Document Type
Article
Publication Date
1-1-2024
Abstract
Background: Cancer cells are intimately intertwined with tumor microenvironment (TME), fostering a 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.
Publication Title
Theranostics
Volume
14
Issue
17
First Page
6543
Last Page
6559
PubMed ID
39479456
Recommended Citation
Li, Meiqian; Cui, Yangyan; Qi, Qi; Liu, Jiakuan; Li, Jiaxuan; Huang, Guifang; Yang, Jiale; Sun, Jingya; Ma, Zhihui; Liang, Shengjie; Zhang, Dianzheng; Jiang, Jun; Zhu, Rujian; Liu, Qiuli; Huang, Ruimin; and Yan, Jun, "SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1." (2024). PCOM Scholarly Works. 2283.
https://digitalcommons.pcom.edu/scholarly_papers/2283
DOI: https://doi.org/10.7150/thno.101575
Comments
This article was published in Theranostics, Volume 14, Issue 17, pages 6543-6559.
The published version is available at https://doi.org/10.7150/thno.101575.
Copyright © 2024 The author(s). CC BY 4.0.