Volume 240, December 2022, 154198Abstract

Atraric acid (AA) is a natural compound used for treatment of benign prostate hyperplasia. This agent has an anti-androgen receptor (AR) activity suppressing androgen-mediated neo-angiogenesis. In the current study, we have analyzed the transcriptome data of prostate cancer cells treated with AA (GSE172205) to find differentially expressed genes (DEGs) with an especial focus on lncRNAs and miRNAs. Then, we assessed expression of the differentially expressed lncRNAs (DElncRNAs) in available online sources to validate their association with prostate cancer and their importance in the determination of survival of patients with this type of cancer. We obtained 1871 DEGs, including 914 down-regulated DEGs (such as DAB1 and CD200) and 957 up-regulated DEGs (such as CHRNA2 and TRGC1), and 25 DElncRNAs, including 15 down-regulated DElncRNAs (such as LINC00639 and HOTTIP) and 10 up-regulated DElncRNAs (such as LINC00844 and LINC00160), and one up-regulated DEmiRNA (MIR29B1). The main pathways for the down-regulated genes and the up-regulated genes were Axon Guidance and Steroid BioSynthesis, respectively. Taken together, AA has been found to affect expression of several lncRNAs which are possibly involved in the pathoetiology of prostate cancer.

Introduction

Atraric acid (AA) is a natural compound extracted from the African tree Pygeum africanum. This agent is used as a medication for treatment of benign prostate hyperplasia [4]. Moreover, it has been shown to be an androgen receptor (AR) antagonist [20]. More recently, AA has been found to suppress androgen-mediated neo-angiogenesis through a VEGF-independent mechanism that involves angiopoietin 2 [5]. Besides, this compound could inhibit cell growth of castration-resistant prostate cancer (CRPC) [5]. Mechanistically, AA not only suppresses activity of the wild-type AR, but also inhibits AR mutants that facilitate resistance to other antagonists of AR possibly though inhibition of the binding of androgens to AR [5]. Furthermore, transcriptome analysis of a CRPC cell line has shown differential expression of a number of genes upon treatment treated with AA. Detailed analyses have shown the regulatory effect of AA on the retinoblastoma protein (pRb) pathway. In addition, AA could alter expression signature of genes in the reverse way of androgen [5].

AR has functional interactions with a number of non-coding RNAs (ncRNAs) with different sizes ranging from microRNAs (miRNAs) to long ncRNAs (lncRNAs) [23]. These interactions are functionally involved in the pathophysiology of human disorders, particularly prostate cancer [23]. In the current study, we have re-analyzed the transcriptome data of prostate cancer cells treated with AA (GSE172205) to find differentially expressed genes (DEGs) with an especial focus on lncRNAs and miRNAs. Then, we assessed expression of the differentially expressed lncRNAs (DElncRNAs) in available online sources to validate their association with prostate cancer and their importance in the determination of survival of patients with this type of cancer.

Section snippetsRNA-seq data collection

We used the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) to find the RNA-seq raw counts of GSE172205 (Illumina NextSeq 500 (Homo sapiens)), which contained 12 samples. Three R1881 (1 nm) samples and three AA samples were chosen for further study.

Dataset quality assessment

In Rstudio software (version 4.0.4), we imported the dataset and assessed its quality. This step involves examining the Euclidean distance of the samples using the Pheatmap package, performing principal component analysis,

Dataset quality assessment

Fig. 1. shows the boxplot of normalized data and Cook’s distance measured for each sample.

Fig. 2 shows the Euclidean distances between the samples as calculated from the regularized log transformation (rlog).

In PCA plot (Fig. 3), the selected 12 samples are shown in the 2D plane spanned by their first two principal components (PC1 and PC2). According to this plot, the AA samples and R1881 samples have the highest variation relative to each other.

The dispersion estimate plot (Fig. 4) shows the

Discussion

AR signaling has an important oncogenic effect in prostate cancer. In fact, the core approaches for treatment of this malignancy are based on controlling AR activity [1]. Acquired resistance to androgen deprivation therapy is the main obstacle in the treatment of this kind of cancer resulting in significant mortality and morbidity [19]. Therefore, identification of the molecular mechanisms of resistance to androgen deprivation therapy would facilitate design of novel therapeutic targets for

Conflict of 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.

Author’s statement

SGF wrote the draft and revised it. MT designed and supervised the study. AS, FR and BMH performed the bioinformatic analysis and designed the figure and tables.

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