Journal of Clinical Medicine

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Preliminary Analysis of the Expression of Selected Proangiogenic and Antioxidant Genes and MicroRNAs in Patients with Non-Muscle-Invasive Bladder Cancer

by Magdalena Kozakowska, Barbara Dobrowolska-Glazar, Krzysztof Okoń, Alicja Józkowicz, Zygmunt Dobrowolski and Józef Dulak

J. Clin. Med. 2016, 5(3), 29; https://doi.org/10.3390/jcm5030029 - 25 Feb 2016

Cited by 22 | Viewed by 5637

Abstract

Heme oxygenase-1 (HO-1) is an enzyme contributing to the development and progression of different cancer types. HO-1 plays a role in pathological angiogenesis in bladder cancer and contributes to the resistance of this cancer to therapy. It also regulates the expression of microRNAs [...] Read more.

Heme oxygenase-1 (HO-1) is an enzyme contributing to the development and progression of different cancer types. HO-1 plays a role in pathological angiogenesis in bladder cancer and contributes to the resistance of this cancer to therapy. It also regulates the expression of microRNAs in rhabdomyosarcoma and non-small cell lung cancer. The expression of HO-1 may be regulated by hypoxia inducible factors (HIFs) and Nrf2 transcription factor. The expression of HO-1 has not so far been examined in relation to Nrf2, HIF-1α, and potential mediators of angiogenesis in human bladder cancer. We measured the concentration of proinflammatory and proangiogenic cytokines and the expression of cytoprotective and proangiogenic mRNAs and miRNAs in healthy subjects and patients with bladder cancer. HO-1 expression was upregulated together with HIF-1α, HIF-2α, and Nrf2 in bladder cancer in comparison to healthy tissue. VEGF was elevated both at mRNA and protein level in the tumor and in sera, respectively. Additionally, IL-6 and IL-8 were increased in sera of patients affected with urothelial bladder cancer. Moreover, miR-155 was downregulated whereas miR-200c was elevated in cancer biopsies in comparison to healthy tissue. The results indicate that the increased expression of HO-1 in bladder cancer is paralleled by changes in the expression of other potentially interacting genes, like Nrf2, HIF-1α, HIF-2α, IL-6, IL-8, and VEGF. Further studies are necessary to also elucidate the potential links with miR-155 and miR-200c. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessArticle

Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow

by Ayaka Okamoto, Tomohiro Asai, Sho Ryu, Hidenori Ando, Noriyuki Maeda, Takehisa Dewa and Naoto Oku

J. Clin. Med. 2016, 5(1), 10; https://doi.org/10.3390/jcm5010010 - 19 Jan 2016

Cited by 17 | Viewed by 5789

Abstract

Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused [...] Read more.

Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused on blood flow in tumors treated with miR499, since some angiogenic vessels are known to lack blood flow. Tetraethylenepentamine-based polycation liposomes (TEPA-PCL) were prepared and modified with Ala-Pro-Arg-Pro-Gly peptide (APRPG) for targeted delivery of miR-499 (APRPG-miR-499) to angiogenic vessels and tumor cells. The tumor blood flow was significantly improved, so-called normalized, after systemic administration of APRPG-miR-499 to Colon 26 NL-17 carcinoma–bearing mice. In addition, the accumulation of doxorubicin (DOX) in the tumors was increased by pre-treatment with APRPG-miR-499. Moreover, the combination therapy of APRPG-miR-499 and DOX resulted in significant suppression of the tumors. Taken together, our present data indicate that miR-499 delivered with APRPG-modified-TEPA-PCL normalized tumor vessels, resulting in enhancement of intratumoral accumulation of DOX. Our findings suggest that APRPG-miR-499 may be a therapeutic, or a combination therapeutic, candidate for cancer treatment. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessArticle

Detection of Exosomal miRNAs in the Plasma of Melanoma Patients

by Susan R. Pfeffer, Kenneth F. Grossmann, Pamela B. Cassidy, Chuan He Yang, Meiyun Fan, Levy Kopelovich, Sancy A. Leachman and Lawrence M. Pfeffer

J. Clin. Med. 2015, 4(12), 2012-2027; https://doi.org/10.3390/jcm4121957 - 17 Dec 2015

Cited by 117 | Viewed by 11593

Abstract

MicroRNAs (miRNAs) are a class of 22–25 nucleotide RNAs that control gene expression at the post-transcriptional level. MiRNAs have potential as cancer biomarkers. Melanoma is a highly aggressive form of skin cancer accounting for almost 4% of cancers among men and women, and [...] Read more.

