Sulfatase 2 Affects Polarization of M2 Macrophages through the IL-8/JAK2/STAT3 Pathway in Bladder Cancer

Wentao Zhang; Fuhan Yang; Zongtai Zheng; Cheng Li; Shiyu Mao; Yuan Wu; Ruiliang Wang; Junfeng Zhang; Yue Zhang; Hong Wang; Wei Li; Jianhua Huang; Xudong Yao

doi:10.3390/cancers15010131

Sulfatase 2 Affects Polarization of M2 Macrophages through the IL-8/JAK2/STAT3 Pathway in Bladder Cancer

Cancers (Basel). 2022 Dec 26;15(1):131. doi: 10.3390/cancers15010131.

Authors

Wentao Zhang^{1

2}, Fuhan Yang^{1

2}, Zongtai Zheng^{1

2}, Cheng Li^{1

2}, Shiyu Mao^{1

2}, Yuan Wu³, Ruiliang Wang^{1

2}, Junfeng Zhang^{1

2}, Yue Zhang⁴, Hong Wang^{1

2}, Wei Li^{1

2}, Jianhua Huang^{1

2}, Xudong Yao^{1

2}

Affiliations

¹ Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200070, China.
² Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai 200070, China.
³ Department of Urology, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, China.
⁴ Department of Central Laboratory, Clinical Medicine Scientific and Technical Innovation Park, Shanghai Tenth People's Hospital, Shanghai 200435, China.

Abstract

Sulfatase 2 (SULF2) affects the occurrence and development of cancer by regulating HSPG-binding factors. However, the mechanism of SULF2 in bladder cancer (BCa) is unknown. To determine this, we analyzed the RNA sequencing of 90 patients with BCa. The results showed that the expression of SULF2 was closely related to the prognosis of BCa. Moreover, in vivo and in vitro experiments revealed that SULF2 promotes tumor proliferation and invasion. Furthermore, using a mouse orthotopic BCa model and flow cytometric analysis, we identified that SULF2 affects the polarization of macrophages. Mechanism studies clarified that SULF2 promoted the release of HSPG-binding factors, such as IL-8, in the microenvironment through β-catenin. Meanwhile, IL-8 activated the JAK2/STAT3 pathway of macrophages to promote the expression of CD163 and CD206, thereby regulating the polarization of macrophages to the M2-type. Conclusively, these results indicate that SULF2 plays an important role in regulating the microenvironment of BCa and promotes the polarization of macrophages to the M2-type by secreting IL-8, which further deepens the malignant progression of BCa.

Keywords: SULF2; bladder cancer; macrophages.

Grants and funding

This research was supported by National Natural Science Foundation of China, Youth Project (#81602469; #82101838), the General Project of Shanghai Natural Science Foundation of China (#20ZR1443000), and the Experimental Animal Fund of Shanghai Science and Technology Commission (#22140903800).