HIF1α Regulates IL17 Signaling Pathway Influencing Sensitivity of Taxane-Based Chemotherapy for Breast Cancer

Abstract

Hypoxia-induced chemotherapy resistance is the main hindrance for solid tumor treatment. Hypoxia inducible factor-1α (HIF1α), an adaptive gene of hypoxia condition, played an important role in affecting chemotherapy sensitivity for many cancer types and various therapeutic regimens. This study focused on the impact of HIF1α on predicting response and survival of taxane-based neoadjuvant therapy (NAT) for breast cancer (BC) patients and the concrete mechanism that HIF1α mediated paclitaxel chemo-insensitivity. We evaluated HIF1α expression immunohistochemically from biopsies of 108 BC patients receiving paclitaxel–cisplatin NAT. Univariate and multivariate logistic regression analysis revealed that high HIF1α expression led to lower rate of pathological complete response (pCR) and worse prognosis. Analysis of GEO datasets also indicated negative association between HIF1α expression and response of taxane-based NAT in BC patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of differential expression genes (DEGs) in different HIF1α expression groups from TCGA database showed that HIF1α participated in interleukin 17 (IL-17) signaling pathway. Correlation analysis suggested that HIF1α was positively related to the IL-17 pathway. CXC motif chemokine ligand 10 (CXCL10) was the only DEG in the IL-17 pathway inversely relating to NAT response. Experiments in vitro verified that HIF1α/IL-17 pathway influences paclitaxel sensitivity to BC cells. Correlation analysis between HIF1α/IL-17A/CXCL10 and infiltration of immune cells in BC uncovered that high expression of all the above three genes were positively correlated to neutrophil infiltration in BC. Collectively, our findings shed novel insight into the mechanism of chemotherapy resistance and implied that HIF1α inhibitor may be a promising drug combined with traditional chemotherapeutic drug to increase the chemotherapy efficacy.

Identification of immune-related biomarkers for predicting neoadjuvant chemotherapy sensitivity in HER2 negative breast cancer via bioinformatics analysis

“…For example, changes in gene expression levels and DNA methylation silencing key genes can inhibit related signaling pathways, leading to drug resistance in BC (21,22). There is much evidence to show (28). The results of our study also revealed that CXCL10 is highly expressed in pCR patients, indicating that a higher expression level of CXCL10 may result in pCR in BC patients.…”

Comprehensive analysis of Linc01436 for neoadjuvant chemotherapy response and its potential enriched pathways in breast cancer

“…Intracellular response to hypoxia is mainly mediated by Hypoxia-inducible factors-1α and -2α (HIF-1α and HIF-2α). Our previously study proved that HIF-1α expression is reversely associated with paclitaxel-based NAC response and HIF-1α could lead to paclitaxel chemoresistance in vitro experiments [27].Therefore, we postulate that HIF-1α might possibly drive Lin01436 expression. Jiao et al reported that Linc01436 could upregulate the expression of MAPK1,Which is known as ERK2, a member of the Ras/Raf/ERK signaling pathway [28].…”

Role of androgen receptor signaling pathway-related lncRNAs in the prognosis and immune infiltration of breast cancer

“…Results from KEGG functional enrichment analysis revealed a close association between the IL-17 signaling pathway and the progression of BRCA. It was also observed that HIF1α could influence the sensitivity of patients toward paclitaxel chemotherapy by regulating the IL17 signaling pathway 36 . Enhanced PD-1/PD-L1 expression was associated with the upregulation of the IL-17 signaling pathway-related genes, and the improved IL-17 signaling was found to be associated with the elevated extents of CD8+ T cell infiltration and changes in TME in patients with BRCA 37 .…”