Critical Roles of PIWIL1 in Human Tumors: Expression, Functions, Mechanisms, and Potential Clinical Implications

Abstract

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a class of small non-coding RNA molecules that are 24-31 nucleotides in length. PiRNAs are thought to bind to PIWI proteins (PIWL1-4, a subfamily of Argonaute proteins), forming piRNA/PIWI complexes that influence gene expression at the transcriptional or post-transcriptional levels. However, it has been recently reported that the interaction of PIWI proteins with piRNAs does not encompass the entire function of PIWI proteins in human tumor cells. PIWIL1 (also called HIWI) is specifically expressed in the testis but not in other normal tissues. In tumor tissues, PIWIL1 is frequently overexpressed in tumor tissues compared with normal tissues. Its high expression is closely correlated with adverse clinicopathological features and shorter patient survival. Upregulation of PIWIL1 drastically induces tumor cell proliferation, epithelial-mesenchymal transition (EMT), invasion, cancer stem-like properties, tumorigenesis, metastasis and chemoresistance, probably via piRNA-independent mechanisms. In this article, we summarize the current existing literature on PIWIL1 in human tumors, including its expression, biological functions and regulatory mechanisms, providing new insights into how the dysregulation of PIWIL1 contributes to tumor initiation, development and chemoresistance through diverse signaling pathways. We also discuss the most recent findings on the potential clinical applications of PIWIL1 in cancer diagnosis and treatment.

Keywords: EMT; HIWI; PIWIL1; cancer metastasis; chemoresistance; piRNA; prognostic biomarker; tumorigenesis.

FIGURE 1

The expression of PIWIL1 in different types of tumors. (A) Comparison of PIWIL1 mRNA levels in different tumors and in normal tissues according to the Oncomine database (https://www.oncomine.org). Red: upregulation; blue: downregulation. (B) Analysis of genetic alterations in PIWIL1 in human tumor tissues using the Cancer Genome Atlas (TCGA) data retrieved from the cBioPortal database (https://www.cbioportal.org). Data are represented as a stacked histogram plot. Colors represent different types of alterations as indicated in the legend. Shown is the “Cancer Types Summary” where green indicates mutation, red indicates amplification, and blue indicates deletion.

FIGURE 2

High PIWIL1 expression predicts poor prognosis in patients with tumors. The probability of overall survival in patients with high or low PIWIL1 expression in different tumors was assessed using the KM plotter database (http://kmplot.com).

FIGURE 3

Mechanisms of PIWIL1 dysregulation in tumor. Several mechanisms that drive overexpression of PIWIL1 have been discovered, including activation of the RASSF1C/MEK/ERK pathway, hypomethylation of the PIWIL1 promoter and enhanced binding of ERα to the PIWIL1 promoter. Also, PIWIL1 is targeted by miR-154-5p and miR-2116-3p in tumor cells. Moreover, lncRNA FALEC indirectly induces PIWIL1 expression by sponging miR-2116-3p. Inhibition of B-RAF with PLX4720 (a selective B-RAF inhibitor) and treatment with Betulinic acid (a plant secondary metabolite isolated from birch trees), causes downregulation of PIWIL1 in cancer cells.

FIGURE 4

Aberrant expression of PIWIL1 mediates tumorigenesis and progression. PIWIL1 controls the expression of numerous downstream targets (such as PTEN, DNMT1, Pinin, p21, E-cadherin, BMI1, Stathmin1, Cyclin D1, OCT4, NANOG, MMP-2, MMP-9, Vimentin, and N-cadherin) involved in biological processes that are crucial for PIWIL1-dependent tumor promotion (including cell proliferation, EMT, migration, invasion, cancer stem-like properties, chemoresistance, tumorigenesis and metastasis). PIWIL1 epigenetically silences the expression of PTEN (a novel inhibitor of the PI3K/AKT pathway) by promoting DNA hypermethylation of the promoter of PTEN.