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MicroRNAs in cancer metastasis: biological and therapeutic implications.

ABSTRACT: Cancer metastasis is the primary cause of cancer-related deaths. The seeding of primary tumours at a secondary site is a highly inefficient process requiring substantial alterations in the genetic architecture of cancer cells. These alterations include significant changes in global gene expression patterns. MicroRNAs are small, non-protein coding RNAs which play a central role in regulating gene expression. Here, we focus on microRNA determinants of cancer metastasis and examine microRNA dysregulation in metastatic cancer cells. We dissect the metastatic process in a step-wise manner and summarise the involvement of microRNAs at each step. We also discuss the advantages and limitations of different microRNA-based strategies that have been used to target metastasis in pre-clinical models. Finally, we highlight current clinical trials that use microRNA-based therapies to target advanced or metastatic tumours.

SUBMITTER: Sell MC

PROVIDER: S-EPMC10407223 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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MicroRNAs in cancer metastasis: biological and therapeutic implications.

Sell Marie C MC Ramlogan-Steel Charmaine A CA Steel Jason C JC Dhungel Bijay P BP

Expert reviews in molecular medicine 20230317

Cancer metastasis is the primary cause of cancer-related deaths. The seeding of primary tumours at a secondary site is a highly inefficient process requiring substantial alterations in the genetic architecture of cancer cells. These alterations include significant changes in global gene expression patterns. MicroRNAs are small, non-protein coding RNAs which play a central role in regulating gene expression. Here, we focus on microRNA determinants of cancer metastasis and examine microRNA dysregu ...[more]

PMID: 36927814

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Project description:ImportanceAccurate clinical staging is important in rectal cancer because it determines the appropriate treatment and prognosis. Despite the use of multiple diagnostic imaging tools, it is sometimes difficult to clinically distinguish stage I tumors from stage II or III locally advanced disease. Identification of differentiating microRNAs (miRNAs) between these 2 groups may improve the clinical diagnostic power and provide insight into the biology of tumor progression.ObjectivesTo investigate differences in the expression of miRNAs in stage I vs stage II or III rectal cancers and integrate matched mRNA profiling data to identify possible functional roles of these miRNAs.Design, setting, and participantsThe primary tumor specimens from patients who were enrolled in 2 prospective clinical trials between March 24, 2004, and November 16, 2012 (American College of Surgeons Oncology Group [ACOSOG] Z6041 and Timing of Rectal Cancer Response to Chemoradiation [TIMING]) were sequenced to arrive at a set of 127 cases (41 stage I and 86 stage II or III tumors) with matched miRNA and messenger RNA (mRNA) profiling data. These findings were also evaluated in an independent cohort of 127 patient specimens (29 stage I and 98 stage II or III tumors) from The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) that also had matched miRNA and mRNA data. Data analysis was performed from September 1, 2019, to September 1, 2020.Main outcomes and measuresAlterations in miRNA expression between stage I and stage II or III tumors and their potential gene targets.ResultsA total of 254 pretreatment rectal adenocarcinoma specimens were analyzed in this study as 2 distinct cohorts: 127 samples in the ACOSOG/TIMING (stage I group: 27 [66%] male; mean [SD] age, 64.4 [10.8] years; stage II or III group: 47 [55%] male; mean [SD] age, 57.0 [11.4] years), and another 127 samples from TCGA-READ (stage I group: 17 [59%] male; mean [SD] age, 63.6 [12.0] years; stage II or III group: 48 [49%] male; mean [SD] age, 64.5 [11.4] years). A total of 19 miRNAs were overexpressed in stage II or III vs stage I tumors in both cohorts. This miRNA signature had an excellent discriminative value for distinguishing stage II or III from stage I rectal tumors (area under the curve, 0.88; 95% CI, 0.83-0.94 in ACOSOG/TIMING cohort and area under the curve, 0.84; 95% CI, 0.77-0.91 in the TCGA-READ cohort). Integrative analysis revealed 3 miRNA-mRNA pairs that exhibited significant correlations in both cohorts: miR-31-5p-SATB2, miR-143-3p-KLF5, and miR-204-5p-EZR.Conclusions and relevanceThis diagnostic study found that many of the dysregulated miRNAs in stage II or III vs stage I rectal cancers have biological implications for tumor progression. The results of this study suggest that these miRNAs could assist as diagnostic biomarkers to better identify patients with locally advanced rectal cancer.

Project description:BackgroundBone metastasis from prostate cancer severely impacts patient outcomes and quality of life. Anoikis, a form of programmed cell death triggered by the loss of cell-matrix interactions, plays a critical role in cancer progression. However, its precise relationship with prostate cancer-induced bone metastasis remains unclear. This study aims to elucidate this relationship, focusing on anoikis-related gene signatures, molecular pathways, and therapeutic implications.MethodsWe used the TCGA-PRAD dataset for training, with MSKCC and GSE70769 as validation cohorts. To evaluate immunotherapy efficacy, we examined IMvigor 210 and GSE91016 datasets, and GSE137829 provided single-cell insights into prostate cancer. Specific anoikis-related genes (ARGs) were identified, and Random Survival Forest analysis and multivariate Cox regression were employed to develop anoikis-linked features. The 'clustanoikisProfilanoikis' and 'GSEA' packages were used to explore potential ARG-related pathways.ResultsAnalyzing 553 samples from TCGA, 231 from MSKCC, 94 from GSE70769, and single-cell data from 6 prostate cancer patients (GSE137829), we constructed a prognostic model based on 9 ARGs. GSVA revealed upregulation of carcinogenic pathways, including epithelial-mesenchymal transition, E2F targets, and angiogenesis, with downregulation of metabolic pathways. Significant differences in somatic mutations were observed between cohorts, with a positive correlation between anoikis scores and tumor mutational burden (TMB). Immune landscape analysis suggested high-risk patients might benefit more from chemotherapy than immunotherapy based on their risk score. Single-cell analysis indicated overactivation of carcinogenic pathways in the high anoikis score group.ConclusionThis study elucidates the complex interplay between anoikis and bone metastasis in prostate cancer. Our findings highlight the critical role of anoikis in metastatic progression, enhancing the understanding of key biomarkers and molecular dynamics. The identified anoikis-related gene signatures and disrupted pathways offer promising avenues for predictive and therapeutic strategies in prostate cancer management.

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MicroRNAs in cancer metastasis: biological and therapeutic implications.

Publications

MicroRNAs in cancer metastasis: biological and therapeutic implications.

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