MicroRNAs (miRNAs) are a class of 22–25 nucleotide RNAs that control gene expression at the post-transcriptional level. MiRNAs have potential as cancer biomarkers. Melanoma is a highly aggressive form of skin cancer accounting for almost 4% of cancers among men and women, and ~80% of skin cancer-related deaths in the US. In the present study we analyzed plasma-derived exosomal miRNAs from clinically affected and unaffected familial melanoma patients (CDKN2A/p16 gene carriers) and compared them with affected (nonfamilial melanoma) and unaffected control subjects in order to identify novel risk biomarkers for melanoma. Intact miRNAs can be isolated from the circulation because of their presence in exosomes. A number of differentially regulated miRNAs identified by NanoString human V2 miRNA array were validated by quantitative PCR. Significantly, miR-17, miR-19a, miR-21, miR-126, and miR-149 were expressed at higher levels in patients with metastatic sporadic melanoma as compared with familial melanoma patients or unaffected control subjects. Surprisingly, no substantial differences in miRNA expression were detected between familial melanoma patients (all inclusive) and unaffected control subjects. The miRNAs differentially expressed in the different patient cohorts, especially in patients with metastatic melanoma, may play important roles in tumor progression and metastasis, and may be used as predictive biomarkers to monitor remission as well as relapse following therapeutic intervention. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessArticle

MicroRNA Library-Based Functional Screening Identified Androgen-Sensitive miR-216a as a Player in Bicalutamide Resistance in Prostate Cancer

by Toshiaki Miyazaki, Kazuhiro Ikeda, Wataru Sato, Kuniko Horie-Inoue, Koji Okamoto and Satoshi Inoue

J. Clin. Med. 2015, 4(10), 1853-1865; https://doi.org/10.3390/jcm4101853 - 21 Oct 2015

Cited by 18 | Viewed by 5538

Abstract

Prostate cancer is a major hormone-dependent tumor affecting men, and is often treated by hormone therapy at the primary stages. Despite its initial efficiency, the disease eventually acquires resistance, resulting in the recurrence of castration-resistant prostate cancer. Recent studies suggest that dysregulation of [...] Read more.

Prostate cancer is a major hormone-dependent tumor affecting men, and is often treated by hormone therapy at the primary stages. Despite its initial efficiency, the disease eventually acquires resistance, resulting in the recurrence of castration-resistant prostate cancer. Recent studies suggest that dysregulation of microRNA (miRNA) function is one of the mechanisms underlying hormone therapy resistance. Identification of critical miRNAs involved in endocrine resistance will therefore be important for developing therapeutic targets for prostate cancer. In the present study, we performed an miRNA library screening to identify anti-androgen bicalutamide resistance-related miRNAs in prostate cancer LNCaP cells. Cells were infected with a lentiviral miRNA library and subsequently maintained in media containing either bicalutamide or vehicle for a month. Microarray analysis determined the amounts of individual miRNA precursors and identified 2 retained miRNAs after one-month bicalutamide treatment. Of these, we further characterized miR-216a, because its function in prostate cancer remains unknown. miR-216a could be induced by dihydrotestosterone in LNCaP cells and ectopic expression of miR-216a inhibited bicalutamide-mediated growth suppression of LNCaP cells. Furthermore, a microarray dataset revealed that the expression levels of miR-216a were significantly higher in clinical prostate cancer than in benign samples. These results suggest that functional screening using an miRNA expression library could be useful for identifying novel miRNAs that contribute to bicalutamide resistance in prostate cancer. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessArticle

Bioinformatic Interrogation of 5p-arm and 3p-arm Specific miRNA Expression Using TCGA Datasets

by Wei-Ting Kuo, Ming-Wei Su, Yungling Leo Lee, Chien-Hsiun Chen, Chew-Wun Wu, Wen-Liang Fang, Kuo-Hung Huang and Wen-chang Lin

J. Clin. Med. 2015, 4(9), 1798-1814; https://doi.org/10.3390/jcm4091798 - 15 Sep 2015

Cited by 16 | Viewed by 8052

Abstract

MicroRNAs (miRNAs) play important roles in cellular functions and developmental processes. They are also implicated in oncogenesis mechanisms and could serve as potential cancer biomarkers. Using high-throughput miRNA sequencing information, expression of both the 5p-arm and 3p-arm mature miRNAs were demonstrated and generated [...] Read more.

