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MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential.

ABSTRACT: Bone is a frequent site of metastasis. Bone metastasis is associated with a short-term prognosis in cancer patients, and current treatments aim to slow its growth, but are rarely curative. Thus, revealing molecular mechanisms that explain why metastatic cells are attracted to the bone micro-environment, and how they successfully settle in the bone marrow-taking advantage over bone resident cells-and grow into macro-metastasis, is essential to propose new therapeutic approaches. MicroRNAs and snoRNAs are two classes of small non-coding RNAs that post-transcriptionally regulate gene expression. Recently, microRNAs and snoRNAs have been pointed out as important players in bone metastasis by (i) preparing the pre-metastatic niche, directly and indirectly affecting the activities of osteoclasts and osteoblasts, (ii) promoting metastatic properties within cancer cells, and (iii) acting as mediators within cells to support cancer cell growth in bone. This review aims to highlight the importance of microRNAs and snoRNAs in metastasis, specifically in bone, and how their roles can be linked together. We then discuss how microRNAs and snoRNAs are secreted by cancer cells and be found as extracellular vesicle cargo. Finally, we provide evidence of how microRNAs and snoRNAs can be potential therapeutic targets, at least in pre-clinical settings, and how their detection in liquid biopsies can be a useful diagnostic and/or prognostic biomarker to predict the risk of relapse in cancer patients.

SUBMITTER: Puppo M

PROVIDER: S-EPMC9818347 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential.

Puppo Margherita M Jaafar Mariam M Diaz Jean-Jacques JJ Marcel Virginie V Clézardin Philippe P

Cancers 20221230 1

Bone is a frequent site of metastasis. Bone metastasis is associated with a short-term prognosis in cancer patients, and current treatments aim to slow its growth, but are rarely curative. Thus, revealing molecular mechanisms that explain why metastatic cells are attracted to the bone micro-environment, and how they successfully settle in the bone marrow-taking advantage over bone resident cells-and grow into macro-metastasis, is essential to propose new therapeutic approaches. MicroRNAs and sno ...[more]

PMID: 36612237

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Project description:Osteolytic bone metastasis leads to skeletal‑related events, resulting in a decline in the patient activities and survival; therefore, it is important to understand the mechanism underlying bone metastasis. Recent studies have suggested that microRNAs (miRNAs or miRs) are involved in osteoclast differentiation and/or osteolytic bone metastasis; however, the roles of miRNAs have not been elucidated. In the present study, the roles of miRNAs in bone destruction caused by breast cancer metastasis were investigated in vitro and in vivo. miR‑16, miR‑133a and miR‑223 were transfected into a human breast cancer cell line, MDA‑MB‑231. The expression of osteolytic factors in conditioned medium (miR‑CM) collected from the culture of transfected cells was assessed. To evaluate the effects of miRNAs on osteoclast differentiation and activities, tartrate‑resistant acid phosphatase (TRAP) staining and bone resorptive assays were performed in osteoclasts following miR‑CM treatment. To create in vivo bone metastasis models for histological and morphometric evaluation, miRNA‑transfected MDA‑MB‑231 cells were transplanted into the proximal tibia of nude mice. Expression of osteolytic factors, including receptor activator for nuclear factor‑κB ligand (RANKL), interleukin (IL)‑1β, IL‑6, parathyroid hormone‑related protein (PTHrP), and tumor necrosis factor (TNF), was increased in miR‑16‑CM, whereas it was decreased in both miR‑133a‑CM and miR‑223‑CM. TRAP staining and bone resorptive assays revealed that osteoclast function and activities were promoted by miR‑16‑CM treatment, whereas they were suppressed by miR‑133a‑CM and miR‑223‑CM. Consistent with in vitro findings, in vivo experiments revealed that the overexpression of miR‑16 increased osteoclast activities and bone destruction in MDA‑MB‑231 cells, whereas the opposite results were observed in both miR‑133a‑ and miR‑223‑transfected MDA‑MB‑231 cells. Our results indicated that miR‑16 promoted osteoclast activities and bone destruction caused by breast cancer metastasis in the bone microenvironment, whereas miR‑133a and miR‑223 suppressed them. These miRNAs could be potential biomarkers and therapeutic targets for breast cancer bone metastasis.

Project description:BackgroundProstate cancer (PCa), the second most prevalent solid tumor among men worldwide, has caused greatly increasing mortality in PCa patients. The effects of lipid metabolism on tumor growth have been explored, but the mechanistic details of the association of lipid metabolism disorders with PCa remain largely elusive.MethodsThe RNA sequencing data of the GSE45604 and The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD) datasets were extracted from the Gene Expression Omnibus (GEO) and UCSC Xena databases, respectively. The Molecular Signatures Database (MSigDB) was utilized to identify lipid metabolism-related genes. The limma R package was used to identify differentially expressed lipid metabolism-related genes (DE-LMRGs) and differentially expressed microRNAs (DEMs). Moreover, least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (XGBoost), and support vector machine-recursive feature elimination (SVM-RFE) were applied to select signature miRNAs and construct a lipid metabolism-related diagnostic model. The expression levels of selected differentially expressed lipid metabolism-related miRNAs (DE-LMRMs) in PCa and benign prostate hyperplasia (BPH) specimens were verified using quantitative real-time polymerase chain reaction (qRT‒PCR). Furthermore, a transcription factor (TF)-miRNA‒mRNA network was constructed. Eventually, Kaplan‒Meier (KM) curves were plotted to illustrate the associations between signature miRNA-related mRNAs and TFs and overall survival (OS) along with biochemical recurrence-free survival (BCR).ResultsForty-seven LMRMs were screened based on the correlation analysis of 29 DE-LMRGs and 56 DEMs, in which 27 LMRMs were stably expressed in the GSE45604 dataset. Subsequently, receiver operating characteristic (ROC) curves and machine learning methods were employed to develop a lipid metabolism-related diagnostic signature, which may be of diagnostic value for PCa patients. qRT‒PCR results showed that all seven key DE-LMRMs were differentially expressed between PCa and BPH tissues. Eventually, a TF-miRNA‒mRNA network was constructed.ConclusionsThese results suggested that 7 key diagnostic miRNAs were closely related to PCa pathological processes and provided new targets for the diagnosis and treatment of PCa. Moreover, CLIC6 and SCNN1A linked to miR-200c-3p had good prognostic potential and provided valuable insights into the pathogenesis of PCa.

Dataset Information

MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential.

Publications

MiRNAs and snoRNAs in Bone Metastasis: Functional Roles and Clinical Potential.

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