miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

Abstract

Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

“…RNAi is a post-transcriptional gene silencing mechanism participating in the natural process of resistance to the invasion of pathogenic, exogenous, double-stranded RNA; it is executed by three types of small non-coding RNAs (microRNA, siRNA, and short hairpin RNA (shRNA)) [ 53 , 54 ]. siRNA and miRNA can knock down the expression of target genes in a sequence-specific way by inducing mRNA degradation (for siRNA and miRNA) or blocking mRNA translation (for miRNA), a kind of post-transcriptional regulation widely investigated in cancer [ 55 , 56 , 57 ]. siRNA consists in a double strand of RNA containing a homologous sequence to a specific gene, with the ability to silence it.…”

MicroRNAs regulating SOX2 in cancer progression and therapy response

“…MiRNA-216a inhibits interaction of cancer cells with CAFs to suppress breast cancer progression (Ref. 294). The studies highlight the fact that SOX2 and miRNAs can affect TME components, such interaction was mentioned about SOX2 and recruiting macrophages.…”

Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer

“…Suppresses stemness and the release of soluble factors associated with cancer-associated fibroblast activation [194] PKCα Survival and migration [195] PAK2 Proliferation and metastasis [196] SDCBP [197] P2X7R Proliferation and survival [198] HDAC8 Proliferation and colony formation [199] miR-223…”

“…Briefly, these four ts-miRNAs could interact with multiple protein partners and suppress the oncogenic properties of breast cancers; 1) miR-26a binds to RNF6 [ 53 ], CHD1 [ 54 ], GREB1 [ 54 ], KPNA2 [ 54 ], metadherin [ 55 ] and MCL-1 [ 56 ], 2) miR-193a/b to DDAH1 [ 172 ], PTP1B [ 173 ], MORC4 [ 174 ], WT1 [ 175 ], RAB22A [ 176 ], uPA [ 178 ], 3) miR-216a/b to TLR4 [ 194 ], PKC-α [ 195 ], PAK2 [ 196 ], SDCBP [ 197 ], P2X7R [ 198 ] and HDAC8 [ 199 ] and 4) miR223 to caprin-1 [ 203 ] and STAT5A [ 206 ]. Particularly, miR-26a, miR-193a/b and miR-223 could re-sensitize breast cancer cell lines to chemotherapeutic drugs.…”