Regulation of macrophage plasticity by circCCDC719-13 through HSP90 inhibition suppresses prostate cancer progression and metastasis: a translational study

Bisheng Cheng; Jianghua Yang; Wenxue Huang; Tianlong Luo; Lingfeng Li; Jilin Wu; Qianghua Zhou; Ruilin Zhuang; Qiong Wang; Kewei Xu; Peng Wu; Hai Huang

doi:10.1097/JS9.0000000000002895

Regulation of macrophage plasticity by circCCDC719-13 through HSP90 inhibition suppresses prostate cancer progression and metastasis: a translational study

Int J Surg. 2025 Jun 27. doi: 10.1097/JS9.0000000000002895. Online ahead of print.

Authors

Bisheng Cheng^{1

2}, Jianghua Yang², Wenxue Huang¹, Tianlong Luo², Lingfeng Li², Jilin Wu³, Qianghua Zhou⁴, Ruilin Zhuang², Qiong Wang¹, Kewei Xu², Peng Wu¹, Hai Huang^{2

5

6

7}

Affiliations

¹ Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Urology, Peking University People's Hospital, Beijing, China.
⁴ Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁵ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
⁶ Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
⁷ Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, Guangdong, China.

PMID: 40576192
DOI: 10.1097/JS9.0000000000002895

Abstract

Background: Macrophages play a crucial role in cancer development by differentiating into M1 or M2 phenotypes with opposing functions.The conversion of M2 to M1 macrophages has significant implications in cancer treatment. Non-coding RNA, such as circRNA and lncRNA, have been shown to regulate macrophage polarization by specific pathways.However, the molecular mechanism of this conversion process is still not fully understood.

Method: In this study, we investigated the role of circCCDC719-13 in regulating macrophage polarization in prostate cancer (PCA). We examined the expression level of circCCDC719-13 in tumor-associated macrophages (TAMs) and M2 macrophages in PCA.We used in vitro experiments to investigate the effects of transfection of circCCDC719-13 overexpression Lentivirus on M2 polarization and the expression level of M2 cytokines.We also assessed the ability of TAM to promote malignant behavior in PCA cells.Furthermore,we explored the downstream target of circCCDC719-13 and its role in macrophage polarization.

Results: We found that circCCDC719-13 was significantly lower in TAMs and M2 macrophages in PCA. Overexpression of circCCDC719-13 inhibited M2 polarization and downregulated the expression level of M2 cytokines.Overexpression of circCCDC719-13 also reduced the ability of TAM to promote malignant behavior in PCA cells.Our study demonstrated that HSP90 was a downstream target of circCCDC719-13, which could regulate macrophage polarization based on inhibition of ferroptosis. Overexpression of HSP90 restored the phenotype of circCCDC719-13 overexpressing macrophages. CircCCD719-13 overexpression of TAMs inhibited the growth and metastasis of PC3M cells.

Conclusions: Our findings suggest that circCCDC719-13 may alter macrophage polarization by inducing ferroptosis and targeting HSP90, which can decrease the ratio of M2 phenotype TAMs and inhibit the progression and metastasis of PCA. The results of this study provide new insights for clarifying the molecular mechanism of macrophage polarization and have reference value for targeted treatment of PCA.

Keywords: ferroptosis; prostate cancer; tumour microenvironment; tumour-associated macrophages.