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Piwi-interacting RNAs (piRNAs) are a class of small RNAs that are about 24-32 nucleotides long. They have a strong uracil bias at the 5' end and 2'-O-methylation at the 3' end. The latest evidence suggests that piRNAs mainly exist in the stem and germ cells of fruit flies, mice, human beings, and other mammals. piRNA forms the piRNA complex by combining with the PIWI protein, which recognizes and binds transposons, cleaved mRNA produced by transposon gene transcription or silenced transposon genes in the cell nucleus, so as to regulate the self-renewal of germ cells and proliferation and differentiation of stem cells. In addition to mammalian germ lines, piRNAs are expressed in various human tissues in tissue-specific ways. Besides, piRNA regulates key signaling pathways at the transcriptional or post-transcriptional level.
Figure 1. piRNAs have a series of regulatory functions. (Li M, et al. 2020)
In recent years, through the researches on the role of piRNA and PIWI in cancer, scientists have found some evidence supporting the close links between piRNA/PIWI and various tumors. Busch, et al. found that different types of piRNA expression were significantly correlated with tumor cell metastasis, which could result in dysregulation of signaling pathways in tumor cells. Abnormal expression of PIWI proteins is related to tumor formation. The expression level of the PIWI protein in breast cancer and lung cancer was significantly higher than that in normal cells. The PIWI protein inhibits tumor cell apoptosis and promotes tumor proliferation through acting on the STAT3/bcl-xl and STAT3/Cyclin D1 signaling pathways. PIWIL2 is a member of the PIWI family; overexpression of PIWIL2 silences tumor-suppressor transposons and promotes tumor development. PIWIL4, a member of the PIWI subgroup, was initially found in animal testicular tissue. PIWIL4 interacts with piRNA and is commonly expressed in various human tissues, including the ovary. The PIWIL4 gene is highly expressed in cholangiocarcinoma tissues, and its up-regulated expression plays a crucial role in the occurrence, development, and prognosis of cholangiocarcinoma.
The abnormal expression of piRNA is related to a variety of cancers and may play a pro-cancer or anti-cancer role in cancer initiation, progression, and metastasis. The potential clinical significance of piRNA and PIWI as diagnostic tools, therapeutic targets, and prognosis biomarkers in cancer was highlighted. Due to the possible role of piRNAs in various carcinogenesis processes, there are new promising opportunities in this field. Among them, an exciting possibility consists in the application of piRNA investigations to provide early diagnosis, and even prevent the development of cancer. This hypothesis is supported by preliminary analyses of piRNA profiles in samples adjacent to tumor tissue, which shows a profile of expressed piRNAs that is more similar to cancer tissue pattern of expression than normal mucosa. Therefore, piRNAs might be considered as possible biomarkers of the cancer field effect.
Table 1. The function of the abnormal expression of piRNA and PIWIL in different cancer cells. (Guo B, et al. 2020)
|Gastric cancer||piR-651||↑||Diagnostic tool or therapeutic target|
|piR-823||↓||Diagnostic tool or therapeutic target|
|Breast cancer||piR-651||↑||Diagnostic tool|
|piR-36,712||↓||Prognosis biomarker or therapeutic target|
|Renal cancer||piR-32051||↑||Prognosis biomarker|
|Colorectal cancer||piR-54265||↑||Therapeutic target|
|Lung cancer||piR-55490||↓||Prognosis biomarker|