The Role of PIWIL4, an Argonaute Family Protein, in Breast Cancer

Abstract

P-element-induced wimpy testis (PIWI) proteins bind to PIWI-interacting RNAs and play key roles in the biogenesis and functions of PIWI-interacting RNAs. It has been reported that PIWI proteins are essential for stem cell self-renewal and germline development in diverse organisms and that they are ectopically expressed in multiple forms of cancer. However, the role of PIWI in cancer remains elusive. Here we report that one of the four PIWI proteins in humans, PIWIL4, is highly expressed in both breast cancer tissues and the cytoplasm of MDA-MB-231 cells derived from breast cancer. Reducing PIWIL4 expression drastically impairs the migration ability of MDA-MB-231 cells, significantly increases their apoptosis, and mildly affects their proliferation. Our transcriptome and proteome analysis reveal that these functions are at least partially achieved via the PIWIL4 regulation of TGF-␤ and FGF signaling pathways and MHC class II proteins. These findings suggest that PIWIL4 may serve as a potential therapeutic target for breast cancer.PIWI 5 proteins represent a subfamily of the Argonaute (Ago) protein family and are highly conserved among eukaryotes and archaea. PIWI proteins bind to a class of non-coding small RNAs called PIWI-interacting RNAs (piRNAs) (1-4). The PIWI-piRNA complex regulates gene expression at epigenetic and posttranscriptional levels (5-8). PIWI proteins and piRNAs are mostly expressed in the germ line, where PIWI proteins have been demonstrated to be essential for germ line development, stem cell self-renewal, and gametogenesis in diverse organisms (4, 9 -14). In addition, there is increasing evidence for somatic expression of PIWI proteins in Drosophila and mouse tissues (14 -16). Furthermore, it has been reported that PIWI proteins have aberrant and ectopic expression in a wide spectrum of cancers (17-23). For example, PIWIl2 is highly expressed in breast cancer (24). Hence, PIWI might be involved in cancer formation and/or progression.Breast cancer comprises four subtypes based on the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER2). Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and HER2 expression (25-27), represents ϳ10 -25% of all breast cancers, and is a clinical therapy hot spot because of the vulnerability of younger women to this subtype of breast cancer (28). Furthermore, TNBC patients do not benefit from targeted treatments such as endocrine therapy or trastuzumab because this subtype of cancer lacks the appropriate targets for these drugs. These challenges point to the pressing need to identify pathogenic pathways in TNBC. Recent studies have identified genetic alterations and gene expression profiles associated with subtypes of TNBC, including the implication of the PI3K/Akt/mTOR (mechanistic target of rapamycin) pathway in TNBC (29 -32). However, therapeutic blockade of this pathway with the PI3K/Akt/mechanistic target of rapamycin inhibitor has not been effective, indicating the existenc...

Germline factor DDX4 functions in blood‐derived cancer cell phenotypes

“…To test for DDX4 expression, we first screened for transcripts using RT‐PCR for each cell line. Expression of another germline factor PIWI‐like2 (PIWIL2) that is known to function with DDX4/Vasa in the germline as well as in some cancer cells was analyzed in parallel. We learned that both ddx4 and piwil2 mRNA were expressed in IM‐9 and THP‐1 cells (Fig.…”

“…For instance, Nanos (RNA‐binding protein) upregulation as a consequence of Rb (Retinoblastoma) inactivation causes inhibition of apoptotic genes and promotes cell proliferation . PIWI (a small RNA regulator) has been reported to be linked to many hallmarks of cancer, including cell proliferation, anti‐apoptosis, genomic instability, and metastasis . These emerging functions of germline factors led us to suggest that germline factors may contribute broadly to cancer cell regulation.…”

In silicoanalysis of piRNAs in retina reveals potential targets in intracellular transport and retinal degeneration

“…Apart from modulation of Akt pathway, we observed significant variation in the phosphorylation levels of STAT3, p53, AMPKα and HSP90 21 . In the similar line, Wang et al have also shown the influence of HIWI2 in the activation of MAPK/ERK, TGFβ and FGF signalling pathways 50 . It is plausible that these changes could be mediated through piRNAs, suggesting its involvement in cell signalling and cell-cell contact.…”

PIWI-interacting RNAs: new biomarkers for diagnosis and treatment of breast cancer

“…Similarly, PIWI proteins also have significant roles in different cancers such as breast cancer. In spite of extensive research about cancer, only recent articles have discussed PIWI proteins roles in this area [86]. PIWIL4 Gene is one of the upregulated genes in breast cancer which is highly expressed not only in breast cell lines but also in breast cancer samples.…”