MicroRNAs (miRNAs) play important roles in cellular functions and developmental processes. They are also implicated in oncogenesis mechanisms and could serve as potential cancer biomarkers. Using high-throughput miRNA sequencing information, expression of both the 5p-arm and 3p-arm mature miRNAs were demonstrated and generated from the single miRNA hairpin precursor. However, current miRNA annotations lack comprehensive 5p-arm/3p-arm feature annotations. Among known human mature miRNAs, only half of them are annotated with arm features. This generated ambiguous results in many miRNA-Sequencing (miRNA-Seq) studies. In this report, we have interrogated the TCGA (the Cancer Genome Atlas) miRNA expression datasets with an improved, fully annotated human 5p-arm and 3p-arm miRNA reference list. By utilizing this comprehensive miRNA arm-feature annotations, enhanced determinations and clear annotations were achieved for the miRNA isoforms (isomiRs) recognized from the sequencing reads. In the gastric cancer (STAD) dataset, as an example, 32 5p-arm/3p-arm OPEN ACCESS J. Clin. Med. 2015, 4 1799 specific miRNAs were found to be down-regulated and 24 5p-arm/3p-arm specific miRNAs were found to be up-regulated. We have further extended miRNA biomarker discoveries to additional TCGA miRNA-Seq datasets and provided extensive expression information on 5p-arm/3p-arm miRNAs across multiple cancer types. Our results identified several miRNAs that could be potential common biomarkers for human cancers. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessCommunication

Identification of Recurrence-Related microRNAs from Bone Marrow in Hepatocellular Carcinoma Patients

by Keishi Sugimachi, Shotaro Sakimura, Akira Tomokuni, Ryutaro Uchi, Hidenari Hirata, Hisateru Komatsu, Yoshiaki Shinden, Tomohiro Iguchi, Hidetoshi Eguchi, Takaaki Masuda, Kazutoyo Morita, Ken Shirabe, Hidetoshi Eguchi, Yoshihiko Maehara, Masaki Mori and Koshi Mimori

J. Clin. Med. 2015, 4(8), 1600-1611; https://doi.org/10.3390/jcm4081600 - 14 Aug 2015

Cited by 5 | Viewed by 5182

Abstract

Hepatocellular carcinoma (HCC) is a poor-prognosis cancer due to its high rate of recurrence. microRNAs (miRNAs) are a class of small non-coding RNA molecules that affect crucial processes in cancer development. The objective of this study is to identify the role of miRNAs [...] Read more.

Hepatocellular carcinoma (HCC) is a poor-prognosis cancer due to its high rate of recurrence. microRNAs (miRNAs) are a class of small non-coding RNA molecules that affect crucial processes in cancer development. The objective of this study is to identify the role of miRNAs in patient bone marrow (BM) and explore the function of these molecules during HCC progression. We purified miRNAs from bone marrow cells of seven HCC patients, and divided them into three fractions by cell surface markers as follows: CD14⁺ (macrophage), CD14⁻/CD45⁺ (lymphocyte), and CD14⁻/CD45⁻/EpCAM⁺ (epithelial cell). We employed microarray-based profiling to analyze miRNA expression in the bone marrow of patients with HCC. Differentially expressed miRNAs were significantly different between fractions from whole bone marrow, macrophages, and lymphocytes, and depended on stages in tumor progression. Differences in expression of miRNAs associated with cell proliferation also varied significantly between HCC patients with recurrence, multiple tumors, and advanced clinical stages. These results suggest that miRNA profiles in separated fractions of BM cells are associated with HCC progression. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessArticle

