MicroRNA-143-5p Suppresses ER-Positive Breast Cancer Development by Targeting Oncogenic HMGA2.

BACKGROUND: About 70%-80% of breast cancers (BCs) express estrogen receptors (ER-positive). MicroRNAs (miRNAs) are a group of small endogenous noncoding RNAs that play a critical regulatory role in cancer development and progression, including in BC. MiRNA deficiency promotes the development of BCs. MiR-143-5p is one of the most commonly dysregulated miRNAs in BC but its role as a tumor suppressor remains unclear. MATERIALS AND METHODS: MiR-143-3p and -5p expression in breast tissue was analyzed using TCGA and StarBase databases. Expression in BC subclasses and survival analyses were conducted. Clinical samples were collected, cell cultures created, and gene expression assays performed following previous studies. Protein expression, luciferase reporter, wound healing, DAPI staining, cell cycle, colony formation, spheroid, CD44 FACS, and proliferation assays were conducted following various protocols. RESULTS: Here, we find that both miR-143-3p and miR-143-5p levels are considerably lower in BC tissue compared to normal breast tissue and low miR-143 expression predicts poor prognosis in ER+ BC patients. In-depth analyses identified 3 miR-143-5p binding sites in the 3' untranslated region (UTR) of the DNA binding protein High Mobility Group AT-Hook 2 (HMGA2). Luciferase reporter assays using wild-type and mutant HMGA2 3'UTR sequences and Western blot analyses demonstrated that HMGA2 is a direct and bona fide miR-143-5p target in BC cells. In addition, we show that restoration of miR-143-5p expression suppresses metastasis-related features of ER+ BC cells, including reduced tumor cell migration, increased E-cadherin expression, and decreased vimentin and N-cadherin expression. Furthermore, miR-143-5p reduces cell proliferation, cell cycle entry, and stemness, while promoting apoptosis moderately. Finally, patient sample pathway analyses demonstrated that these mechanisms are also active in BC. CONCLUSIONS: Altogether, our findings shed new light on miR-143-5p's anticancer biological functions in BC progression by directly targeting HMGA2. This suggests that restoration of miR-143-5p could be a promising new therapeutic approach for the treatment of ER+ BC.

Mutant P53 in the formation and progression of the tumor microenvironment: Friend or foe.

TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.

Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs.

Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.

MicroRNAs in the cancer cell-to-cell communication: An insight into biological vehicles.

Cell-to-cell communication networks have indispensable roles in coordinating various biological processes in cancer cells or altering metabolism activity in both cancer and non-cancer cells. Exosomes, migrasomes, ectosomes, apoptotic bodies, and exomeres belonging to the heterogeneous world of extracellular vesicles (EVs), which have gained significant attention in recent years due to their principal role in cell-to-cell communication, including Extracellular Circulating miRNAs (ECmiRNAs) as a rich cargo content. ECmiRNAs can be taken up by target cells to mediate heterotypic cell-interactions and facilitate recipient repression in neighboring cells. The complex of ECmiRNAs with EVs, proteins, and lipoproteins structures such as TLR, AGO protein complex, HDL, and LDL can be more effective as mediators between cancer cells. The mechanism of multidrug resistance and angiogenesis in cancer cells may be altered during special signaling of EVs-ECmiRNAs during cell-to-cell communication. Also, those complexes may serve as novel biomarkers in cancer prognostication.

The Role of microRNAs in Multidrug Resistance of Glioblastoma.

Glioblastoma (GBM) is an aggressive brain tumor that develops from neuroglial stem cells and represents a highly heterogeneous group of neoplasms. These tumors are predominantly correlated with a dismal prognosis and poor quality of life. In spite of major advances in developing novel and effective therapeutic strategies for patients with glioblastoma, multidrug resistance (MDR) is considered to be the major reason for treatment failure. Several mechanisms contribute to MDR in GBM, including upregulation of MDR transporters, alterations in the metabolism of drugs, dysregulation of apoptosis, defects in DNA repair, cancer stem cells, and epithelial-mesenchymal transition. MicroRNAs (miRNAs) are a large class of endogenous RNAs that participate in various cell events, including the mechanisms causing MDR in glioblastoma. In this review, we discuss the role of miRNAs in the regulation of the underlying mechanisms in MDR glioblastoma which will open up new avenues of inquiry for the treatment of glioblastoma.

The synergy between miR-486-5p and tamoxifen causes profound cell death of tamoxifen-resistant breast cancer cells.

Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486-5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486-5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486-5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486-5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486-5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486-5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC.