HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk

Journal of Hematology & Oncology

Yani Wu¹  Hengyu Li¹  Jin Zhang²  Pinghua Yang²  JingHan Wang³  Tao Han⁴  Yingjie Jiang⁵  Qianyun Ma⁶  Daimin Xiang⁷ 

[1] Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, 230 Changhai Road, 200433, Shanghai, China;Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, 200438, Shanghai, China;Department of Hepatic Surgery, Third Affiliated Hospital of Naval Military Medical University, 200438, Shanghai, China;Department of Hepatobiliary Surgery, East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China;Department of Oncology, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, 110001, Shenyang, China;Department of Pathology, Changhai Hospital, Naval Military Medical University, 200433, Shanghai, China;Department of Urology Surgery, Changhai Hospital, Naval Military Medical University, 200433, Shanghai, China;State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xietu Road, 200127, Shanghai, China;

关键词: Triple-negative breast cancer;    Tumor-associated macrophages;    TGF-β1/SMAD3/HLF/IL-6/JAK2/STAT3 pathway;    GGT1;    Ferroptosis;   

DOI  :  10.1186/s13045-021-01223-x

来源: Springer

【 摘 要 】

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment (TME) which are closely associated with the tumor malignant progression. However, the regulatory mechanisms by which TAMs influence the progression of triple-negative breast cancer (TNBC) remain unclear. Here, we report that hepatic leukemia factor (HLF) acts as a novel oncoprotein in TNBC. We found that HLF was regulated by transforming growth factor-beta1 (TGF-β1) that is secreted by TAMs. Then, HLF transactivated gamma-glutamyltransferase 1 (GGT1) to promote the ferroptosis resistance, thus driving TNBC cell proliferation, metastasis and cisplatin resistance. Reciprocally, IL-6 produced by TNBC cells activated the JAK2/STAT3 axis to induce TGF-β1 secretion by TAMs, thus constituted a feed-forward circuit. The accuracy of TNBC patient prognosis could be improved by employing a combination of HLF and GGT1 values. Thus, our findings document that the interactive dialogue between TNBC cells and TAMs promotes sustained activation of HLF in tumor cells through the IL-6-TGF-β1 axis. Subsequently, HLF promotes the ferroptosis resistance in TNBC cells via GGT1 and ultimately facilitates the malignant tumor progression. Our study provides a potential target for the treatment of TNBC.

【 授权许可】

CC BY