A Circulating MicroRNA Signature as a Biomarker for Prostate Cancer in a High Risk Group

by Brian D. Kelly, Nicola Miller, Karl J. Sweeney, Garrett C. Durkan, Eamon Rogers, Killian Walsh and Michael J. Kerin

J. Clin. Med. 2015, 4(7), 1369-1379; https://doi.org/10.3390/jcm4071369 - 7 Jul 2015

Cited by 86 | Viewed by 7526

Abstract

Introduction: Mi(cro)RNAs are small non-coding RNAs whose differential expression in tissue has been implicated in the development and progression of many malignancies, including prostate cancer. The discovery of miRNAs in the blood of patients with a variety of malignancies makes them an ideal, [...] Read more.

Introduction: Mi(cro)RNAs are small non-coding RNAs whose differential expression in tissue has been implicated in the development and progression of many malignancies, including prostate cancer. The discovery of miRNAs in the blood of patients with a variety of malignancies makes them an ideal, novel biomarker for prostate cancer diagnosis. The aim of this study was to identify a unique expression profile of circulating miRNAs in patients with prostate cancer attending a rapid access prostate assessment clinic. Methods: To conduct this study blood and tissue samples were collected from 102 patients (75 with biopsy confirmed cancer and 27 benign samples) following ethical approval and informed consent. These patients were attending a prostate assessment clinic. Samples were reverse-transcribed using stem-loop primers and expression levels of each of 12 candidate miRNAs were determined using real-time quantitative polymerase chain reaction. miRNA expression levels were then correlated with clinicopathological data and subsequently analysed using qBasePlus software and Minitab. Results: Circulating miRNAs were detected and quantified in all subjects. The analysis of miRNA mean expression levels revealed that four miRNAs were significantly dysregulated, including let-7a (p = 0.005) which has known tumour suppressor characteristics, along with miR-141 (p = 0.01) which has oncogenic characteristics. In 20 patients undergoing a radical retropubic-prostatectomy, the expression levels of miR-141 returned to normal at day 10 post-operatively. A panel of four miRNAs could be used in combination to detect prostate cancer with an area under the curve (AUC) of 0.783 and a PPV of 80%. Conclusion: These findings identify a unique expression profile of miRNA detectable in the blood of prostate cancer patients. This confirms their use as a novel, diagnostic biomarker for prostate cancer. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Review

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Open AccessReview

The Role of microRNAs in the Diagnosis and Treatment of Pancreatic Adenocarcinoma

by Maria Diab, Irfana Muqbil, Ramzi M. Mohammad, Asfar S. Azmi and Philip A. Philip

J. Clin. Med. 2016, 5(6), 59; https://doi.org/10.3390/jcm5060059 - 16 Jun 2016

Cited by 30 | Viewed by 5839

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy. Disease is diagnosed in an advanced stage in the vast majority of patients, and PDAC cells are often resistant to conventional cytotoxic drugs. Targeted therapies have made no progress in the management of this [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy. Disease is diagnosed in an advanced stage in the vast majority of patients, and PDAC cells are often resistant to conventional cytotoxic drugs. Targeted therapies have made no progress in the management of this disease, unlike other cancers. microRNAs (miRs) are small non-coding RNAs that regulate the expression of multitude number of genes by targeting their 3′-UTR mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. In PDAC, a series of miRs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for therapeutic response in patients. In this mini-review, we present an update on the various different miRs that have been defined in PDAC biology. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Considering Exosomal miR-21 as a Biomarker for Cancer

by Jian Shi

J. Clin. Med. 2016, 5(4), 42; https://doi.org/10.3390/jcm5040042 - 29 Mar 2016

Cited by 89 | Viewed by 7715

Abstract

Cancer is a fatal human disease. Early diagnosis of cancer is the most effective method to prevent cancer development and to achieve higher survival rates for patients. Many traditional diagnostic methods for cancer are still not sufficient for early, more convenient and accurate, [...] Read more.

