LncRNAs and microRNAs as Essential Regulators of Stemness in Breast Cancer Stem Cells

Abstract

Breast cancer is an aggressive disease with a high incidence in women worldwide. Two decades ago, a controversial hypothesis was proposed that cancer arises from a subpopulation of “tumor initiating cells” or “cancer stem cells-like” (CSC). Today, CSC are defined as small subset of somatic cancer cells within a tumor with self-renewal properties driven by the aberrant expression of genes involved in the maintenance of a stemness-like phenotype. The understanding of the underlying cellular and molecular mechanisms involved in the maintenance of CSC subpopulation are fundamental in the development and persistence of breast cancer. Nowadays, the hypothesis suggests that genetic and epigenetic alterations give rise to breast cancer stem cells (bCSC), which are responsible for self-renewal, tumor growth, chemoresistance, poor prognosis and low survival in patients. However, the prominence of bCSC, as well as the molecular mechanisms that regulates and promotes the malignant phenotypes, are still poorly understood. The role of non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as oncogenes or tumor suppressor genes has been recently highlighted by a plethora of studies in breast cancer. These ncRNAs positively or negatively impact on different signaling pathways that govern the cancer hallmarks associated with bCSC, making them attractive targets for therapy. In this review, we present a current summary of the studies on the pivotal roles of lncRNAs and microRNAs in the regulation of genes associated to stemness of bCSC.

Cell-Permeable Oct4 Gene Delivery Enhances Stem Cell-like Properties of Mouse Embryonic Fibroblasts

“…In the field of regenerative medicine, direct conversion has advantages in situ and in the generation of clinically relevant cells, including hard-to-achieve cells, from easily obtained cells such as fibroblasts [37,38]. The viral carrier transport efficiency of gene delivery can be high, depending on the type of vector used [15,27]; however, the risk of integration of viral DNA into the host genome raises potential safety issues for potential therapeutics and poses concerns like inefficient/unpredictable reprogramming outcomes, genomic integration, and unwarranted immune responses and toxicity.…”

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

“…More attention has been paid to molecular mechanisms that play a key role in the development of HCC. It has been observed that many cell signaling pathways are essential in regulating critical cell processes, such as cell proliferation, cell cycle progression, and apoptosis [ 41 – 43 ]. As a ceRNA, LncRNA also participates in HCC cell proliferation, epithelial to mesenchymal transition (EMT), invasion and metastasis by regulating signaling pathways in HCC, such as nuclear factor κB (NF-kB) pathway, phosphatidylinositol 3′-kinase(PI3K)-Akt signaling pathway, Wnt/β-catenin pathway, TGF-β pathway, and Janus kinase signal transducer and activator of transcription (JAK/STAT) pathway, which are very important in the process of carcinogenesis (Fig.…”

Epigenetic Regulation of Breast Cancer Stem Cells Contributing to Carcinogenesis and Therapeutic Implications

“…There is a growing list of miRNA genes abnormally methylated in cancer, resulting in dysfunction in normal biological processes and carcinogenesis [ 179 ]. There are two categories for cancer-associated miRNAs: the oncogenic miRNAs (oncomiRs) are usually highly expressed, and they contribute to cancer development and progression and could be useful for diagnosis, prognosis and treatment [ 69 , 70 , 182 ], and the tumor-suppressive miRNAs (miRsupps), which inhibit tumorigenesis by regulating cell proliferation, apoptosis, invasion, metastasis and therapeutic resistance in BCSCs [ 25 , 183 ] ( Figure 2 ). For example, miR-31 is overexpressed in breast cancer and is directly activated by the NF-κB signaling pathway.…”

“…In addition to miRNAs, lncRNAs (200 nucleotides) have emerged as new players in stem cell signaling through multiple mechanisms, mainly via transcriptional, post-transcriptional and epigenetic regulation of genes and proteins, and both play pivotal roles in tumorigenesis, pluripotency, apoptosis, chemoresistance, angiogenesis, self-renewal and metastasis in BCSC subpopulations [ 183 , 196 , 197 ]. Unlike miRNAs and mRNAs, lncRNAs have low expression in breast [ 198 ].…”

“…Interestingly, lncRNAs could act as sponges of miRNAs in BCSC. Hence, lncRNAs could also regulate the expression levels of the targets of miRNA, and this results in a complex interplay among lncRNAs, miRNAs and proteins [ 183 ]. MANCR (mitotically associated noncoding RNA) is upregulated in breast cancer, and downregulation of MANCR reduces TNBC cell proliferation [ 199 ].…”