late upregulating phase at 24 h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers radioresistance to cancer cells. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expression. Conclusions LPAR5 is an important upstream regulator of IR-induced EMT that modulates the ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and identifies promising targets for improving the effectiveness of cancer radiation therapy. |
| first_indexed | 2024-04-13T23:50:14Z |
| format | Article |
| id | doaj.art-bead81d631b84d3aa7ea3d6d2bedc185 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-13T23:50:14Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-bead81d631b84d3aa7ea3d6d2bedc1852022-12-22T02:24:08ZengBMCJournal of Translational Medicine1479-58762022-10-0120111610.1186/s12967-022-03673-4LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathwayXiao-Ya Sun0Hao-Zheng Li1Da-Fei Xie2Shan-Shan Gao3Xin Huang4Hua Guan5Chen-Jun Bai6Ping-Kun Zhou7College of Public Health, Hengyang Medical School, University of South ChinaCollege of Public Health, Hengyang Medical School, University of South ChinaDepartment of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation MedicineDepartment of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation MedicineDepartment of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation MedicineDepartment of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation MedicineDepartment of Radiation Biology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation MedicineCollege of Public Health, Hengyang Medical School, University of South ChinaAbstract Background Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However, the upstream molecules driving the signaling pathways of radiation-induced EMT have not been fully delineated. Methods In this study, RNA-seq-based transcriptome analysis was performed to identify the early responsive genes of HeLa cells to γ-ray irradiation. EMT-associated genes were knocked down by siRNA technology or overexpressed in HeLa cells and A549 cells, and the resulting changes in phenotypes of EMT and radiosensitivity were assessed using qPCR and Western blotting analyses, migration assays, colony-forming ability and apoptosis of flow cytometer assays. Results Through RNA-seq-based transcriptome analysis, we found that LPAR5 is downregulated in the early response of HeLa cells to γ-ray irradiation. Radiation-induced alterations in LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., the early downregulating phase at 2 ~ 4 h and the late upregulating phase at 24 h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers radioresistance to cancer cells. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expression. Conclusions LPAR5 is an important upstream regulator of IR-induced EMT that modulates the ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and identifies promising targets for improving the effectiveness of cancer radiation therapy.https://doi.org/10.1186/s12967-022-03673-4LPAR5ERKRadioresistanceEMTRadiotherapy |
| spellingShingle | Xiao-Ya Sun Hao-Zheng Li Da-Fei Xie Shan-Shan Gao Xin Huang Hua Guan Chen-Jun Bai Ping-Kun Zhou LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway Journal of Translational Medicine LPAR5 ERK Radioresistance EMT Radiotherapy |
| title | LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway |
| title_full | LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway |
| title_fullStr | LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway |
| title_full_unstemmed | LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway |
| title_short | LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway |
| title_sort | lpar5 confers radioresistance to cancer cells associated with emt activation via the erk snail pathway |
| topic | LPAR5 ERK Radioresistance EMT Radiotherapy |
| url | https://doi.org/10.1186/s12967-022-03673-4 |
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