Cancer is a fatal human disease. Early diagnosis of cancer is the most effective method to prevent cancer development and to achieve higher survival rates for patients. Many traditional diagnostic methods for cancer are still not sufficient for early, more convenient and accurate, and noninvasive diagnosis. Recently, the use of microRNAs (miRNAs), such as exosomal microRNA-21(miR-21), as potential biomarkers was widely reported. This initial systematic review analyzes the potential role of exosomal miR-21 as a general biomarker for cancers. A total of 10 studies involving 318 patients and 215 healthy controls have covered 10 types of cancers. The sensitivity and specificity of pooled studies were 75% (0.70–0.80) and 85% (0.81–0.91), with their 95% confidence intervals (CIs), while the area under the summary receiver operating characteristic curve (AUC) was 0.93. Additionally, we examined and evaluated almost all other issues about biomarkers, including cutoff points, internal controls and detection methods, from the literature. This initial meta-analysis indicates that exosomal miR-21 has a strong potential to be used as a universal biomarker to identify cancers, although as a general biomarker the case number for each cancer type is small. Based on the literature, a combination of miRNA panels and other cancer antigens, as well as a selection of appropriate internal controls, has the potential to serve as a more sensitive and accurate cancer diagnosis tool. Additional information on miR-21 would further support its use as a biomarker in cancer. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

MicroRNA In Lung Cancer: Novel Biomarkers and Potential Tools for Treatment

by Kentaro Inamura and Yuichi Ishikawa

J. Clin. Med. 2016, 5(3), 36; https://doi.org/10.3390/jcm5030036 - 9 Mar 2016

Cited by 166 | Viewed by 10481

Abstract

Lung cancer is the leading cause of cancer death in men and women worldwide. The lack of specific and sensitive tools for early diagnosis as well as still-inadequate targeted therapies contribute to poor outcomes. MicroRNAs are small non-coding RNAs, which regulate gene expression [...] Read more.

Lung cancer is the leading cause of cancer death in men and women worldwide. The lack of specific and sensitive tools for early diagnosis as well as still-inadequate targeted therapies contribute to poor outcomes. MicroRNAs are small non-coding RNAs, which regulate gene expression post-transcriptionally by translational repression or degradation of target mRNAs. A growing body of evidence suggests various roles of microRNAs including development and progression of lung cancer. In lung cancer, several studies have showed that certain microRNA profiles classified lung cancer subtypes, and that specific microRNA expression signatures distinguished between better-prognosis and worse-prognosis lung cancers. Furthermore, microRNAs circulate in body fluids, and therefore may serve as promising biomarkers for early diagnosis of lung cancer as well as for predicting prognosis of patients. In the present review, we briefly summarize microRNAs in the development and progression of lung cancer, focusing on possible applications of microRNAs as novel biomarkers and tools for treatment. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

Decoding the Secret of Cancer by Means of Extracellular Vesicles

by Nobuyoshi Kosaka

J. Clin. Med. 2016, 5(2), 22; https://doi.org/10.3390/jcm5020022 - 4 Feb 2016

Cited by 56 | Viewed by 8761

Abstract

One of the recent outstanding developments in cancer biology is the emergence of extracellular vesicles (EVs). EVs, which are small membrane vesicles that contain proteins, mRNAs, long non-coding RNAs, and microRNAs (miRNAs), are secreted by a variety of cells and have been revealed [...] Read more.

One of the recent outstanding developments in cancer biology is the emergence of extracellular vesicles (EVs). EVs, which are small membrane vesicles that contain proteins, mRNAs, long non-coding RNAs, and microRNAs (miRNAs), are secreted by a variety of cells and have been revealed to play an important role in intercellular communications. These molecules function in the recipient cells; this has brought new insight into cell-cell communication. Recent reports have shown that EVs contribute to cancer cell development, including tumor initiation, angiogenesis, immune surveillance, drug resistance, invasion, metastasis, maintenance of cancer stem cells, and EMT phenotype. In this review, I will summarize recent studies on EV-mediated miRNA transfer in cancer biology. Furthermore, I will also highlight the possibility of novel diagnostics and therapy using miRNAs in EVs against cancer. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

MicroRNA Regulation of Human Breast Cancer Stem Cells

by Yohei Shimono, Junko Mukohyama, Shun-ichi Nakamura and Hironobu Minami

J. Clin. Med. 2016, 5(1), 2; https://doi.org/10.3390/jcm5010002 - 25 Dec 2015

Cited by 80 | Viewed by 11471

Abstract

MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells [...] Read more.

