MiR-873/PD-L1 axis regulates the stemness of breast cancer cells

Abstract

Background Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear. Methods Lentivirus infection was used to construct stable cell lines. The correlation between PD-L1 and stemness markers expression was evaluated in clinical samples. Additionally, luciferase reporter assay combined with RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were used to verify the direct binding of miR-873 on PD-L1. Furthermore, flow cytometry, mammosphere formation combined with nude mouse tumor xenograft model were carried out to examine the effects of miR-873/PD-L1 axis on the stemness of breast cancer cells. Finally, MTT assay was performed to determine the effects of miR-873/PD-L1 axis on drug resistance. Findings PD-L1 expression was positively correlated with the expression of stemness markers, and overexpression of PD-L1 contributed to chemoresistance and stemness-like properties in breast cancer cells via activating PI3K/Akt and ERK1/2 pathways. Mechanistically, miR-873 inhibited PD-L1 expression through directly binding to its 3′-untranslated region (UTR), and miR-873 attenuated the stemness and chemoresistance of breast cancer cells which was dependent on PD-L1 and the downstream PI3K/Akt and ERK1/2 signaling. Notably, the promotion of PD-L1 on the stemness and chemoresistance was enhanced by recombinant PD-1 (rPD-1), this effect was attenuated by PD-1/PD-L1 inhibitor. Interpretation miR-873/PD-L1 regulatory axis might serve as a therapeutic target to enhance the chemo-sensitivity and eliminate the stemness of breast cancer cells. Fund This work was supported by the National Nature Science Foundation of China, No. 81702957, China Postdoctoral Science Foundation, No. 2017M620230, the Postdoctoral Research Funding Scheme of Jiangsu Province (2017), No. 1701197B, and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

“…miR-873 attenuated both the stemness and chemoresistance of BC cells via direct targeting of PD-L1, thus inactivating downstream PI3K/Akt and ERK1/2 signaling. It is notable that compared with the results of Akt/ERK1/2 inhibitors, the results of miR-873/PD-L1 in decreasing the cancer stemness are much more effective, indicating that there must be other pathways involved in the miR-873/PD-L1 axis for CSC generation [71].…”

The role of cancer-derived microRNAs in cancer immune escape

“…Increased immune checkpoint ligands especially PD-L1 is closely related with cancerassociated miRNA expression pattern. To be more specific, previous studies have indicated that the loss of miR-3609, miR-195-5p, miR-148a-3p, miR-873, miRNA-497-5p, miR-191-5p, miR-34a, and miR-138 closely correlated with the increased PD-L1 expression on numerous cancer cells [86][87][88][89][90][91][92][93][94]. In addition, Dong et al found that decreased miR-140, miR-142, miR-340, and miR-383 enormously elevated PD-L1 expression on cervical cancer cells [95].…”

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies

“…PD-L1 in CSCs also confers immune evasion, thereby sustaining the tumorigenesis of CSCs [141]. Recently, miR-873-5p was shown to target PD-L1, thus attenuating breast cancer stemness [142] (Table 4).…”

“…Over-expression of miR-145-5p sensitizes cells to cisplatin and 5-fluorouracil in gastric cancer. This miRNA also enhances the efficacy of radiation and oxaliplatin [144,145] miR-186-5p YY1 Glioblastoma Ectopic expression of miR-186-5p improves the cisplatin cytotoxicity [149] miR-195-5p NOTCH2, RBPJ Colorectal cancer Over-expression of miR-195-5p subdues resistance to 5-fluorouracil [126] miR-196-5p SOCS1, SOCS3 Colorectal cancer Knockdown of miR-196-5p sensitizes cancer cells to 5-fluorouracil by augmenting apoptosis [129] miR-324-5p SMO, GLI1 Multiple myeloma Over-expression of miR-324-5p heightens the efficacy of bortezomib in multiple myeloma cells [135] miR-381-3p NEFL Glioblastoma Silencing of miR-381-3p increases the sensitivity of cells to temozolomide [150] miR-423-5p ING4 Glioblastoma Over-expression of miR-423-5p significantly attenuates the chemosensitivity of glioma cells to temozolomide [137] miR-450b-5p SOX2 Colorectal cancer Ectopic expression of miR-450b-5p sensitizes cells to 5-fluorouracil [143] miR-589-5p SOCS2, SOCS5, PTPN1, PTPN11 Hepatocellular carcinoma Ectopic expression of miR-589-5p promotes the emergence of acquired resistance to doxorubicin [131] miR-873-5p PD-L1 Breast cancer Over-expression of miR-873-5p attenuates therapeutic resistance to doxorubicin [142] miR-1246 CCNG2 Oral cancer Knockdown of miR-1246 sensitizes cancer cells to cisplatin [117]…”