Abstract
Simple SummaryBreast cancer is the second leading cause of cancer-related death in women in the United States and exhibits significant racial disparities in clinical outcomes. Earlier, we reported that the levels of resistin and IL-6 were significantly more elevated in the serum of African American women with breast cancer than in their Caucasian American counterparts. Here, we uncover its mechanistic significance by characterizing a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of breast cancer cells.Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, we examined the role of resistin in the regulation of Let-7 miRNAs and studied its downstream consequences. We found that resistin treatment led to the reduced expression of Let-7 family miRNAs in breast cancer (BC) cells, with the highest downregulation reported for Let-7a. Furthermore, resistin induced the expression of LIN28A, and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity, and sphere-forming ability of BC cells. Restoration of Let-7a also suppressed the resistin-induced expression of genes associated with growth, survival, and stemness. Pathway analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. In silico analysis identified STAT3 and its upstream modifier, IL-6, as putative Let-7a gene targets, which were later confirmed by 3′UTR-reporter assays. Together, our findings demonstrate a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of BC cells.
Highlights
Breast cancer (BC) is the most commonly diagnosed non-cutaneous malignancy and the foremost cause of cancer-related death in women in the United States [1]
For the first time, that resistin-induced Let-7a downregulation is associated with induced expression of STAT3 and IL6 in BC cells by directly targeting of their 3 untranslated regions
A repressive effect of resistin was observed on all Let7 family miRNAs; the most noticeable and significant downregulation was observed for Let7a in both the cell lines (Figure 1A)
Summary
Breast cancer (BC) is the most commonly diagnosed non-cutaneous malignancy and the foremost cause of cancer-related death in women in the United States [1]. It is extremely important to improve our understanding of breast tumor biology and delineate the molecular causes underlying disparate clinical outcomes among patients. Such information can help develop novel mechanism-based therapies and deliver them to the targeted patient population stratified based on the molecular features of the cancer. Aberrant expression of miRNAs has been reported in almost all cancers and is associated with their pathobiology [6,7]. An aberrant expression of the Let-7 family of miRNAs has been reported in BC and shown to be involved in disease progression and therapy resistance [15,16]
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