PiRNA-based Cancer Therapeutics



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PiRNA-based Cancer Therapeutics

As a class of noncoding small RNA of 24-32 nucleotides, piRNAs are mainly known as "repeat associated small interfering RNAs (rasiRNAs)". But due to their interaction with PIWI subfamily of Argonaute proteins, they were formally defined as piRNAs in mammalian systems in 2006. By binding to PIWI proteins to form a piRNA/ PIWIcomplex, piRNAs exert a silencing effect in the PIWI-dependent transposon silencing, gene and protein regulation, genome rearrangement, epigenetic regulation, and germ stem cell maintenance. Besides, piRNAs play a pivotal role in reproduction and fertility regulation, which were accumulated at the onset of meiosis or during spermatogenesis. Knockout mutations in Piwi proteins could lead to defects in sperm development. In recent years, some studies have shown that piRNAs' abnormal expression is related to tumor progression, which may become the diagnostic tools, therapeutic targets, and prognosis biomarkers for cancer.

The Role of piRNAs in Cancer

Unlike miRNAs, most piRNAs are not complementary to the mRNA of potential target genes, suggesting that piRNAs may be involved in epigenetic regulation instead of post-transcriptional regulation for controlling diverse biologic phenomena, including cancer. Epigenetic global alterations of cancers include DNA hypomethylation, gene-specific DNA hypermethylation and histones hypoacetylation, which leads to oncogene activation (R-ras, cyclin D2) and tumor suppressor silencing (RB1, p16). In tumor tissues, aberrantly expressed piRNAs implicated by global hypomethylation and local hypermethylation may be potential cancer-specific features. More and more evidence shows that although only a small number of piRNAs are currently expressed in somatic tissues, several piRNAs have been involved in the development of cancer.

Biological functions, target genes and potential clinical application of piRNAs in cancer.Figure 1. Biological functions, target genes and potential clinical application of piRNAs in cancer. (Yu Y, et al. 2019)

The relationship between piRNAs and carcinogenesis has been suggested by results of microarray screening, next generation sequencing, and real-time quantitative reverse transcription-polymerase chain reaction analysis. The upregulated expression of piRNA4987, piRNA20365, piRNA20485, and piRNA20582 was observed in cancer cell lines and in primary tumors compared to matched noncancerous tissues. Recently, piRNAHep1 was also found to be upregulated in hepatocellular carcinoma tumors compared to their corresponding adjacent noncancerous liver tissues. Although the mechanisms of how the piRNA pathway promotes tumorigenesis are still unclear, these data highlight the importance of understanding the role of the piRNA pathway during somatic cell division and suggest that this pathway may be a target for cancer therapeutics.

piRNAs and Cancer Therapeutics

In addition to the role of piRNAs as biomarkers, studies have also demonstrated their potential role as therapeutic tools. It has been reported that artificial piRNAs, generated by the expression of sense and antisense transcripts, were sufficient to induce epigenetic silencing of the target gene in a mouse model, highlighting the potential of piRNAs as clinical therapeutic targets. According to the characteristics of piRNAs, a variety of therapeutic strategies could be designed.

Cancer therapy by targeting piRNAs and PIWI proteins.Figure 2. Cancer therapy by targeting piRNAs and PIWI proteins. (Han Y N, et al. 2017)

  • Using synthetic piRNAs as bullets to block the synthesis of cancer-related proteins by binding to mRNAs, as miRNAs have tried, is an appealing application and may have the advantage of not requiring processing by enzymes which is required by miRNAs, such as Dicer. Other putative advantages of piRNAs over miRNAs include the possibility of targets with better specificity.
  • Studies have shown that inhibition of PIWI proteins could inhibit cell proliferation and the cell cycle, and induce apoptosis, and PIWI proteins were negatively associated with patient OS. Besides, PIWI can increase resistance to chemotherapy such as cisplatin. Therefore, an alternative strategy for treatment based on piRNAs is to design specific piRNAs to bind PIWI proteins; thereby, piRNAs could silence PIWI genes at the transcriptional level and block the harmful results. Silencing PIWI proteins and piRNAs as oncogenes in cancer or overexpression of piRNAs as tumor suppressors can alter the recruitment of epigenetic factors, thereby affecting the progression of cancer.

Further study of the mechanistic role of piRNA in tumor progression across a wider spectrum of tissue types, as well as the increased investigation into baseline functions of piRNA in human somatic tissue, will surely produce novel insights in this fast-growing field of non-coding RNA in cancer biology. The goal of the IntegrateRNA is to support basic and applied research in RNA biology to generate new and novel insights into the role of RNA in health and disease and provide new tools and targets for RNA research, diagnostics and therapies. For further information, please feel free to contact us.

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For research use only. Not intended for any clinical use.
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