Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment
Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin tr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/15/3/715 |
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| author | Sadia Afrin Malini Ramaiyer Umme Aoufa Mafruha Begum Mostafa A. Borahay |
| author_facet | Sadia Afrin Malini Ramaiyer Umme Aoufa Mafruha Begum Mostafa A. Borahay |
| author_sort | Sadia Afrin |
| collection | DOAJ |
| description | Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-β1, TGF-β2, and TGF-β3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-β3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways. |
| first_indexed | 2024-03-11T09:30:26Z |
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| id | doaj.art-67212583f73c426c8321d76accd1f77e |
| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-11T09:30:26Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Nutrients |
| spelling | doaj.art-67212583f73c426c8321d76accd1f77e2023-11-16T17:40:56ZengMDPI AGNutrients2072-66432023-01-0115371510.3390/nu15030715Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly MicroenvironmentSadia Afrin0Malini Ramaiyer1Umme Aoufa Mafruha Begum2Mostafa A. Borahay3Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USASchool of Medicine, Johns Hopkins University, Baltimore, MD 21205, USADepartment of Gynecology and Obstetrics, Khulna City Medical College Hospital, 25-26, KDA Ave., Khulna 9100, BangladeshDepartment of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAUterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1/2/total ERK1/2, phosphorylated STAT3/total STAT3, and phosphorylated AKT1/2/3/total AKT1/2/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2/STAT3, MAPK/ERK, and PI3K/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFNγ, IL-8, IL-6, GM-CSF, MCP-1, and TNF-α), fibrotic (TGF-β1, TGF-β2, and TGF-β3), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK/ERK, JAK2/STAT3, and PI3k/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-α, TGF-β3, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways.https://www.mdpi.com/2072-6643/15/3/715adipocyteleptinleiomyomaJAK2/STAT3MAPK/ERKPI3K/AKT |
| spellingShingle | Sadia Afrin Malini Ramaiyer Umme Aoufa Mafruha Begum Mostafa A. Borahay Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment Nutrients adipocyte leptin leiomyoma JAK2/STAT3 MAPK/ERK PI3K/AKT |
| title | Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment |
| title_full | Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment |
| title_fullStr | Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment |
| title_full_unstemmed | Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment |
| title_short | Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment |
| title_sort | adipocyte and adipokines promote a uterine leiomyoma friendly microenvironment |
| topic | adipocyte leptin leiomyoma JAK2/STAT3 MAPK/ERK PI3K/AKT |
| url | https://www.mdpi.com/2072-6643/15/3/715 |
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