The Heterochronic microRNA let-7 Inhibits Cell Motility by Regulating the Genes in the Actin Cytoskeleton Pathway in Breast Cancer

Abstract

The heterochronic gene let-7 serves as a tumor suppressor microRNA by targeting various oncogenic pathways in cancer cells. Considerable evidence indicates that reduced expression of let-7 might be associated with poor clinical outcome in patients with cancer. Here, we report that the expression levels of three let-7 family members, let-7a, let-7b, and let-7g, were significantly decreased in the breast cancer patients with lymph node metastasis compared to those without lymph node metastasis. Enforced expression of let-7b significantly inhibits breast cancer cell motility and affects actin dynamics. Using bioinformatic and experimental approaches, four genes in the actin cytoskeleton pathway, including PAK1, DIAPH2, RDX, and ITGB8, were identified as let-7 direct targets. Blocking the expression of PAK1, DIAPH2, and RDX significantly inhibits breast cancer cell migration induced by let-7b repression. Our results indicate reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease.

Tumor-suppressive microRNA-let-7a inhibits cell proliferation via targeting of E2F2 in osteosarcoma cells

“…Several studies have shown that the downregulation of let-7a is closely related to the abnormal potential in malignant tumors (13,25,26). However, the biological roles of let-7a in OS cells have not yet been clarified.…”

Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

“…In addition, ␣v␤8 integrin signals via the effector protein Band 4.1B during embryonic heart morphogenesis (66), likely in migratory cardiac neural crest cells. Primary tumors in the lung, mouth, skin, and other organs commonly upregulate ␤8 integrin gene expression during metastatic dispersal, and inhibition of integrin expression diminishes metastasis (67)(68)(69)(70). Hence, the ␣v␤8 integrin-PTP-PEST-RhoGDI1 signaling unit probably modulates leading edge dynamics and motility in divergent cell types.…”

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…The let-7a-1/let-7d/let-7f-1 cluster (denoted as let-7adf cluster), with three members let-7a-1, let-7f-1, and let7d, is an important cluster of the let-7 family, accounting for about 25% of total let-7 precursors (Wang et al, 2011). Studies using various mouse models of cancer indicate that let-7 usually inhibits tumor growth in adult mice (Esquela-Kerscher et al, 2008;Hu et al, 2013;Wu et al, 2015). A handful of previous studies have also implicated let-7 in the regulation of glucose metabolism and amino acid sensing (Boyerinas et al, 2010;Dubinsky et al, 2014;Jiang and Baltimore, 2016;Nguyen and Zhu, 2015;Zhu et al, 2011).…”