PIWI interacting RNAs perspectives: a new avenues in future cancer investigations

Figures & data

Table 1. Characteristics of major noncoding RNAs (ncRNAs)

	piRNA	miRNA	siRNA
Structure	5′ terminal uridine or tenth adenosine and 2′ O-methyl group on the 3′ ribose	phosphorylated 5ʹ ends and hydroxylated 3ʹ ends	phosphorylated 5ʹ ends and hydroxylated 3ʹ ends with two overhanging nucleotides
Size	24–32 nt	20–24 nt	21–23 nt
Processing	Dicer-independent	Dicer-dependent	Dicer-dependent
Precursor	single-stranded RNA	double-stranded RNA	double-stranded RNA
Associated protein	PIWI subfamily proteins (mainly enriched in germline)	AGO subfamily proteins (ubiquitously expressed)	AGO subfamily proteins (ubiquitously expressed)
Organism	Eukaryotes	Eukaryotes	Eukaryotes
Source	Genomic loci (transposons, repeats, piRNA loci)	Genomic loci (miRNA loci, introns)	Exogenous siRNA: Viral or other exogenous RNAs Endogenous siRNA: Genomic loci (mRNAs, Transposons, repeats), miRNA-cleaved RNAs, bidirectional transcripts
number of loci in the human genome	>30,000	2,000	Endogenous siRNA: More than 200
Expression	Highly enriched in the germline	Broad expression in most cell and tissue types	Broad expression in most cell and tissue types
Major target genes	Transposons and other genes	Coding genes	Transposons and exogenous genes
Primary functional mechanism	Transcriptional repression, heterochromatin formation (DNA methylation), RNA cleavage	Translational repression of mRNA, mRNA cleavage	Exogenous siRNA: Cleavage of exogenous RNA endogenous siRNA:RNA cleavage

Figure 1. The two pathways of piRNA biogenesis: primary and secondary (Ping-Pong cycle) amplification Aub, Aubergine; Ago3, Argonaute-3; PIWI, P-element-induced wimpy testis; TE, Transposable Element

Table 2. Cancer-associated piRNAs

Malignancy	PiRNA	Expression	Mechanisms in cancer	References
Breast cancer	piR-932 piR-651 piR-021285 piR-4987 piR-36712 piRNA-823	Overexpression Overexpression Overexpression Overexpression Underexpression Overexpression	Stemness, EMT, and invasion Proliferation, invasion, and metastasis Increase ARHGAP11A mRNA expression and invasiveness Associated with lymph node metastasis Restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA Involved in cancer stem cell regulation through altering DNA methylation	[124,142] [H. 125] [126] [L. 127] [128]
Gastric cancer	piR-651 piR-823 piR-59056	Overexpression Underexpression Overexpression	Proliferation, invasion, and metastasis Inhibit cancer cell growth, tumor-node and distant metastasis Associated with recurrence	[129] [Y.-N. 130, 205] [L. 147]
Lung cancer	piR-L-163 piR-651 piR-55490	Underexpression Overexpression Underexpression	Proliferation and invasion Proliferation, invasion, and metastasis Suppress the activation of Akt/mTOR pathway	[94,122,124]
Colon cancer	piR-651 piR-59056	Overexpression Overexpression	Proliferation, invasion, and metastasis Associated with recurrence-free survival	[Y. 131] [L. 147]
Bladder cancer	piR-ABC piR-60152	Underexpression Underexpression	Proliferation suppression, encourage apoptosis Regulate the expression of TNFSF4	[132,132]
Liver cancer	piR-Hep1 piR-823	Overexpression Overexpression	Migration and invasion Increase the production of a-SMA and COL1a1	[133,134,143]
Prostate cancer	piR-001773 piR-017184 piR-19166	Overexpression Underexpression	Promote cancer progression Inhibits migration and metastasis	[L. 135] [136]
Multiple myeloma	piR-823 piR-004800	Overexpression Overexpression	DNA methylation and angiogenesis Keeps myeloma cell survival by inhibition of apoptotic and autophagic cell death	[H. 125] [H. 137]
Glioma	piR-598	Overexpression	Promote cell proliferation	[138]

