Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer

Abstract

MicroRNA-155 (miR-155) is frequently up-regulated in various types of human cancer; however, its role in cancer angiogenesis remains unknown. Here, we demonstrate the role of miR-155 in angiogenesis through targeting von Hippel-Lindau tumour suppressor (VHL) in breast cancer. Ectopic expression of miR-155 induced whereas knockdown of miR-155 inhibited HUVEC network formation, proliferation, invasion, and migration. Furthermore, mammary fat pad xenotransplantation of ectopically expressed miR-155 resulted in extensive angiogenesis, proliferation, tumour necrosis, and recruitment of pro-inflammatory cells such as tumour associated macrophages. Expression of VHL abrogated these miR-155 effects. Moreover, miR-155 expression inversely correlates with VHL expression level and is associated with late stage, lymph node metastasis, and poor prognosis as well as triple-negative tumour in breast cancer. These findings indicate that miR-155 plays a pivotal role in tumour angiogenesis by downregulation of VHL, and provide a basis for miR-155-expressing tumours to embody an aggressive malignant phenotype, and therefore, miR-155 is an important therapeutic target in breast cancer.

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

“…Previous studies reported that TGF-β-mediated Smad4 expression induces miR-155 promoter activity and enriches miR-155 expression to contribute to cell migration and invasion (38), and found that NF-κB, STAT5, or CCAAT/enhancer binding protein beta (C/EBPβ) could bind to miR-155 promoter region and induce miR-155 expression in colon cancer, cutaneous T-cell lymphoma, or fat cells (20,39,40). miR-155 has been considered an "oncomicroRNA" by targeting several tumor suppressors, including SOCS1, FOXO3a, RhoA, C/EBPβ, PP2A/C, and von Hippel-Lindau tumor suppressor (VHL), and it has been found to promote the EMT, invasion, metastasis, growth, and angiogenesis of cancer cells (20,(41)(42)(43). In addition, the up-regulation of miR-155 has been reported to promote tumor angiogenesis by targeting VHL and is associated with poor prognosis for breast cancer (43); additionally, the loss of VHL has been reported to induce NF-κB activity (44).…”

“…miR-155 has been considered an "oncomicroRNA" by targeting several tumor suppressors, including SOCS1, FOXO3a, RhoA, C/EBPβ, PP2A/C, and von Hippel-Lindau tumor suppressor (VHL), and it has been found to promote the EMT, invasion, metastasis, growth, and angiogenesis of cancer cells (20,(41)(42)(43). In addition, the up-regulation of miR-155 has been reported to promote tumor angiogenesis by targeting VHL and is associated with poor prognosis for breast cancer (43); additionally, the loss of VHL has been reported to induce NF-κB activity (44). These findings support our results that miR-155 decreased VHL expression, which in turn activated NF-κB; this may contribute to the positive feedback activation of miR-155 and promote gefitinib resistance and cancer stemness.…”

Double-stranded microRNA mimics can induce length- and passenger strand–dependent effects in a cell type–specific manner

“…In contrast, a study of human breast cancer cell lines, ZR-75-1 and MCF-10A, showed that gain-of-function mutant p53 induces expression of miR-155, which inhibits TGF-β signaling by targeting ZNF652 to promote cancer cell invasiveness (Neilsen et al 2013). Moreover, validated miR-155 target transcripts in the context of breast cancer include both tumor-suppressor genes, like CEBP-β, FOXO3a, ZNF652, and VHL, and oncogenes, like BACH1 and SATB1 (Yin et al 2008;Kong et al 2010Kong et al , 2014McInnes et al 2012;Johansson et al 2013;Neilsen et al 2013).…”

miR-1291 targets mucin 1 inhibiting cell proliferation and invasion to promote cell apoptosis in esophageal squamous cell carcinoma

“…Numerous studies have been performed on the role and related mechanism of miRNAs in numerous different kinds of diseases (9)(10)(11)(12). miRNAs bind primarily to the 3'-untranslated region (3'UTR) of their target messenger RNAs (mRNAs) to reduce their stability and decrease the expression of target mRNAs at the post-transcriptional level (13), which play important roles in various biological processes including cell growth, proliferation, differentiation and death (14)(15)(16)(17)(18)(19). Concerning chemotherapy in various types of cancers such as breast cancer, lung adenocarcinoma, glioblastoma, and ovarian cancer, recent studies have shown that miRNAs also act in important roles (20)(21)(22)(23)(24).…”