The role of 17β‑estradiol‑induced upregulation of Piwi‑like�4 in modulating gene expression and motility in breast cancer cells

Abstract

A majority of breast cancer cases are positive for the estrogen receptor (ER), which means that they can respond to the estrogen hormone to achieve growth. Hence, the ER signaling pathway has been extensively targeted in pharmaceutical research and development in order to suppress tumor growth. However, prevalent hormone therapy and targeted therapy often become ineffective as cancer cells ultimately develop resistance, suggesting that there could be unidentified signaling molecules and events that regulate breast cancer growth. Notably, recent studies have uncovered that Piwi-like (Piwil) proteins, which were initially found in germline cells, are expressed in a wide spectrum of human cancers, including breast cancers. Although Piwil proteins have been well established to silence retrotransposons and to promote heterochromatin formation in germline cells, their somatic functions in cancer cells remain largely unknown. In the present study, we profiled the expression of four Piwi homologs in an ER-positive breast cancer cell line, MCF-7, and found that only Piwil4 was upregulated by 17β-estradiol treatment. Notably, Piwil4 upregulation was not observed in an ER-positive but non-tumorigenic breast cancer cell line, MCF-12A. In addition, the induced expression of Piwil4 was dependent on estrogen/ERα signaling. To explore the biological significance of Piwil4 in breast cancer growth, we knocked down Piwil4 with multiple siRNAs and observed the suppressed expression of some canonical targets of ER. The knockdown of Piwil4 expression also decreased the migration and invasion capabilities of MCF-7 cells. Furthermore, the loss-of-function of Piwil4 reduced the motility of MCF-7 cells in wound-healing assays, which could be associated to decreased expression of vimentin and N-cadherin. Collectively, these findings revealed that Piwil4 is a novel regulator of ER signaling that could be targeted to inhibit breast cancer growth and migration.

The Clinical Significance of PIWIL3 and PIWIL4 Expression in Pancreatic Cancer

“…Here, we observed how PIWIL3 and PIWIL4 knockdown decreased motility of both tumor and normal cells through a mesenchymal arrest in favor of the epithelial phenotype. This reduction of the cell motility by PIWIL4 downregulation has previously been described in breast cancer cells through an impairment of Vimentin and N-Cadherin [33]. However, this study only provided evidence of migration delay in MCF-7 tumor cell line but not in a non-tumor cell line.…”

“…On the one hand, high expression of PIWIL4 is found in tumor tissues of colorectal cancer [29], cervical cancer [30], gastric cancer [31] and primary and metastatic foci of ovarian cancer [21] compared with their adjacent tissues. Its downregulation not only enhanced significantly the apoptotic effect of treatment in Leydig cell tumor [32] but also apoptosis, migration and invasion of breast cancer cells in vitro [33,34]. In hepatocellular carcinoma, the nuclear expression of PIWIL4 together with PIWIL2 has been found to confer worse outcome [35].…”

An Integrated mRNA-lncRNA Signature for Overall Survival Prediction in Cholangiocarcinoma

“…Published records of mRNAs identi ed in our signature indicate that overexpressed CFHR3 (Complement Factor H-Related Protein 3) would suppress proliferation and promote apoptosis of hepatocellular carcinoma (HCC) cells [31] and is a potential prognosis biomarker for HCC [32]. PIWIL4 (piwi like RNA-mediated gene silencing 4) belongs to Piwi-like (Piwil) proteins and is aberrantly expressed in various human cancers, including breast cancer [33], retinoblastoma [34], and hepatocellular carcinoma [35]. As for the two antisense lncRNAs identi ed in this study, their functional roles have not been elucidated in any cancer.…”

PIWI‑interacting RNA in cancer: Molecular mechanisms and possible clinical implications (Review)

“…BC has surpassed lung cancer as the leading cause of global cancer incidence in 2020, with an estimated 2.3 million new cases and is the fifth leading cause of cancer mortality worldwide (33). piRNAs are involved in the occurrence of BC (71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81).…”

“…In human BC cells, the expression level of PIWIL4 is relatively high as it is required for cell growth, migration, and invasion (79) (Table Ⅲ). Given that estrogen receptor (ER) signaling is involved in BC growth, an interaction occurs between PIWIL4 and ER signaling pathway (79). PIWIL4 expression can be induced by ER signaling, and PIWIL4 triggers ER pathway by upregulating the canonical ER signaling molecules, such as growth regulation by estrogen in breast cancer 1, trefoil factor 1, calcitonin receptor, and cyclin D1 (79).…”