Figure 2. Biological functions, target genes, and clinical applications of piRNAs in cancer

Table 3. Clinical applications of piRNAs in cancer

Cancer	PiRNA	Clinical application	References
Breast cancer	piR-932 piR-008114 piR-019676 piR-000552 piR-020548 piR-008113 piR-016735 piR-020450 piR-017033 piR-020365 piR-019675 piR-019914 piR-015249 piR-009294 piR-021032 piR-009051 piR-000753 piR-008112 piR-020814 piR-001318 piR-006426 piR-018,849 piR-021285 piR-017184 piR-020829 piR-019912 piR-018780	Therapeutic target Therapeutic targets	[H. 160] [161]
Gastric cancer	piR-823 piR-651	Therapeutic target and diagnostic marker Diagnostic marker	[J. 156] [L. 147]
Lung cancer	piR-651 piR-L-163 piR-55,490	Therapeutic target Diagnostic marker Therapeutic target	[D. 162, 163] [94] [L. Pe164]
Colorectal cancer	piR-1245 piR-015551 piR-020619 piR-020450 piR-54265 piR-823 piR-19521 piR-18849 piR-28876 piR-5937	Prognostic marker Risk assessment Diagnostic markers Valuable biomarker for screening, early diagnosis and clinical surveillance Therapeutic target Prognostic marker Prognostic marker Diagnostic marker Diagnostic marker	[129,165] [Z. 152] [166] [J. 167] [J. 168] [151]
Multiple myeloma	piR-823	Therapeutic target	[H. 125]
Prostate cancer	piR-651 piR-823	Therapeutic targets	[169]
Liver cancer	piR-Hep1	Prognostic marker	[143]
Kidney cancer	piR-823 piR-43,607 piR-32,051 piR-39,894 piR-38,756 piR-30,924 piR-51810 piR-57125 piR-34536	Prognostic marker Prognostic markers Prognostic marker Prognostic marker Prognostic marker	[149] [Y. 131] [170] [C. 10] [171] [C. 10]
Papillary thyroid carcinoma	piR-13643 piR-21238	Diagnostic markers	[172]
Diffuse Large B-Cell Lymphoma(DLBCL)	PiR-30473	Prognostic marker	[H. 173]

Table 4. Cancer-related PIWI Proteins

PIWI Proteins	Cancer	Expression	Function	References
PIWIL1/HIWI	Seminoma Cancer Colorectal cancer Breast cancer Gastric cancer Lung cancer Ovarian cancer Glioma Sarcomas Endometrial cancer Hepatocellular carcinoma Cervix cancer	Increased Increased Increased Increased Increased Increased Increased Increased Decreased Decreased Increased	Encourage cell propagation Inhibit migration and invasion Increase cell proliferation and stemness Encourage cell proliferation CSC self-renewa1 Migration and invasion Increase cell propagation Genomic instability Related to DNA hypermethylation Reduce cell proliferation and migration Migration and invasion	[61,124,170,182–190,190–192]
PIWIL2/HILI	Colon cancer Liver cancer Breast cancer Gastric cancer Ovarian cancer Cervix cancer Esophageal cancer Soft-tissue sarcoma	Increased Increased Increased Increased Increased Increased Increased Decreased	Proliferation, migration, and invasion Apoptosis inhibition Proliferation, apoptosis inhibition, migration, and invasion Related to poor prognosis Genomic instability Inhibit apoptosis Related to poor prognosis Reduce cell proliferation and increase apoptosis	[193, Z. 194] [J. H. 67, 195] [J. H. 196, H. 160] [175,185,190,197,198]
PIWIL3/HIWI3	Breast cancer Gastric cancer	Increased Increased	Prognosis relevance Proliferation, migration and invasion	[143,199]
PIWIL4/HIWI2	Cervical cancer Lung cancer Colon cancer Breast cancer	Increased Increased Increased Increased	Impair apoptosis, promote invasion Proliferation Migration and invasion Prognosis relevance	[D.-W. 200, X. [201] [L. 202] [143]

Lim SL, Ricciardelli C, Oehler MK, et al. Overexpression of piRNA pathway genes in epithelial ovarian cancer. PLoS One. 2014;9(6):e99687.

