Abstract
Cellular senescence occurs as a response to extracellular and intracellular stresses and contributes to aging and age-related pathologies. Emerging evidence suggests that cellular senescence also acts as a potent tumor suppression mechanism that prevents the oncogenic transformation of primary human cells. Recent reports have indicated that miRNAsact as key modulators of cellular senescence by targeting critical regulators of the senescence pathways. We previously reported that miR-127 is up-regulated in senescent fibroblasts. In this report, we identified miR-127 as a novel regulator of cellular senescence that directly targets BCL6. We further showed that miR-127 is down-regulated in breast cancer tissuesand that this down-regulation is associated with up-regulation of BCL6. Over-expression of miR-127 or depletion of BCL6 inhibits breast cancer cell proliferation. Our data suggest that miR-127 may function as a tumor suppressor that modulates the oncogene BCL6.
Highlights
Cellular senescence was originally described by Hayflick five decades agoas an irreversible proliferation arrest of normal somatic cells [1]
We previously identified a set of miRNAs differentially expressed in proliferating versus senescent human fibroblasts. miR-127-3p is one of the miRNAs that was upregulated in senescent WI-38 and IMR-90 cells [9]. miR-127-3p and miR-127-5p are two mature miRNAs that are processed from the same precursor miRNA; hereafter, miR-127-3p will be referred to as miR-127. miR-127 is located in chromosome region 14q32.2 and belongs to a cluster that includes miR-431, miR-433, miR-127, miR-432, and miR-136 [10]. miR-127 and miR-433 are transcribed from independent promoters in overlapping genomic regions,and expression of these two miRNAs is induced by estrogen related receptor gamma (ERRc) and inhibited by small heterodimer partner (SHP), a unique orphan nuclear receptor and transcriptional repressor [11,12,13]
Microarray studies have identified large subsets of miRNAs that are up-regulated or down-regulated in senescent cells, but only a few miRNAs have been shown to modulate senescence experimentally. miR-34a is a tumor suppressor that down-regulates a program of genes that promote cell cycle progression and isalso a potent inducer of cellular senescence [19]. miR-203 induces senescence by targeting the E2F3 protein in human melanoma cells [20]
Summary
Cellular senescence was originally described by Hayflick five decades agoas an irreversible proliferation arrest of normal somatic cells [1]. Cellular senescence occurs in culture and in vivo as a response to extracellular and intracellular stresses, including telomere dysfunction, DNA damage caused by radiation or chemicals, and oncogenic or mitogenic stimuli [2,3]. Cellular senescence causes permanent cell cycle arrest and, thereby, acts as a potent tumor suppression mechanism that prevents the oncogenic transformation of primary human cells [2,4]. Senescence is a defining feature of premalignant tumors, andsenescent cells do not exist in malignant tumors. The induction and maintenance of cellular senescence is largely dependent on either or both of the p53/p21 and p16INK4a/pRB tumor suppressor pathways [5]. Recent studies haveindicated that microRNAs regulate cellular senescence by targeting the key regulators of cellular senescence pathways [6]
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