Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation.

Deshmukh, Sachin Kumar; Srivastava, Sanjeev Kumar; Zubair, Haseeb; Khan, Mohammad Aslam; Singh, Ajay Pratap; Singh, Seema

Simple Summary: Breast 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.

INTERLEUKINS; BIOCHEMISTRY; MICRORNA; CELL physiology; PHENOMENOLOGY; RESISTIN; GENE expression; CELLULAR signal transduction; CELL lines; BIOLOGICAL assay; BREAST tumors; CARRIER proteins; PHENOTYPES

Cancers, 2021, Vol 13, Issue 18, p4498

2072-6694

Academic Journal

10.3390/cancers13184498