Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line
Cancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NS...
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/8/4284 |
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| author | Hae-Ran Park Yeo-Jin Choi Jee-Young Kim In-Gyu Kim Uhee Jung |
| author_facet | Hae-Ran Park Yeo-Jin Choi Jee-Young Kim In-Gyu Kim Uhee Jung |
| author_sort | Hae-Ran Park |
| collection | DOAJ |
| description | Cancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NSCLC cancer cells. Here, A549 cells were exposed to fractionated irradiation at a cumulative dose of 52 Gy (4 Gy × 13 times) for a generation of radioresistant cells. After fractionated irradiation, surviving A549 cells exhibited resistance to IR and enhanced expression of various cancer stem cell markers. They also showed upregulation of mesenchymal molecular markers and downregulation of epithelial molecular markers, correlating with an increase in the migration and invasion. Fractionated irradiation triggered the secretion of TGF-β1 and DLX2 expression. Interestingly, the increased DLX2 following fractionated irradiation seemed to induce the expression of the gene for the EGFR-ligand betacellulin via Smad2/3 signaling. To contrast, DLX2 knockdown dramatically decreased the expression of CSC markers, migration, and proliferation. Moreover, A549 cells expressing DLX2 shRNA formed tumors with a significantly smaller volume compared to those expressing control shDNA in a mouse xenograft assay. These results suggest that DLX2 overexpression in surviving NSCLC cancer cells after fractionated IR exposure is involved in the cancer stemness, radioresistance, EMT, tumor survival, and tumorigenic capability. |
| first_indexed | 2024-03-10T12:08:46Z |
| format | Article |
| id | doaj.art-9318a347389044fb9d973c89dd14bbef |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:08:46Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9318a347389044fb9d973c89dd14bbef2023-11-21T16:22:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01228428410.3390/ijms22084284Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell LineHae-Ran Park0Yeo-Jin Choi1Jee-Young Kim2In-Gyu Kim3Uhee Jung4Biotechnology Research Division, Korea Atomic Energy Research Institute, Jeonbuk 56212, KoreaBiotechnology Research Division, Korea Atomic Energy Research Institute, Jeonbuk 56212, KoreaBiotechnology Research Division, Korea Atomic Energy Research Institute, Jeonbuk 56212, KoreaEnvironmental Safety Evaluation Research Division, Korea Atomic Energy Research Institute, Daejeon 34057, KoreaEnvironmental Safety Evaluation Research Division, Korea Atomic Energy Research Institute, Daejeon 34057, KoreaCancer stem cells (CSCs) play an important role in cancer recurrence and metastasis. It is suggested that the CSC properties in heterogeneous cancer cells can be induced by ionizing radiation (IR). This study investigated the role of DLX2 in the radioresistance and CSC properties induced by IR in NSCLC cancer cells. Here, A549 cells were exposed to fractionated irradiation at a cumulative dose of 52 Gy (4 Gy × 13 times) for a generation of radioresistant cells. After fractionated irradiation, surviving A549 cells exhibited resistance to IR and enhanced expression of various cancer stem cell markers. They also showed upregulation of mesenchymal molecular markers and downregulation of epithelial molecular markers, correlating with an increase in the migration and invasion. Fractionated irradiation triggered the secretion of TGF-β1 and DLX2 expression. Interestingly, the increased DLX2 following fractionated irradiation seemed to induce the expression of the gene for the EGFR-ligand betacellulin via Smad2/3 signaling. To contrast, DLX2 knockdown dramatically decreased the expression of CSC markers, migration, and proliferation. Moreover, A549 cells expressing DLX2 shRNA formed tumors with a significantly smaller volume compared to those expressing control shDNA in a mouse xenograft assay. These results suggest that DLX2 overexpression in surviving NSCLC cancer cells after fractionated IR exposure is involved in the cancer stemness, radioresistance, EMT, tumor survival, and tumorigenic capability.https://www.mdpi.com/1422-0067/22/8/4284ionizing radiationDLX2non-small cell lung cancerradioresistancecancer stem cellepithelial to mesenchymal transition (EMT) |
| spellingShingle | Hae-Ran Park Yeo-Jin Choi Jee-Young Kim In-Gyu Kim Uhee Jung Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line International Journal of Molecular Sciences ionizing radiation DLX2 non-small cell lung cancer radioresistance cancer stem cell epithelial to mesenchymal transition (EMT) |
| title | Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line |
| title_full | Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line |
| title_fullStr | Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line |
| title_full_unstemmed | Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line |
| title_short | Repeated Irradiation with γ-Ray Induces Cancer Stemness through TGF-β-DLX2 Signaling in the A549 Human Lung Cancer Cell Line |
| title_sort | repeated irradiation with γ ray induces cancer stemness through tgf β dlx2 signaling in the a549 human lung cancer cell line |
| topic | ionizing radiation DLX2 non-small cell lung cancer radioresistance cancer stem cell epithelial to mesenchymal transition (EMT) |
| url | https://www.mdpi.com/1422-0067/22/8/4284 |
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