MicroRNAs (miRNAs) are involved in virtually all biological processes, including stem cell maintenance, differentiation, and development. The dysregulation of miRNAs is associated with many human diseases including cancer. We have identified a set of miRNAs differentially expressed between human breast cancer stem cells (CSCs) and non-tumorigenic cancer cells. In addition, these miRNAs are similarly upregulated or downregulated in normal mammary stem/progenitor cells. In this review, we mainly describe the miRNAs that are dysregulated in human breast CSCs directly isolated from clinical specimens. The miRNAs and their clusters, such as the miR-200 clusters, miR-183 cluster, miR-221-222 cluster, let-7, miR-142 and miR-214, target the genes and pathways important for stem cell maintenance, such as the self-renewal gene BMI1, apoptosis, Wnt signaling, Notch signaling, and epithelial-to-mesenchymal transition. In addition, the current evidence shows that metastatic breast CSCs acquire a phenotype that is different from the CSCs in a primary site. Thus, clarifying the miRNA regulation of the metastatic breast CSCs will further advance our understanding of the roles of human breast CSCs in tumor progression. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

microRNA-34a as a Therapeutic Agent against Human Cancer

by Yoshimasa Saito, Toshiaki Nakaoka and Hidetsugu Saito

J. Clin. Med. 2015, 4(11), 1951-1959; https://doi.org/10.3390/jcm4111951 - 16 Nov 2015

Cited by 67 | Viewed by 7547

Abstract

microRNAs (miRNAs) are small non-coding RNAs that down-regulate expression of various target genes. Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis. We and other researchers have demonstrated that important tumor suppressor miRNAs are silenced by epigenetic alterations, [...] Read more.

microRNAs (miRNAs) are small non-coding RNAs that down-regulate expression of various target genes. Cancer-related miRNAs are aberrantly expressed and act as tumor suppressors or oncogenes during carcinogenesis. We and other researchers have demonstrated that important tumor suppressor miRNAs are silenced by epigenetic alterations, resulting in the activation of target oncogenes in cancer cells. miR-34a was identified as a target of p53 and induces a G1 cell cycle arrest, senescence and apoptosis in response to DNA damage. miR-34a is an important tumor suppressor whose expression is epigenetically silenced in various human cancers. Enforced expression of miR-34a induces cell cycle arrest, apoptosis, senescence, and suppression of epithelial-mesenchymal transition and inhibits cell proliferation of cancer stem cells. Epigenetic therapy with chromatin-modifying drugs such as inhibitors of DNA methylation and histone deacetylase has shown clinical promise for the treatment of malignancies. Restoring of miR-34a expression by epigenetic therapy and/or delivery of miR-34a mimics may be a promising therapeutic strategy against human cancer. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

Circulating microRNA Biomarkers as Liquid Biopsy for Cancer Patients: Pros and Cons of Current Assays

by Shigeshi Ono, Stella Lam, Makoto Nagahara and Dave S. B. Hoon

J. Clin. Med. 2015, 4(10), 1890-1907; https://doi.org/10.3390/jcm4101890 - 23 Oct 2015

Cited by 109 | Viewed by 11007 | Correction

Abstract

An increasing number of studies have focused on circulating microRNAs (cmiRNA) in cancer patients’ blood for their potential as minimally-invasive biomarkers. Studies have reported the utility of assessing specific miRNAs in blood as diagnostic/prognostic biomarkers; however, the methodologies are not validated or standardized [...] Read more.