 PubMed Web of Science ®Google Scholar

Huang G-L, Hu H, Xue X, et al. Altered expression of piRNAs and their relation with clinicopathologic features of breast cancer. Clin Transl Oncol. 2013;15(7):563–568.

 PubMed Web of Science ®Google Scholar

Yan H, Wu Q, Sun C, et al. piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma. Leukemia. 2015;29(1):196–206.

 PubMed Web of Science ®Google Scholar

Martinez VD, Vucic EA, Thu KL, et al. Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. Sci Rep. 2015;5(1):1–17.

 Google Scholar

Tan L, Mai D, Zhang B, et al. PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA. Mol Cancer. 2019;18(1):1–15.

 PubMedGoogle Scholar

Ding X, Li Y, Lü J, et al. piRNA-823 is involved in cancer stem cell regulation through altering DNA methylation in association with luminal breast cancer. Front Cell Dev Biol. 2021;9. DOI:10.3389/fcell.2021.641052

 Web of Science ®Google Scholar

Weng W, Liu N, Toiyama Y, et al. Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer. 2018;17(1):16.

 PubMedGoogle Scholar

Jacobs DI, Qin Q, Lerro MC, et al. PIWI-interacting RNAs in gliomagenesis: evidence from post-GWAS and functional analyses. Cancer Epidemiol Prev Biomarkers. 2016;25(7):1073–1080.

 PubMed Web of Science ®Google Scholar

Han Y-N, Li Y, Xia S-Q, et al. PIWI proteins and PIWI-interacting RNA: emerging roles in cancer. Cell Physiol Biochem. 2017;44(1):1–20.

 PubMedGoogle Scholar

Cui L, Lou Y, Zhang X, et al. Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using piRNAs as markers. Clin Biochem. 2011;44(13):1050–1057.

 PubMed Web of Science ®Google Scholar

Mei Y, Wang Y, Kumari P, et al. A piRNA-like small RNA interacts with and modulates p-ERM proteins in human somatic cells. Nat Commun. 2015;6(1):7316.

 PubMedGoogle Scholar

Siddiqi S, Matushansky I. Piwis and piwi‐interacting RNAs in the epigenetics of cancer. J Cell Biochem. 2012;113(2):373–380.

 PubMed Web of Science ®Google Scholar

Li Y, Wu X, Gao H, et al. Piwi-interacting RNAs (piRNAs) are dysregulated in renal cell carcinoma and associated with tumor metastasis and cancer-specific survival. Mol Med. 2015;21(1):381–388.

 PubMedGoogle Scholar

Chu H, Hui G, Yuan L, et al. Identification of novel piRNAs in bladder cancer. Cancer Lett. 2015;356(2):561–567.

 PubMed Web of Science ®Google Scholar

Xiao Z, Shen J, Zhang L, et al. Therapeutic targeting of noncoding RNAs in hepatocellular carcinoma: recent progress and future prospects. Oncol Lett. 2018;15(3):3395–3402.

 PubMed Web of Science ®Google Scholar

Tang X, Xie X, Wang X, et al. The combination of piR-823 and eukaryotic initiation factor 3 B (EIF3B) activates hepatic stellate cells via upregulating TGF-β1 in liver fibrogenesis. Med Sci Monit. 2018;24:9151.

 PubMed Web of Science ®Google Scholar

Law PT-Y, Qin H, Ching A-K-K, et al. Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma. J Hepatol. 2013;58(6):1165–1173.

 PubMed Web of Science ®Google Scholar

Zhang L, Meng X, Li D, et al. piR-001773 and piR-017184 promote prostate cancer progression by interacting with PCDH9. Cell Signal. 2020;76:109780.

 PubMed Web of Science ®Google Scholar

Qi T, Cao H, Sun H, et al. piR-19166 inhibits migration and metastasis through CTTN/MMPs pathway in prostate carcinoma. Aging (Albany NY). 2020;12(18):18209.

 PubMedGoogle Scholar

Ma H, Wang H, Tian F, et al. PIWI-interacting RNA-004800 is regulated by S1P receptor signaling pathway to keep myeloma cell survival. Front Oncol. 2020;10:438.

