Cyclin D1 promotes secretion of pro-oncogenic immuno-miRNAs and piRNAs

Abstract

The molecular mechanisms governing the secretion of the non-coding genome are poorly understood. We show herein that cyclin D1, the regulatory subunit of the cyclin-dependent kinase that drives cell-cycle progression, governs the secretion and relative proportion of secreted non-coding RNA subtypes (miRNA, rRNA, tRNA, CDBox, scRNA, HAcaBox. scaRNA, piRNA) in human breast cancer. Cyclin D1 induced the secretion of miRNA governing the tumor immune response and oncogenic miRNAs. miR-21 and miR-93, which bind Toll-Like Receptor 8 to trigger a pro-metastatic inflammatory response, represented >85% of the cyclin D1-induced secreted miRNA transcripts. Furthermore, cyclin D1 regulated secretion of the P-element Induced WImpy testis (PIWI)-interacting RNAs (piRNAs) including piR-016658 and piR-016975 that governed stem cell expansion, and increased the abundance of the PIWI member of the Argonaute family, piwil2 in ERα positive breast cancer. The cyclin D1-mediated secretion of pro-tumorigenic immuno-miRs and piRNAs may contribute to tumor initiation and progression.

piRNA-823 Is Involved in Cancer Stem Cell Regulation Through Altering DNA Methylation in Association With Luminal Breast Cancer

“…Lin − CD24 −/low CD44 + or ALDH + cell subpopulations have been well-validated as CSCs in human breast cancer tumors (Al-Hajj et al, 2003;Ginestier et al, 2007), which are characterized by self-renewal, differentiation, and have the strong capability to regenerate tumors after transplantation in vivo. The aberrant expression of PIWI proteins and piRNAs in breast CSCs have been recently reported (Amaar and Reeves, 2020;Lü et al, 2020). The regulation of CSC expansion by piR-016658 and piR-016975 was demonstrated in our previous study (Lü et al, 2020).…”

“…The aberrant expression of PIWI proteins and piRNAs in breast CSCs have been recently reported (Amaar and Reeves, 2020;Lü et al, 2020). The regulation of CSC expansion by piR-016658 and piR-016975 was demonstrated in our previous study (Lü et al, 2020). Targeting piRNAs in suppressing CSCs may provide a novel strategy to treat cancer patients, especially in the prevention of CSC-induced drug resistance and cancer relapse.…”

“…Emerging evidence shows the presence of a subset of piRNAs with aberrant expression in tumor cells (Martinez et al, 2015;Lü et al, 2020). Our previous work (Lü et al, 2020) demonstrated the expression of PIWIL2, but not PIWIL1, in human breast cancer cells. A total of 415 piRNA sequences were identified from the secretome of MCF-7 cells (Lü et al, 2020).…”

“…Our previous work (Lü et al, 2020) demonstrated the expression of PIWIL2, but not PIWIL1, in human breast cancer cells. A total of 415 piRNA sequences were identified from the secretome of MCF-7 cells (Lü et al, 2020). Consistent with these findings, a high-throughput deep sequencing analysis identified a group of small RNA sequences matching piRNAs in breast cancer (Hashim et al, 2014).…”

Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma

“…miR-21 and miR-93, which bind Toll-Like Receptor 8 to trigger a pro-metastatic inflammatory response, represent >85% of the Cyclin D1-induced secreted miRNA transcripts. Thus, these researches, demonstrate an unknown function of Cyclin D1, suggesting increased secretion of immuno-miRNAs that lead a pro-tumorigenic immune phenotype [ 64 ].…”