SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1
文献类型：期刊论文
| 作者 | Li, Meiqian1,2,8; Cui, Yangyan2; Qi, Qi8; Liu, Jiakuan1,8; Li, Jiaxuan3; Huang, Guifang4; Yang, Jiale4,7; Sun, Jingya4; Ma, Zhihui4; Liang, Shengjie1,8 |
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2024 |
| 卷号 | 14期号:17页码:6543-6559 |
| 关键词 | SPOP bladder cancer tumor-associated macrophage STAT3/CCL2/IL-6 axis VEZF1 |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.101575 |
| 通讯作者 | Zhu, Rujian(tzzhurj@163.com) ; Liu, Qiuli(liuqiuli900827@163.com) ; Huang, Ruimin(rmhuang@simm.ac.cn) ; Yan, Jun(yan_jun@fudan.edu.cn) |
| 英文摘要 | Background: Cancer cells are intimately intertwined with tumor microenvironment (TME), fostering symbiotic relationship propelling cancer progression. However, the interaction between cancer cells and tumor-associated macrophages (TAMs) in urothelial bladder cancer (UBC) remains poorly understood. Methods: UBC cell lines (5637, T24 and SW780), along with a monocytic cell line (U937) capable of differentiating into macrophage, were used in a co-culture system for cell proliferation and stemness by MTT, sphere formation assays. VEZF1/SPOP/STAT3/CCL2/ IL-6 axis was determined by luciferase reporter, ChIP, RNA-seq, co-IP, in vitro ubiquitination, RT-qPCR array and ELISA analyses. Results: We observed the frequent downregulation of SPOP, an E3 ubiquitin ligase, was positively associated with tumor progression and TAM infiltration in UBC patients and T24 xenografts. Cancer cell-TAM crosstalk promoting tumor aggressiveness was demonstrated dependent on SPOP deficiency: 1) In UBC cells, STAT3 was identified as a novel substrate of SPOP, and SPOP deficiency increased STAT3 protein stability, elevated chemokine CCL2 secretion, which induced chemotaxis and M2 polarization of macrophage; 2) In co-cultured macrophages, IL-6 secretion enhanced UBC cell proliferation and stemness. Additionally, transcription factor VEZF1 could directly activate SPOP transcription, and its overexpression suppressed the above effects in UBC cells. Conclusions: A pivotal role of SPOP in maintaining UBC stemness and remodeling immunosuppressive TME was revealed. Both the intrinsic signaling (dysregulated VEZF1/SPOP/STAT3 axis) and the extrinsic cues from TME (CCL2-IL-6 axis based on macrophages) promoted UBC progression. Targeting this crosstalk may offer a promising therapeutic strategy for UBC patients with SPOP deficiency. |
| WOS关键词 | TUMOR-ASSOCIATED MACROPHAGES ; STEMNESS ; NICHE ; DEGRADATION ; EXPRESSION ; RECEPTOR |
| 资助项目 | National Natural Science Foundation[82073234] ; National Natural Science Foundation[81872373] ; National Natural Science Foundation[82172001] ; Shanghai Municipal Science and Technology Major Project[21S11900600] ; Shanghai Municipal Science and Technology Major Project[21140903700] ; Project of Shanghai Municipal Health Commission[202140267] ; Project of Key Medical Specialty and Treatment Center of Pudong Hospital of Fudan University[Zdzk2020-01] ; Talents Training Program of Shanghai Pudong Hospital[LJ202203] ; Outstanding Leaders Training Program of Pudong Health Committee of Shanghai[PWRl2023-04] |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001358116700006 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314589]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhu, Rujian; Liu, Qiuli; Huang, Ruimin; Yan, Jun |
| 作者单位 | 1.Fudan Univ, Shanghai Pudong Hosp, Dept Urol, Pudong Med Ctr, Shanghai 201399, Peoples R China 2.Nanjing Univ, MOE Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing 210061, Peoples R China 3.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Sch Publ Hlth, Shanghai 200032, Peoples R China 4.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 5.Army Med Univ, Daping Hosp, Dept Urol, Chongqing 400042, Peoples R China 6.Philadelphia Coll Osteopath Med, Dept Biomed Sci, Philadelphia, PA 19131 USA 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 8.Fudan Univ, Lab Anim Ctr, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Meiqian,Cui, Yangyan,Qi, Qi,et al. SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1[J]. THERANOSTICS,2024,14(17):6543-6559. |
| APA | Li, Meiqian.,Cui, Yangyan.,Qi, Qi.,Liu, Jiakuan.,Li, Jiaxuan.,...&Yan, Jun.(2024).SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1.THERANOSTICS,14(17),6543-6559. |
| MLA | Li, Meiqian,et al."SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1".THERANOSTICS 14.17(2024):6543-6559. |
入库方式： OAI收割
来源：上海药物研究所
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