piR-001773 and piR-017184 promote prostate cancer progression by interacting with PCDH9

Highlights

• PCDH9 was down-regulated and acted as a tumor suppressor in PCa.

• PCDH9 was post-transcriptionally regulated by piR-001773 and piR-017184.

• piR-001773 and piR-017184 were the oncogenic RNAs in PCa.

Abstract

Prostate cancer is one of the most common malignancies and the major cause of cancer-related death in men. Increasing evidence has revealed that P-element-induced wimpy (piwi)-interacting RNAs (piRNAs) play an important role in tumor progression. Few studies have been explored the functional mechanism of piRNAs in prostate cancer progression. In the present study, we demonstrated that piR-001773 and piR-017184 were increased in prostate cancer tissues. Protocadherin 9 (PCDH9) was downregulated and acted as a tumor suppressor in prostate cancer cells. PCDH9 could bind to p85α, the regulatory subunit of PI3K. The downregulation of PCDH9 in PCa cells resulted in an increase in AKT phosphorylation and activity. PCDH9 was posttranscriptionally regulated by piR-001773 and piR-017184. The upregulation of piR-001773 and piR-017184 promoted tumor growth both in vitro and in vivo. In addition, the downregulation of piR-001773 and piR-017184 markedly inhibited tumor growth. In conclusion, these results indicated that piR-001773 and piR-017184 are oncogenic RNAs and thus might be therapeutic targets in prostate cancer.

Introduction

In recent decades, noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long ncRNAs (lncRNAs) have attracted considerable attention in cancer research because of their roles in regulating gene expression and functionally interacting with other molecules [1]. P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are another subclass of small ncRNAs that have been recently recognized to be relevant to cancer biology. An increasing number of studies have shown that aberrant piRNA expression is a signature feature across multiple tumor types [[2], [3], [4]]. Furthermore, the aberrant expression of certain piRNAs and their correlation with prognosis and other clinical features in malignant tissues point to a role for piRNAs in cancer [[5], [6], [7], [8], [9], [10]]. In addition, few studies have explored the molecular mechanism of piRNAs in cancer development and progression [4,11]. Therefore, it would be interesting to identify cancer-related piRNAs and elucidate their mechanisms of action. It has been shown that piRNAs specifically bind to PIWI proteins to form the piRNA-PIWI complexes to recognize and silence complementary sequences [12]. Numerous studies have found that piRNAs regulate posttranscriptional networks to inhibit target RNAs through piRNA-RNA interactions, similar to miRNA mechanisms. These RNAs include mRNAs [13], transcribed pseudogenes [14], and lncRNAs [15].

Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide and a major cause of cancer-related mortality [16]. The number of new PCa cases worldwide was 1.3 million in 2018 [17]. The identification of new biomarkers for PCa diagnosis, therapy decisions and prognosis is urgently needed to realize an individualized precise therapeutic regimen. Since piRNAs are emerging as playing key roles in cancer, we hypothesized that some piRNAs might be implicated in the development and progression of PCa. To examine this hypothesis, we analyzed the expression profile of piRNAs in PCa by small RNA sequencing and then validated them in our clinical PCa tissue samples.

Here, we reported that piR-001773 and piR-017184 were two of the most elevated piRNAs in PCa compared with their adjacent normal tissues and acted as possible oncogenic RNAs. We have revealed a complex molecular mechanism for the function of piR-001773 and piR-017184 in PCa cells both in vitro and in vivo. Furthermore, we also found that the downregulated expression of piR-001773 and piR-017184 had anticancer effects on PCa cells.