Expression of Treg-associated lncRNAs in breast cancer

Elsevier

Available online 7 December 2022, 154270

Pathology - Research and PracticeAuthor links open overlay panelAbstract

Regulatory T cells (Tregs) have important functions in tumor microenvironment, particularly for induction of immune evasion. In order to find the underlying mechanism of dysregulation of Tregs in breast cancer tissues, we designed the current study to appraise expression of five Treg-related long non-coding RNAs (lncRNAs), namely FLICR (FOXP3 Regulating Long Intergenic Non-Coding RNA), NEST (IFNG-AS1), RMRP (RNA Component of Mitochondrial RNA Processing Endoribonuclease), MAFTRR (MAF Transcriptional Regulator RNA) and TH2-LCR (Th2 Cytokine Locus Control Region) in paired breast cancer and nearby noncancerous tissues. Expression levels of RMRP, TH2-LCR, MAFTRR and GATA3-AS1 were significantly higher in breast cancer samples compared with non-tumoral tissues. The calculated AUC values for GATA3-AS1, TH2-LCR, RMRP and MAFTRR were 0.66, 0.63, 0.63 and 0.60, respectively. There were significant positive associations between expression level of RMRP gene in tumor tissues and nuclear grade, tubule formation and tumor sizes. In addition, there was a significant positive association between expression levels of MAFTRR genes in tumor tissues and nuclear grade. Besides, expression levels of FLICR were different among tumors with different levels of HER2/neu receptor. Taken together, Treg-associated lncRNAs might contribute to the pathogenesis of breast cancer.

Introduction

Breast cancer is a malignancy with high frequency among women [16]. This type of cancer is associated with extensive cellular and molecular heterogeneity and vast numbers of molecular procedures contributing to cell growth, differentiation, proliferation, invasion, and metastasis [3]. A bulk of evidence has highlighted the importance of a subpopulation of T cells, named T regulatory cells (Tregs) in the progression of breast cancer [13], [18]. These cells contribute to the maintenance of tolerance to self-antigens [7]. In fact, Forkhead box P3 (FoxP3)-expressing Tregs have a crucial role in suppression of unwanted immune responses. In comparison to other subpopulations of T cells, Tregs have high reactivity to the selecting ligands in the thymus even following negative selection by the ligands [7]. It has become evident that the host immune responses contribute to the immune surveillance and demolition of cancer cells [14]. The presence of Tregs in the tumor microenvironment influences the immune responses to breast cancer cells and is implicated in the subsequent immunopathogenesis. Tumor-residing Treg cells have been shown to exert potent suppressive effects and their transcript signature resembles that of normal breast tissues, but differs from activated circulatory Tregs [13]. However, expression profile of some cytokine and chemokine receptor genes has been found to be different between tumor-resident and normal tissue residing Tregs [13].

It has also been evident that non-coding RNAs can modulate function and differentiation of Tregs [12]. Aberrant expression of non-coding RNAs is also implicated in the etiology of conditions that are linked with the activation of Tregs. In order to find the underlying mechanism of dysregulation of Tregs in breast cancer tissues, we intended to appraise expression of five Treg-related long non-coding RNAs (lncRNAs), namely FLICR (FOXP3 Regulating Long Intergenic Non-Coding RNA), NEST (IFNG-AS1), RMRP (RNA Component of Mitochondrial RNA Processing Endoribonuclease), MAFTRR (MAF Transcriptional Regulator RNA) and TH2-LCR (Th2 Cytokine Locus Control Region) in paired breast cancer and nearby noncancerous tissues.

Section snippetsSelection of lncRNAs

Treg-related lncRNAs were selected through a literature-based approach as described previously [1], [4].

Patients

A total of 40 patients with approved diagnosis of breast cancer were enlisted in the present study. Expressions of Treg-related lncRNAs were estimated in breast tumors and nearby non-tumoral specimens. Tissue specimens were obtained from Farmanieh and Sina hospitals, Tehran, Iran during 2017-2020. All samples were quickly frozen in liquid nitrogen and transported to Medical Genetic Lab. Then,

Results

Table 2 shows the information about studied genes.

The study included 40 patients with breast cancer. Clinicopathological features of cases are shown in Table 3.

There was significant difference in expression of all lncRNAs between tumoral and non-tumoral tissues, except for FLICR and NEST whose expression were not different between these two types of tissues (Fig. 1).

Expression levels of RMRP, TH2-LCR, MAFTRR and GATA3-AS1 were significantly higher in breast cancer samples compared with

Discussion

Tregs have immunosuppressive properties and act in favor of progression of breast cancer [2], [21]. Thus, identification of the mechanism of dysregulation of this subpopulation of T cells has practical significance in the management of this kind of cancer. The present study aimed at evaluation of expression of five Treg-related lncRNAs in breast cancer tissues. Expression levels of RMRP, TH2-LCR, MAFTRR and GATA3-AS1 were significantly higher in breast tumors compared with non-tumoral tissues.

Ethics approval and consent to Participant

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent forms were obtained from all study participants. The study protocol was approved by the ethical committee of Shahid Beheshti University of Medical Sciences (IR.SBMU.RETECH.REC.1400.045). All methods were performed in

Funding

Not applicable.

Authors’ contributions

SGF wrote the draft and revised it. MT and EJ designed and supervised the study. BMH, LMR, MD, MFR and AG collected the data and designed the figures and tables. SE analyzed the data. All the authors read the submitted version and approved it.

Competing Interest

The authors declare they have no conflict of interest

Acknowledgement

The authors would like to thank the clinical Research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their support, cooperation and assistance throughout the period of study (Grant Number 4300920).

Consent of publication

Not applicable

References (21)

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