RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells
Abstract Background Progestins are used as fertility‐sparing regimens for young patients with stage 1A endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH). CD163+ macrophages promote estrogen‐dependent EEC development, but whether they induce progestin insensitivity rema...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.5396 |
| _version_ | 1797866819794501632 |
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| author | Lulu Wang Qiaoying Lv Pengfei Wu Shuhan Luo Sijia Liu Xiaojun Chen Xuezhen Luo |
| author_facet | Lulu Wang Qiaoying Lv Pengfei Wu Shuhan Luo Sijia Liu Xiaojun Chen Xuezhen Luo |
| author_sort | Lulu Wang |
| collection | DOAJ |
| description | Abstract Background Progestins are used as fertility‐sparing regimens for young patients with stage 1A endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH). CD163+ macrophages promote estrogen‐dependent EEC development, but whether they induce progestin insensitivity remains unclear. This study aimed to investigate the possible effects of CD163+ macrophages on progestin response in AEH/EEC patients. Methods The number of infiltrating CD163+ macrophages in progestin‐insensitive and ‐sensitive endometrial lesions was compared. The effects of CD163+ macrophages on progestin responses and progesterone receptor (PR) expression in EC cells were evaluated in vitro. ATAC‐seq and RNA‐seq were combined to identify molecular/biological changes induced by CD163+ macrophages in progestin‐insensitive EC cells. Results Increased CD163+ macrophage infiltration was significantly associated with progestin insensitivity and longer treatment durations in AEH/EEC patients. Additionally, the number of CD163+ macrophages was negatively correlated with PR expression in AEH/EEC tissues. Furthermore, the CD163+ macrophage‐mediated microenvironment and secreted cytokines downregulated PR expression and impaired the response of EC cells to medroxyprogesterone acetate (MPA). RNA‐seq analysis demonstrated that CD163+ macrophages antagonized PR signaling by blocking or even reversing MPA‐regulated differential gene expression. Based on RNA‐seq and ATAC‐seq analyses, extracellular matrix (ECM) signaling and ECM‐related transcription factors, FOXF2, POU1F1, and RUNX1were identified to potentially be involved in CD163+ macrophage‐induced progestin insensitivity in endometrial cancer patients. Conclusions We identified CD163+ macrophages as an important mediator of progestin desensitization and an unfavorable factor for the efficacy of fertility‐preserving treatment in AEH/EEC patients. |
| first_indexed | 2024-04-09T23:31:28Z |
| format | Article |
| id | doaj.art-1403f936dc784b33bb29c49b2c63ab95 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-09T23:31:28Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-1403f936dc784b33bb29c49b2c63ab952023-03-21T05:20:40ZengWileyCancer Medicine2045-76342023-03-011255964597810.1002/cam4.5396RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cellsLulu Wang0Qiaoying Lv1Pengfei Wu2Shuhan Luo3Sijia Liu4Xiaojun Chen5Xuezhen Luo6Obstetrics and Gynecology Hospital Fudan University Shanghai ChinaObstetrics and Gynecology Hospital Fudan University Shanghai ChinaObstetrics and Gynecology Hospital Fudan University Shanghai ChinaObstetrics and Gynecology Hospital Fudan University Shanghai ChinaObstetrics and Gynecology Hospital Fudan University Shanghai ChinaObstetrics and Gynecology Hospital Fudan University Shanghai ChinaObstetrics and Gynecology Hospital Fudan University Shanghai ChinaAbstract Background Progestins are used as fertility‐sparing regimens for young patients with stage 1A endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH). CD163+ macrophages promote estrogen‐dependent EEC development, but whether they induce progestin insensitivity remains unclear. This study aimed to investigate the possible effects of CD163+ macrophages on progestin response in AEH/EEC patients. Methods The number of infiltrating CD163+ macrophages in progestin‐insensitive and ‐sensitive endometrial lesions was compared. The effects of CD163+ macrophages on progestin responses and progesterone receptor (PR) expression in EC cells were evaluated in vitro. ATAC‐seq and RNA‐seq were combined to identify molecular/biological changes induced by CD163+ macrophages in progestin‐insensitive EC cells. Results Increased CD163+ macrophage infiltration was significantly associated with progestin insensitivity and longer treatment durations in AEH/EEC patients. Additionally, the number of CD163+ macrophages was negatively correlated with PR expression in AEH/EEC tissues. Furthermore, the CD163+ macrophage‐mediated microenvironment and secreted cytokines downregulated PR expression and impaired the response of EC cells to medroxyprogesterone acetate (MPA). RNA‐seq analysis demonstrated that CD163+ macrophages antagonized PR signaling by blocking or even reversing MPA‐regulated differential gene expression. Based on RNA‐seq and ATAC‐seq analyses, extracellular matrix (ECM) signaling and ECM‐related transcription factors, FOXF2, POU1F1, and RUNX1were identified to potentially be involved in CD163+ macrophage‐induced progestin insensitivity in endometrial cancer patients. Conclusions We identified CD163+ macrophages as an important mediator of progestin desensitization and an unfavorable factor for the efficacy of fertility‐preserving treatment in AEH/EEC patients.https://doi.org/10.1002/cam4.5396CD163+ macrophagesendometrial cancerextracellular matrixprogesterone receptorprogestin insensitivity |
| spellingShingle | Lulu Wang Qiaoying Lv Pengfei Wu Shuhan Luo Sijia Liu Xiaojun Chen Xuezhen Luo RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells Cancer Medicine CD163+ macrophages endometrial cancer extracellular matrix progesterone receptor progestin insensitivity |
| title | RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells |
| title_full | RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells |
| title_fullStr | RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells |
| title_full_unstemmed | RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells |
| title_short | RNA‐seq and ATAC‐seq analysis of CD163+ macrophage‐induced progestin‐insensitive endometrial cancer cells |
| title_sort | rna seq and atac seq analysis of cd163 macrophage induced progestin insensitive endometrial cancer cells |
| topic | CD163+ macrophages endometrial cancer extracellular matrix progesterone receptor progestin insensitivity |
| url | https://doi.org/10.1002/cam4.5396 |
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