An increasing number of studies have focused on circulating microRNAs (cmiRNA) in cancer patients’ blood for their potential as minimally-invasive biomarkers. Studies have reported the utility of assessing specific miRNAs in blood as diagnostic/prognostic biomarkers; however, the methodologies are not validated or standardized across laboratories. Unfortunately, there is often minimum limited overlap in techniques between results reported even in similar type studies on the same cancer. This hampers interpretation and reliability of cmiRNA as potential cancer biomarkers. Blood collection and processing, cmiRNA extractions, quality and quantity control of assays, defined patient population assessment, reproducibility, and reference standards all affect the cmiRNA assay results. To date, there is no reported definitive method to assess cmiRNAs. Therefore, appropriate and reliable methodologies are highly necessary in order for cmiRNAs to be used in regulated clinical diagnostic laboratories. In this review, we summarize the developments made over the past decade towards cmiRNA detection and discuss the pros and cons of the assays. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

MicroRNAs and Osteolytic Bone Metastasis: The Roles of MicroRNAs in Tumor-Induced Osteoclast Differentiation

by Tadayoshi Kagiya

J. Clin. Med. 2015, 4(9), 1741-1752; https://doi.org/10.3390/jcm4091741 - 28 Aug 2015

Cited by 37 | Viewed by 10198

Abstract

Osteolytic bone metastasis frequently occurs in the later stages of breast, lung, and several other cancers. Osteoclasts, the only cells that resorb bone, are hijacked by tumor cells, which break down bone remodeling systems. As a result, osteolysis occurs and may cause patients [...] Read more.

Osteolytic bone metastasis frequently occurs in the later stages of breast, lung, and several other cancers. Osteoclasts, the only cells that resorb bone, are hijacked by tumor cells, which break down bone remodeling systems. As a result, osteolysis occurs and may cause patients to suffer bone fractures, pain, and hypercalcemia. It is important to understand the mechanism of bone metastasis to establish new cancer therapies. MicroRNAs are small, noncoding RNAs that are involved in various biological processes, including cellular differentiation, proliferation, apoptosis, and tumorigenesis. MicroRNAs have significant clinical potential, including their use as new therapeutic targets and disease-specific biomarkers. Recent studies have revealed that microRNAs are involved in osteoclast differentiation and osteolytic bone metastasis. In this review focusing on microRNAs, the author discusses the roles of microRNAs in osteoclastogenesis and osteolytic bone metastasis. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

Clinical Potential of microRNA-7 in Cancer

by Jessica L. Horsham, Felicity C. Kalinowski, Michael R. Epis, Clarissa Ganda, Rikki A. M. Brown and Peter J. Leedman

J. Clin. Med. 2015, 4(9), 1668-1687; https://doi.org/10.3390/jcm4091668 - 25 Aug 2015

Cited by 43 | Viewed by 6872

Abstract

microRNAs (miRNAs) are a family of short, non-coding RNA molecules that drive a complex network of post-transcriptional gene regulation by enhancing target mRNA decay and/or inhibiting protein synthesis from mRNA transcripts. They regulate genes involved in key aspects of normal cell growth, development [...] Read more.

microRNAs (miRNAs) are a family of short, non-coding RNA molecules that drive a complex network of post-transcriptional gene regulation by enhancing target mRNA decay and/or inhibiting protein synthesis from mRNA transcripts. They regulate genes involved in key aspects of normal cell growth, development and the maintenance of body homeostasis and have been closely linked to the development and progression of human disease, in particular cancer. Over recent years there has been much interest regarding their potential as biomarkers and as therapeutic agents or targets. microRNA-7 (miR-7) is a 23 nucleotide (nt) miRNA known primarily to act as a tumour suppressor. miR-7 directly inhibits a number of oncogenic targets and impedes various aspects of cancer progression in vitro and in vivo, however, some studies have also implicated miR-7 in oncogenic roles. This review summarises the role of miR-7 in cancer, its potential in miRNA-based replacement therapy and its capacity as both a diagnostic and prognostic biomarker. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

MicroRNA Processing and Human Cancer

by Masahisa Ohtsuka, Hui Ling, Yuichiro Doki, Masaki Mori and George Adrian Calin

J. Clin. Med. 2015, 4(8), 1651-1667; https://doi.org/10.3390/jcm4081651 - 21 Aug 2015

Cited by 165 | Viewed by 14083

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs of 20 to 25 nucleotides that regulate gene expression post-transcriptionally mainly by binding to a specific sequence of the 3′ end of the untranslated region (3′UTR) of target genes. Since the first report on the clinical relevance [...] Read more.

