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16 pages, 3835 KiB

Open AccessArticle

MiR-150-5p Overexpression in Triple-Negative Breast Cancer Contributes to the In Vitro Aggressiveness of This Breast Cancer Subtype

by Bruna M. Sugita, Yara Rodriguez, Aline S. Fonseca, Emanuelle Nunes Souza, Bhaskar Kallakury, Iglenir J. Cavalli, Enilze M. S. F. Ribeiro, Ritu Aneja and Luciane R. Cavalli

Cancers 2022, 14(9), 2156; https://doi.org/10.3390/cancers14092156 - 26 Apr 2022

Cited by 11 | Viewed by 1990

Abstract

MiR-150-5p is frequently deregulated in cancer, with expression and mode of action varying according to the tumor type. Here, we investigated the expression levels and role of miR-150-5p in the aggressive breast cancer subtype triple-negative breast cancer (TNBC). MiR-150-5p expression levels were analyzed [...] Read more.

MiR-150-5p is frequently deregulated in cancer, with expression and mode of action varying according to the tumor type. Here, we investigated the expression levels and role of miR-150-5p in the aggressive breast cancer subtype triple-negative breast cancer (TNBC). MiR-150-5p expression levels were analyzed in tissue samples from 113 patients with invasive breast cancer (56 TNBC and 57 non-TNBC) and 41 adjacent non-tumor tissues (ANT). Overexpression of miR-150-5p was observed in tumor tissues compared with ANT tissues and in TNBC compared with non-TNBC tissues. MiR-150-5p expression levels were significantly associated with high tumor grades and the Caucasian ethnicity. Interestingly, high miR-150-5p levels were associated with prolonged overall survival. Manipulation of miR-150-5p expression in TNBC cells modulated cell proliferation, clonogenicity, migration, and drug resistance. Manipulation of miR-150-5p expression also resulted in altered expression of its mRNA targets, including epithelial-to-mesenchymal transition markers, MYB, and members of the SRC pathway. These findings suggest that miR-150-5p is overexpressed in TNBC and contributes to the aggressiveness of TNBC cells in vitro. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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15 pages, 3114 KiB

Open AccessArticle

Overexpression of miR-20a-5p in Tumor Epithelium Is an Independent Negative Prognostic Indicator in Prostate Cancer—A Multi-Institutional Study

by Maria J. Stoen, Sigve Andersen, Mehrdad Rakaee, Mona I. Pedersen, Lise M. Ingebriktsen, Tom Donnem, Ana P. G. Lombardi, Thomas K. Kilvaer, Lill-Tove R. Busund and Elin Richardsen

Cancers 2021, 13(16), 4096; https://doi.org/10.3390/cancers13164096 - 14 Aug 2021

Cited by 11 | Viewed by 1838

Abstract

Objective: assessing the prognostic role of miR-20a-5p, in terms of clinical outcome, in a large multi-institutional cohort study. Methods: Tissue microarrays from 535 patients’ prostatectomy specimens were constructed. In situ hybridization was performed to assess the expression level of miR-20a-5p in different tissue [...] Read more.

Objective: assessing the prognostic role of miR-20a-5p, in terms of clinical outcome, in a large multi-institutional cohort study. Methods: Tissue microarrays from 535 patients’ prostatectomy specimens were constructed. In situ hybridization was performed to assess the expression level of miR-20a-5p in different tissue subregions: tumor stroma (TS) and tumor epithelium (TE). In vitro analysis was performed on prostate cancer cell lines. Results: A high miR-20a-5p expression was found negatively in association with biochemical failure in TE, TS and TE + TS (p = 0.001, p = 0.003 and p = 0.001, respectively). Multivariable analysis confirmed that high miR-20a-5p expression in TE independently predicts dismal prognosis for biochemical failure (HR = 1.56, 95% CI: 1.10–2.21, p = 0.014). Both DU145 and PC3 cells exhibited increased migration ability after transient overexpression of miR-20a-5p, as well as significant elevation of invasion in DU145 cells. Conclusion: A high miR-20a-5p expression in tumor epithelium is an independent negative predictor for biochemical prostate cancer recurrence. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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23 pages, 5392 KiB

Open AccessArticle

miR-92b-3p Regulates Cell Cycle and Apoptosis by Targeting CDKN1C, Thereby Affecting the Sensitivity of Colorectal Cancer Cells to Chemotherapeutic Drugs

by Fangqing Zhao, Zhongmin Yang, Xiaofan Gu, Lixing Feng, Mingshi Xu and Xiongwen Zhang

Cancers 2021, 13(13), 3323; https://doi.org/10.3390/cancers13133323 - 02 Jul 2021

Cited by 5 | Viewed by 2767

Abstract

Colorectal cancer (CRC) is the third most common malignant tumor in the world and the second leading cause of cancer death. Multidrug resistance (MDR) has become a major obstacle in the clinical treatment of CRC. The clear molecular mechanism of MDR is complex, [...] Read more.