 PubMed Web of Science ®Google Scholar

Baylin SB, Jones PA. A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer. 2011;11(10):726–734.

 PubMed Web of Science ®Google Scholar

Zhang H, Ren Y, Xu H, et al. The expression of stem cell protein Piwil2 and piR-932 in breast cancer. Surg Oncol. 2013;22(4):217–223.

 PubMed Web of Science ®Google Scholar

Krishnan P, Ghosh S, Graham K, et al. Piwi-interacting RNAs and PIWI genes as novel prognostic markers for breast cancer. Oncotarget. 2016;7(25):37944.

 PubMedGoogle Scholar

Cheng J, Deng H, Xiao B, et al. piR-823, a novel non-coding small RNA, demonstrates in vitro and in vivo tumor suppressive activity in human gastric cancer cells. Cancer Lett. 2012;315(1):12–17.

 PubMed Web of Science ®Google Scholar

Li D, Luo Y, Gao Y, et al. piR-651 promotes tumor formation in non-small cell lung carcinoma through the upregulation of cyclin D1 and CDK4. Int J Mol Med. 2016;38(3):927–936.

 PubMed Web of Science ®Google Scholar

Yao J, Wang YW, Fang BB, et al. piR-651 and its function in 95-D lung cancer cells. Biomed Rep. 2016;4(5):546–550.

 PubMed Web of Science ®Google Scholar

Peng L, Song L, Liu C, et al. piR-55490 inhibits the growth of lung carcinoma by suppressing mTOR signaling. Tumor Biol. 2016;37(2):2749–2756.

 PubMedGoogle Scholar

Chu H, Xia L, Qiu X, et al. Genetic variants in noncoding PIWI‐interacting RNA and colorectal cancer risk. Cancer. 2015;121(12):2044–2052.

 PubMed Web of Science ®Google Scholar

Wang Z, Yang H, Ma D, et al. Serum PIWI-interacting RNAs piR-020619 and piR-020450 are promising novel biomarkers for early detection of colorectal cancer. Cancer Epidemiol Prev Biomarkers. 2020;29(5):990–998.

 PubMed Web of Science ®Google Scholar

Mai D, Zheng Y, Guo H, et al. Serum piRNA-54265 is a new biomarker for early detection and clinical surveillance of human colorectal cancer. Theranostics. 2020;10(19):8468.

 PubMed Web of Science ®Google Scholar

Yin J, Jiang XY, Qi W, et al. piR‐823 contributes to colorectal tumorigenesis by enhancing the transcriptional activity of HSF 1. Cancer Sci. 2017;108(9):1746–1756.

 PubMed Web of Science ®Google Scholar

Yin J, Qi W, Ji CG, et al. Small RNA sequencing revealed aberrant piRNA expression profiles in colorectal cancer. Oncol Rep. 2019;42(1):263–272.

 PubMed Web of Science ®Google Scholar

Vychytilova-Faltejskova P, Stitkovcova K, Radova L, et al. Circulating PIWI-interacting RNAs piR-5937 and piR-28876 are promising diagnostic biomarkers of colon cancer. Cancer Epidemiology Biomarkers & Prevention. 2018;27(9):1019–1028.

 PubMed Web of Science ®Google Scholar

Öner Ç, Turgut Coşan D, Çolak E. Estrogen and androgen hormone levels modulate the expression of PIWI interacting RNA in prostate and breast cancer. PLoS One. 2016;11(7):e0159044.

 PubMed Web of Science ®Google Scholar

Iliev R, Fedorko M, Machackova T, et al. Expression levels of PIWI-interacting RNA, piR-823, are deregulated in tumor tissue, blood serum and urine of patients with renal cell carcinoma. Anticancer Res. 2016;36(12):6419–6423.

 PubMed Web of Science ®Google Scholar

Busch J, Ralla B, Jung M, et al. Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas. J Exp Clin Cancer Res. 2015b;34(1):61.

 PubMedGoogle Scholar

Zhao C, Tolkach Y, Schmidt D, et al. Mitochondrial PIWI-interacting RNAs are novel biomarkers for clear cell renal cell carcinoma. World J Urol. 2019;37(8):1639–1647.

