HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk.
Hengyu LiPinghua YangJingHan WangJin ZhangQianyun MaYingjie JiangYani WuTao HanDaimin XiangPublished in: Journal of hematology & oncology (2022)
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.
Keyphrases
- transforming growth factor
- induced apoptosis
- cell cycle arrest
- cell death
- cell proliferation
- epithelial mesenchymal transition
- signaling pathway
- adipose tissue
- poor prognosis
- bone marrow
- stem cells
- case report
- acute myeloid leukemia
- transcription factor
- risk assessment
- long non coding rna
- cell cycle
- single cell
- climate change
- smoking cessation
- cancer stem cells