1. Academic Validation
  2. A novel STAT3/ NFκB p50 axis regulates stromal-KDM2A to promote M2 macrophage-mediated chemoresistance in breast cancer

A novel STAT3/ NFκB p50 axis regulates stromal-KDM2A to promote M2 macrophage-mediated chemoresistance in breast cancer

  • Cancer Cell Int. 2023 Oct 11;23(1):237. doi: 10.1186/s12935-023-03088-1.
Jia-Shing Chen 1 Yu-Ning Teng 2 3 Cheng-Yi Chen 4 Jing-Yi Chen 5 6
Affiliations

Affiliations

  • 1 School of Medicine for International Students, College of Medicine, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung, 82425, Taiwan.
  • 2 School of Medicine, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung, 82445, Taiwan ROC.
  • 3 Department of Pharmacy, E-Da Cancer Hospital, 21 Yida Road, Kaohsiung, 82445, Taiwan ROC.
  • 4 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan ROC.
  • 5 School of Medicine for International Students, College of Medicine, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung, 82425, Taiwan. JingYi62@gmail.com.
  • 6 Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, No.8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung, 82425, Taiwan ROC. JingYi62@gmail.com.
Abstract

Background: Lysine Demethylase 2A (KDM2A) plays a crucial role in Cancer cell growth, differentiation, metastasis, and the maintenance of Cancer stemness. Our previous study found that cancer-secreted IL-6 can upregulate the expression of KDM2A to promote further the transition of cells into cancer-associated fibroblasts (CAFs). However, the molecular mechanism by which breast cancer-secreted IL-6 regulates the expression of KDM2A remains unclear. Therefore, this study aimed to elucidate the underlying molecular mechanism of IL-6 in regulating KDM2A expression in CAFs and KDM2A-mediated paclitaxel resistance in breast Cancer.

Methods: The ectopic vector expression and biochemical inhibitor were used to analyze the KDM2A expression regulated by HS-578 T conditioned medium or IL-6 in mammary fibroblasts. Immunoprecipitation and chromatin immunoprecipitation assays were conducted to examine the interaction between STAT3 and NFκB p50. M2 macrophage polarization was assessed by analyzing M2 macrophage-specific markers using flow cytometry and RT-PCR. ESTIMATE algorithm was used to analyze the tumor microenvironment-dominant breast Cancer samples from the TCGA database. The correlation between stromal KDM2A and CD163 + M2 macrophages was analyzed using the Pearson correlation coefficient. Cell viability was determined using trypan blue exclusion assay.

Results: IL-6 regulates gene expression via activation and dimerization of STAT3 or collaboration of STAT3 and NFκB. However, STAT3, a downstream transcription factor of the IL-6 signaling pathway, was directly complexed with NFκB p50, not NFκB p65, to upregulate the expression of KDM2A in CAFs. Enrichment analysis of immune cells/stromal cells using TCGA-breast Cancer RNA-seq data unveiled a positive correlation between stromal KDM2A and the abundance of M2 macrophages. CXCR2-associated chemokines secreted by KDM2A-expressing CAFs stimulated M2 macrophage polarization, which in turn secreted CCL2 to increase paclitaxel resistance in breast Cancer cells by activating CCR2 signaling.

Conclusion: This study revealed the non-canonical molecular mechanism of IL-6 secreted by breast Cancer upregulated KDM2A expression in CAFs via a novel STAT3/NFκB p50 axis, which STAT3 complexed with NFκB p50 in NFκB p50 binding motif of KDM2A promoter. KDM2A-expressing CAFs dominantly secreted the CXCR2-associated chemokines to promote M2 macrophage polarization and enhance paclitaxel resistance in breast Cancer. These findings underscore the therapeutic potential of targeting the CXCR2 or CCR2 pathway as a novel strategy for paclitaxel-resistant breast Cancer.

Keywords

Cancer-associated fibroblasts; Lysine demethylase 2A; Paclitaxel resistance; Tumor-associated macrophage.

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