 PubMed Web of Science ®Google Scholar

Busch J, Ralla B, Jung M, et al. Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas. J Exp Clin Cancer Res. 2015a;34(1):1–11.

 PubMedGoogle Scholar

Chang Z, Ji G, Huang R, et al. PIWI-interacting RNAs piR-13643 and piR-21238 are promising diagnostic biomarkers of papillary thyroid carcinoma. Aging (Albany NY). 2020;12(10):9292.

 PubMedGoogle Scholar

Han H, Fan G, Song S, et al. piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL. Blood. 2021;137(12):1603–1614.

 PubMed Web of Science ®Google Scholar

Sasaki T, Shiohama A, Minoshima S, et al. Identification of eight members of the Argonaute family in the human genome☆. Genomics. 2003;82(3):323–330.

 PubMed Web of Science ®Google Scholar

Oh S-J, Kim S-M, Kim Y-O, et al. Clinicopathologic implications of PIWIL2 expression in colorectal cancer. Korean J Pathol. 2012;46(4):318.

 PubMedGoogle Scholar

Yan Z, Qu L-K, Lin M, et al. HIWI expression profile in cancer cells and its prognostic value for patients with colorectal cancer. Chin Med J (Engl). 2011;124(14):2144–2149.

 PubMed Web of Science ®Google Scholar

Lee JH, Schütte D, Wulf G, et al. Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway. Hum Mol Genet. 2006;15(2):201–211.

 PubMed Web of Science ®Google Scholar

Xie Y, Yang Y, Ji D, et al. Hiwi downregulation, mediated by shRNA, reduces the proliferation and migration of human hepatocellular carcinoma cells. Mol Med Rep. 2015;11(2):1455–1461.

 PubMed Web of Science ®Google Scholar

Lee JH, Jung C, Javadian-Elyaderani P, et al. Pathways of proliferation and antiapoptosis driven in breast cancer stem cells by stem cell protein piwil2. Cancer Res. 2010;70(11):4569–4579.

 PubMed Web of Science ®Google Scholar

Qiao D, Zeeman A-M, Deng W, et al. Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas. Oncogene. 2002;21(25):3988–3999.

 PubMed Web of Science ®Google Scholar

Sugimoto K, Kage H, Aki N, et al. The induction of H3K9 methylation by PIWIL4 at the p16Ink4a locus. Biochem Biophys Res Commun. 2007;359(3):497–502.

 PubMed Web of Science ®Google Scholar

Taubert H, Greither T, Kaushal D, et al. Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma. Oncogene. 2007;26(7):1098–1100.

 PubMed Web of Science ®Google Scholar

Klein JD, Qu C, Yang X, et al. c-Fos repression by piwi regulates Drosophila ovarian germline formation and tissue morphogenesis. PLoS Genet. 2016;12(9):e1006281.

 PubMed Web of Science ®Google Scholar

He G, Chen L, Ye Y, et al. Piwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16INK4a. Am J Transl Res. 2010;2(2):156.

 PubMed Web of Science ®Google Scholar

Jiang L, Wang W-J, Li Z-W, et al. Downregulation of Piwil3 suppresses cell proliferation, migration and invasion in gastric cancer. Cancer Biomarkers. 2017;20(4):499–509.

 PubMed Web of Science ®Google Scholar

Wang D-W, Wang Z-H, Wang -L-L, et al. Overexpression of hiwi promotes growth of human breast cancer cells. Asian Pac J Cancer Prev. 2014;15(18):7553–7558.

 PubMedGoogle Scholar

Qu X, Liu J, Zhong X, et al. PIWIL2 promotes progression of non-small cell lung cancer by inducing CDK2 and Cyclin A expression. J Transl Med. 2015;13(1):301.

 PubMedGoogle Scholar

Li L, Yu C, Gao H, et al. Argonaute proteins: potential biomarkers for human colon cancer. BMC Cancer. 2010;10(1):38.

 PubMedGoogle Scholar

Data availability

Data sharing is not applicable to this article as no new data are created or analyzed in this study.