ABSTRACT
BACKGROUND: Transforming growth factor-beta1 (TGF-ß1) acts as a most effective growth inhibitor for normal epithelial cells. Loss of this anti-proliferative factor in breast tissues favors invasion and development of osteolytic metastases, aided by a master transcription factor, runt-related transcription factor 2 (Runx2). Several reports identified Runx2 regulation with the help of non-coding RNAs such as microRNAs (miRNAs) under physiological and pathological conditions. METHODS: Using bioinformatics tools such as miRDB, STarMir, Venny, TarBase, a unique list of miRNAs that putatively target the 3' UTR Runx2 was identified. Further, the expression patterns of those miRNAs at the precursor and mature levels were studied by RT-qPCR analyses. Following this, computational analyses using software like TransmiR and bc-GenExMiner v4.6 were done to speculate the miRNA's other target genes that indirectly regulate Runx2 activity in breast cancer. RESULTS: There were 13 miRNAs that putatively target Runx2 identified using bioinformatics tools. Among these miRNAs, miR-5703 expression was significantly downregulated at both precursor and mature levels upon TGF-ß1-treatment in human breast cancer cells. Computational analyses speculated an indirect targeting of Runx2 by miR-5703 by influencing multiple Runx2 regulatory signaling pathways including Jak/Stat, MAPK, Wnt/ß-Catenin, Notch, BMP, and PKA pathways. Furthermore, a correlation of the expression profiles of the speculated genes and Runx2 with miR-5703 was depicted in triple-negative breast cancer patients. CONCLUSION: Identification of miR-5703 and its network for Runx2 regulation directly or indirectly in breast cancer cells could significantly advance our understanding of breast cancer-mediated bone metastasis. In addition, it would potentially pave the way for miRNAs to be used as biomarkers and therapeutic agents in cancer research.
Subject(s)
Breast Neoplasms , MicroRNAs , Breast Neoplasms/genetics , Core Binding Factor Alpha 1 Subunit/genetics , Female , Humans , MicroRNAs/genetics , Signal Transduction , Transforming Growth Factor beta1/geneticsABSTRACT
Breast cancer (BC) is a critical health care issue that substantially affects women worldwide. Though surgery and chemotherapy can effectively control tumor growth, metastasis remains a primary concern. Metastatic BC cells predominantly colonize in bone, owing to their rigid osseous nutrient-rich nature. There are recently increasing studies investigating the context-dependent roles of non-coding RNAs (ncRNAs) in metastasis regulation. ncRNAs, including microRNAs, long non-coding RNAs, circular RNAs, and small interference RNAs, control the BC metastasis via altered mechanisms. Additionally, these ncRNAs have been reported in regulating a unique class of genes known as Metastatic suppressors. Metastasis suppressors like BRMS1, NM23, LIFR, and KAI1, etc., have been extensively studied for their role in inducing apoptosis, inhibiting metastasis, and maintaining homeostasis. In this review, we have emphasized the direct regulation of ncRNAs for effectively controlling the distant spread of BC. Furthermore, we have highlighted the ncRNA-mediated modulation of the metastatic suppressors, thereby delineating their indirect influence over metastasis.
Subject(s)
Bone Neoplasms , Breast Neoplasms , Neoplasm Proteins , RNA, Neoplasm , RNA, Untranslated , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Bone Neoplasms/secondary , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Neoplasm Metastasis , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , RNA, Untranslated/genetics , RNA, Untranslated/metabolismABSTRACT
In recent years, phytochemicals have been widely researched and utilized for the treatment of various medical conditions such as cancer, cardiovascular diseases, age-related problems and are also said to have bone regenerative effects. In this study, phytol (3,7,11,15-tetramethylhexadec-2-en-1-ol), an acyclic unsaturated diterpene alcohol and a secondary metabolite derived from aromatic plants was investigated for its effect on osteogenesis. Phytol was found to be nontoxic in mouse mesenchymal stem cells (C3H10T1/2). At the cellular level, phytol-treatment promoted osteoblast differentiation, as seen by the increased calcium deposits. At the molecular level, phytol-treatment stimulated the expression of Runx2 (a bone-related transcription factor) and other osteogenic marker genes. MicroRNAs (miRNAs) play an essential role in controlling bone metabolism by targeting genes at the post-transcriptional level. Upon phytol-treatment in C3H10T1/2 cells, mir-21a and Smad7 levels were increased and decreased, respectively. It was previously reported that mir-21a targets Smad7 (an antagonist of TGF-beta1 signaling) and thus, protects Runx2 from its degradation. Thus, based on our results, we suggest that phytol-treatment promoted osteoblast differentiation in C3H10T1/2 cells via Runx2 due to downregulation of Smad7 by mir-21a. Henceforth, phytol was identified to bolster osteoblast differentiation, which in turn may be used for bone regeneration.