Colorectal cancer (CRC) is the third most common malignant tumor in the world and the second leading cause of cancer death. Multidrug resistance (MDR) has become a major obstacle in the clinical treatment of CRC. The clear molecular mechanism of MDR is complex, and miRNAs play an important role in drug resistance. This study used small RNAomic screens to analyze the expression profiles of miRNAs in CRC HCT8 cell line and its chemoresistant counterpart HCT8/T cell line. It was found that miR-92b-3p was highly expressed in HCT8/T cells. Knockdown of miR-92b-3p reversed the resistance of MDR HCT8/T cells to chemotherapeutic drugs in vitro and in vivo. Paclitaxel (PTX, a chemotherapy medication) could stimulate CRC cells to up-regulate miR-92b-3p expression and conferred cellular resistance to chemotherapeutic drugs. In studies on downstream molecules, results suggested that miR-92b-3p directly targeted Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, which encodes a cell cycle inhibitor p57Kip2) to inhibit its expression and regulate the sensitivity of CRC cells to chemotherapeutic drugs. Mechanism study revealed that the miR-92b-3p/CDKN1C axis exerted a regulatory effect on the sensitivity of CRC cells via the regulation of cell cycle and apoptosis. In conclusion, these findings showed that miR-92b-3p/CDKN1C was an important regulator in the development of drug resistance in CRC cells, suggesting its potential application in drug resistance prediction and treatment. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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14 pages, 1738 KiB

Open AccessArticle

Cancer Cells’ Metabolism Dynamics in Renal Cell Carcinoma Patients’ Outcome: Influence of GLUT-1-Related hsa-miR-144 and hsa-miR-186

by Mariana Morais, Francisca Dias, Inês Nogueira, Anabela Leão, Nuno Gonçalves, Luís Araújo, Sara Granja, Fátima Baltazar, Ana L Teixeira and Rui Medeiros

Cancers 2021, 13(7), 1733; https://doi.org/10.3390/cancers13071733 - 06 Apr 2021

Cited by 12 | Viewed by 2744

Abstract

The cancer cells’ metabolism is altered due to deregulation of key proteins, including glucose transporter 1 (GLUT-1), whose mRNA levels are influenced by microRNAs (miRNAs). Renal cell carcinoma (RCC) is the most common and lethal neoplasia in the adult kidney, mostly due to [...] Read more.

The cancer cells’ metabolism is altered due to deregulation of key proteins, including glucose transporter 1 (GLUT-1), whose mRNA levels are influenced by microRNAs (miRNAs). Renal cell carcinoma (RCC) is the most common and lethal neoplasia in the adult kidney, mostly due to the lack of accurate diagnosis and follow-up biomarkers. Being a metabolic associated cancer, this study aimed to understand the hsa-miR-144-5p and hsa-miR-186-3p’s potential as biomarkers of clear cell RCC (ccRCC), establishing their role in its glycolysis status. Using three ccRCC lines, the intra- and extracellular levels of both miRNAs, GLUT-1’s mRNA expression and protein levels were assessed. Glucose consumption and lactate production were evaluated as glycolysis markers. A decrease of intracellular levels of these miRNAs and increase of their excretion was observed, associated with an increase of GLUT-1’s levels and glycolysis’ markers. Through a liquid biopsy approach, we found that RCC patients present higher plasmatic levels of hsa-miR-186-3p than healthy individuals. The Hsa-miR144-5p’s higher levels were associated with early clinical stages. When patients were stratified according to miRNAs plasmatic levels, low plasmatic levels of hsa-miR-144-5p and high plasmatic levels of hsa-miR-186-3p (high-risk group) showed the worst overall survival. Thus, circulating levels of these miRNAs may be potential biomarkers of ccRCC prognosis. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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Review

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24 pages, 1557 KiB

Open AccessEditor’s ChoiceReview

The Roles of microRNAs in Cancer Multidrug Resistance

by Lucia Pavlíková, Mário Šereš, Albert Breier and Zdena Sulová

Cancers 2022, 14(4), 1090; https://doi.org/10.3390/cancers14041090 - 21 Feb 2022

Cited by 20 | Viewed by 3362

Abstract

Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes [...] Read more.

