Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop
Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucida...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2023-01-01
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| Series: | Analytical Cellular Pathology |
| Online Access: | http://dx.doi.org/10.1155/2023/8334881 |
| _version_ | 1811158461196533760 |
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| author | Tongshuo Zhang Jing Yang Yang Sun Jiangnan Song Dandan Gao Suhui Huang Aibo Pang Jianhui Zhang Junhong Wang Yue Wang Yanqiu Li |
| author_facet | Tongshuo Zhang Jing Yang Yang Sun Jiangnan Song Dandan Gao Suhui Huang Aibo Pang Jianhui Zhang Junhong Wang Yue Wang Yanqiu Li |
| author_sort | Tongshuo Zhang |
| collection | DOAJ |
| description | Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial–mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC. |
| first_indexed | 2024-04-10T05:25:05Z |
| format | Article |
| id | doaj.art-aff5dbdc793a44adafacfb62582d9f80 |
| institution | Directory Open Access Journal |
| issn | 2210-7185 |
| language | English |
| last_indexed | 2024-04-10T05:25:05Z |
| publishDate | 2023-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Analytical Cellular Pathology |
| spelling | doaj.art-aff5dbdc793a44adafacfb62582d9f802023-03-08T00:01:10ZengHindawi LimitedAnalytical Cellular Pathology2210-71852023-01-01202310.1155/2023/8334881Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback LoopTongshuo Zhang0Jing Yang1Yang Sun2Jiangnan Song3Dandan Gao4Suhui Huang5Aibo Pang6Jianhui Zhang7Junhong Wang8Yue Wang9Yanqiu Li10School of Integrative MedicineDepartment of Pathogenic BiologyDepartment of Gynaecology and ObstetricsDepartment of Pathogenic BiologySchool of Integrative MedicineDepartment of Pathogenic BiologyMedical School of Chinese People’s Liberation Army (PLA)Affiliated Beichen HospitalSchool of Integrative MedicineSchool of Integrative MedicineDepartment of Clinical LaboratoryExtensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial–mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.http://dx.doi.org/10.1155/2023/8334881 |
| spellingShingle | Tongshuo Zhang Jing Yang Yang Sun Jiangnan Song Dandan Gao Suhui Huang Aibo Pang Jianhui Zhang Junhong Wang Yue Wang Yanqiu Li Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop Analytical Cellular Pathology |
| title | Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop |
| title_full | Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop |
| title_fullStr | Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop |
| title_full_unstemmed | Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop |
| title_short | Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop |
| title_sort | interleukin 6 and hypoxia synergistically promote emt mediated invasion in epithelial ovarian cancer via the il 6 stat3 hif 1α feedback loop |
| url | http://dx.doi.org/10.1155/2023/8334881 |
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