PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a

Xiaojia Huang,Xiaofang Guo,Xinhua Xie,Xiaoming Xie,Hailin Tang,Zhi Tian,Hua Wang,Lijuan Zhang,Xiangsheng Xiao,Lu Yang

doi:10.1186/s13046-017-0593-2

Abstract

BackgroudThe purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a.MethodsWestern blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3’UTR and LDHA 3’UTR and miR-34a in TNBC.ResultsWe found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3’UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC.ConclusionsThis study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC.

Highlights

Programmed death ligand 1 (PDL1) is highly expressed on the surface of a variety of cancer cells
PDL1 Is highly expressed in triple negative breast cancer (TNBC) and correlated with a poor outcome We used quantitative RT-PCR (qRT-PCR) analysis and Western blotting to detect the expression of PDL1 in seven different mammary cell lines, including the human mammary epithelial (HME) cell line MCF-10A and six TNBC cell lines
The results showed that compared with MCF-10A cells, PDL1 was upregulated in TNBC cell lines, especially in HCC38 and MDA-MB-231 cells (Fig. 1a)

Summary

Introduction

Programmed death ligand 1 (PDL1) is highly expressed on the surface of a variety of cancer cells. It is well known that PDL1 inhibits the proliferation and function of tumor-infiltrating lymphocytes (TILs), leading to an immunosuppressive environment in cancers [1,2,3,4]. There is still not enough evidence regarding the Altered energy metabolism is common in cancer cells and has been regarded as a hallmark of cancer [5]. Oncogene-induced metabolic reprogramming fuels the growth and proliferation of cancer cells [6]. Lactate dehydrogenase A (LDHA) is a glycolytic enzyme that is essential for cancer energy metabolism, and it is highly expressed in cancer cells and correlated with poor survival [7]. Inhibition of LDHA has an anti-proliferative effect on cancer cells. The expression pattern and functions of LDHA in TNBC are still not clear

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