The Circular RNA circFGFR4 Facilitates Resistance to Anti-PD-1 of Triple-Negative Breast Cancer by Targeting the miR-185-5p/CXCR4 Axis

Abstract

Purpose One of the most catastrophic malignant tumors is triple negative breast cancer (TNBC). It is characterized by rapid progression in the clinic. CircRNAs are abnormally expressed in almost all cancers and play important roles in tumor immune evasion. Nevertheless, the biological roles of the circular fibroblast growth factor receptor 4 RNA (circFGFR4) in TNBC remain unclear. Methods The expression of circFGFR4 in TNBC tissues and paired nontumor tissues was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The role of circFGFR4 in TNBC immune evasion was estimated by analyzing clinical tissues. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore interaction between circFGFR4 and miR-185-5p. Results Our results indicated that circFGFR4 was significantly overexpressed in TNBC tissues. Upregulated circFGFR4 expression was correlated with decreased CD8 + T cell infiltration in tumor tissues and resistance to anti-programmed cell death 1 (PD-1) immunotherapy in TNBC patients and mice bearing TNBC tumors. Forced circFGFR4 expression inhibited CD8 + T cell infiltration in tissue sections from TNCB tumor bearing mice. Mechanistically, circFGFR4 competitively sponged miR-185-5p and prevented miR-185-5p from decreasing the levels of C-X-C motif chemokine receptor 4 (CXCR4). Conclusion Ultimately, our results indicated that circFGFR4 plays an important role in immune evasion and anti-PD-1 immunotherapy resistance via regulates miR-185-5p/CXCR4 axis in TNBC, thus suggesting that circFGFR4 has significant potential as a biomarker for predicting sensitivity to anti-PD-1 immunotherapy and as an immunotherapeutic target for TNBC.

Circular RNAs in breast cancer diagnosis, treatment and prognosis

“…CircFGFR4 is overexpressed in TNBC. CircFGFR4 acts as a decoy of miR-185-5p and increases the expression of CXCR4, so overexpression of circFGFR4 led to reduced infiltration of CD8+ T cells and enhanced resistance against anti-PD-1 immunotherapy in TNBC [ 68 ]. The circHIPK3 level is elevated and associated with a lower immunotherapy response in breast cancer [ 79 ].…”

MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: targeting PD-1/PD-L1 and CTLA-4 pathways

“…The circular RNA circFGFR4 plays a crucial role in immune evasion and resistance to anti-PD-1 immunotherapy in TNBC by modulating the miR-185-5p/CXCR4 axis. Elevated levels of circFGFR4 were associated with reduced infiltration of CD8 + T cells in tumor tissues and resistance to anti-PD-1 immunotherapy in both TNBC patients and mice with TNBC tumors [ 99 ]. As well as, the binding of miR-149-3p to the 3'UTRs of mRNAs that encode T-cell inhibitor receptors such as PD-1, TIM-3, BTLA, and Foxp1 was predicted in breast cancer.…”

The therapeutic potential of circular RNA in triple-negative breast cancer

“…In addition, CircDUSP1 enhances expression of the disheveled binding antagonist of beta-catenin 2 (DACT2) via miR-761, thereby promoting TNBC sensitivity to paclitaxel [ 40 ] ; circUBE2D2 silences miR-512-3p to enhance CDCA3 to promote doxorubicin resistance in TNBC [ 41 ] ; and CircNCOR1 mediates TNBC radiotherapy resistance via hsa-miR-638 [ 42 ] . At the immune microenvironment level, circFGFR4 promotes TNBC immune evasion and resistance to PD-1 immunotherapy through miR-185-5p [ 43 ] . A number of circRNA-miRNA networks were summarized in Table 1 .…”

“…Using a patient-derived organoid, they revealed that circCREIT overexpression greatly enhanced doxorubicin sensitivity of TNBC cells and demonstrated that this function is mainly achieved by stabilizing PKR [ 97 ] . In addition, circNCOR1 was shown to modulate TNBC radiotherapy resistance [ 42 ] , and circFGFR4 was associated with TNBC immunotherapy resistance [ 43 ] . Although basic research has demonstrated that circRNAs play an important role in TNBC resistance, relevant clinical trials have not yet been performed.…”

“…In terms of drug resistance, it was found that CircEGFR regulates expression of the epidermal growth factor receptor (EGFR) through miR-1299, which in turn promotes TNBC progression and resistance to trastuzumab and pertuzumab in combination with taxanes (THP) therapy [39] . In addition, CircDUSP1 enhances expression of the disheveled binding antagonist of beta-catenin 2 (DACT2) via miR-761, thereby promoting TNBC sensitivity to paclitaxel [40] ; circUBE2D2 silences miR-512-3p to enhance CDCA3 to promote doxorubicin resistance in TNBC [41] ; and CircNCOR1 mediates TNBC radiotherapy resistance via hsa-miR-638 [42] . At the immune microenvironment level, circFGFR4 promotes TNBC immune evasion and resistance to PD-1 immunotherapy through miR-185-5p [43] .…”