Cancer chemotherapy may induce a multidrug resistance (MDR) phenotype. The development of MDR is based on various molecular causes, of which the following are very common: induction of ABC transporter expression; induction/activation of drug-metabolizing enzymes; alteration of the expression/function of apoptosis-related proteins; changes in cell cycle checkpoints; elevated DNA repair mechanisms. Although these mechanisms of MDR are well described, information on their molecular interaction in overall multidrug resistance is still lacking. MicroRNA (miRNA) expression and subsequent RNA interference are candidates that could be important players in the interplay of MDR mechanisms. The regulation of post-transcriptional processes in the proteosynthetic pathway is considered to be a major function of miRNAs. Due to their complementarity, they are able to bind to target mRNAs, which prevents the mRNAs from interacting effectively with the ribosome, and subsequent degradation of the mRNAs can occur. The aim of this paper is to provide an overview of the possible role of miRNAs in the molecular mechanisms that lead to MDR. The possibility of considering miRNAs as either specific effectors or interesting targets for cancer therapy is also analyzed. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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15 pages, 9787 KiB

Open AccessFeature PaperReview

The Molecular Networks of microRNAs and Their Targets in the Drug Resistance of Colon Carcinoma

by Francesca Crudele, Nicoletta Bianchi, Annalisa Astolfi, Silvia Grassilli, Federica Brugnoli, Anna Terrazzan, Valeria Bertagnolo, Massimo Negrini, Antonio Frassoldati and Stefano Volinia

Cancers 2021, 13(17), 4355; https://doi.org/10.3390/cancers13174355 - 28 Aug 2021

Cited by 6 | Viewed by 2672

Abstract

Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs (miRNAs) are a subgroup of non-coding [...] Read more.

Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs (miRNAs) are a subgroup of non-coding RNAs increasingly found to be associated with the regulation of tumorigenesis and drug resistance. We performed a systematic review of the articles concerning miRNAs and drug resistance in human colon cancer published from 2013 onwards in journals with an impact factor of 5 or higher. First, we built a network with the most studied miRNAs and targets (as nodes) while the drug resistance/s are indicated by the connections (edges); then, we discussed the most relevant miRNA/targets interactions regulated by drugs according to the network topology and statistics. Finally, we considered the drugs as nodes in the network, to allow an alternative point of view that could flow through the treatment options and the associated molecular pathways. A small number of microRNAs and proteins appeared as critically involved in the most common drugs used for the treatment of patients with colon cancer. In particular, the family of miR-200, miR34a, miR-155 and miR-17 appear as the most relevant microRNAs. Thus, regulating these miRNAs could be useful for interfering with some drug resistance mechanisms in colorectal carcinoma. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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14 pages, 498 KiB

Open AccessReview

MicroRNAs as Potential Predictors of Response to CDK4/6 Inhibitor Treatment

by Angeliki Andrikopoulou, Almog Shalit, Eleni Zografos, Konstantinos Koutsoukos, Anna-Maria Korakiti, Michalis Liontos, Meletios-Athanasios Dimopoulos and Flora Zagouri

Cancers 2021, 13(16), 4114; https://doi.org/10.3390/cancers13164114 - 16 Aug 2021

Cited by 13 | Viewed by 2529

Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as novel treatment options in the management of advanced or metastatic breast cancer. MicroRNAs are endogenous non-coding 19–22-nucleotide-long RNAs that regulate gene expression in development and tumorigenesis. Herein, we systematically review all microRNAs associated with response [...] Read more.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as novel treatment options in the management of advanced or metastatic breast cancer. MicroRNAs are endogenous non-coding 19–22-nucleotide-long RNAs that regulate gene expression in development and tumorigenesis. Herein, we systematically review all microRNAs associated with response to CDK4/6 inhibitors in solid tumors and hematological malignancies. Eligible articles were identified by a search of the MEDLINE and ClinicalTrials.gov databases for the period up to1 January 2021; the algorithm consisted of a predefined combination of the words “microRNAs”, “cancer” and “CDK 4/6 inhibitors”. Overall, 15 studies were retrieved. Six microRNAs (miR-126, miR-326, miR3613-3p, miR-29b-3p, miR-497 and miR-17-92) were associated with sensitivity to CDK4/6 inhibitors. Conversely, six microRNAs (miR-193b, miR-432-5p, miR-200a, miR-223, Let-7a and miR-21) conferred resistance to treatment with CDK4/6 inhibitors. An additional number of microRNAs (miR-124a, miR9, miR200b and miR-106b) were shown to mediate cellular response to CDK4/6 inhibitors without affecting sensitivity to treatment. Collectively, our review provides evidence that microRNAs could serve as predictive biomarkers for treatment with CDK4/6 inhibitors. Moreover, microRNA-targeted therapy could potentially maximize sensitivity to CDK4/6 inhibition. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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54 pages, 3225 KiB

Open AccessReview

Regulators at Every Step—How microRNAs Drive Tumor Cell Invasiveness and Metastasis

by Tomasz M. Grzywa, Klaudia Klicka and Paweł K. Włodarski

Cancers 2020, 12(12), 3709; https://doi.org/10.3390/cancers12123709 - 10 Dec 2020

Cited by 22 | Viewed by 4862

Abstract

Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by [...] Read more.

Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial–mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis. Full article

(This article belongs to the Special Issue The Roles of microRNAs in Cancer Aggressiveness and Drug Resistance)

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