MicroRNAs (miRNAs) are short non-coding RNAs of 20 to 25 nucleotides that regulate gene expression post-transcriptionally mainly by binding to a specific sequence of the 3′ end of the untranslated region (3′UTR) of target genes. Since the first report on the clinical relevance of miRNAs in cancer, many miRNAs have been demonstrated to act as oncogenes, whereas others function as tumor suppressors. Furthermore, global miRNA dysregulation, due to alterations in miRNA processing factors, has been observed in a large variety of human cancer types. As previous studies have shown, the sequential miRNA processing can be divided into three steps: processing by RNAse in the nucleus; transportation by Exportin-5 (XPO5) from the nucleus; and processing by the RNA-induced silencing complex (RISC) in the cytoplasm. Alteration in miRNA processing genes, by genomic mutations, aberrant expression or other means, could significantly affect cancer initiation, progression and metastasis. In this review, we focus on the biogenesis of miRNAs with emphasis on the potential of miRNA processing factors in human cancers. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

Exploring miRNA-Associated Signatures with Diagnostic Relevance in Glioblastoma Multiforme and Breast Cancer Patients

by Véronique C. LeBlanc and Pier Morin, Jr.

J. Clin. Med. 2015, 4(8), 1612-1630; https://doi.org/10.3390/jcm4081612 - 14 Aug 2015

Cited by 13 | Viewed by 5881

Abstract

The growing attention that non-coding RNAs have attracted in the field of cancer research in recent years is undeniable. Whether investigated as prospective therapeutic targets or prognostic indicators or diagnostic biomarkers, the clinical relevance of these molecules is starting to emerge. In addition, [...] Read more.

The growing attention that non-coding RNAs have attracted in the field of cancer research in recent years is undeniable. Whether investigated as prospective therapeutic targets or prognostic indicators or diagnostic biomarkers, the clinical relevance of these molecules is starting to emerge. In addition, identification of non-coding RNAs in a plethora of body fluids has further positioned these molecules as attractive non-invasive biomarkers. This review will first provide an overview of the synthetic cascade that leads to the production of the small non-coding RNAs microRNAs (miRNAs) and presents their strengths as biomarkers of disease. Our interest will next be directed at exploring the diagnostic utility of miRNAs in two types of cancer: the brain tumor glioblastoma multiforme (GBM) and breast cancer. Finally, we will discuss additional clinical implications associated with miRNA detection as well as introduce other non-coding RNAs that have generated recent interest in the cancer research community. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

MicroRNAs and Growth Factors: An Alliance Propelling Tumor Progression

by Merav Kedmi, Aldema Sas-Chen and Yosef Yarden

J. Clin. Med. 2015, 4(8), 1578-1599; https://doi.org/10.3390/jcm4081578 - 13 Aug 2015

Cited by 21 | Viewed by 6992

Abstract

Tumor progression requires cancer cell proliferation, migration, invasion, and attraction of blood and lymph vessels. These processes are tightly regulated by growth factors and their intracellular signaling pathways, which culminate in transcriptional programs. Hence, oncogenic mutations often capture growth factor signaling, and drugs [...] Read more.

Tumor progression requires cancer cell proliferation, migration, invasion, and attraction of blood and lymph vessels. These processes are tightly regulated by growth factors and their intracellular signaling pathways, which culminate in transcriptional programs. Hence, oncogenic mutations often capture growth factor signaling, and drugs able to intercept the underlying biochemical routes might retard cancer spread. Along with messenger RNAs, microRNAs play regulatory roles in growth factor signaling and in tumor progression. Because growth factors regulate abundance of certain microRNAs and the latter modulate the abundance of proteins necessary for growth factor signaling, the two classes of molecules form a dense web of interactions, which are dominated by a few recurring modules. We review specific examples of the alliance formed by growth factors and microRNAs and refer primarily to the epidermal growth factor (EGF) pathway. Clinical applications of the crosstalk between microRNAs and growth factors are described, including relevance to cancer therapy and to emergence of resistance to specific drugs. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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Open AccessReview

Role of MicroRNAs-221/222 in Digestive Systems

by Juntaro Matsuzaki and Hidekazu Suzuki

J. Clin. Med. 2015, 4(8), 1566-1577; https://doi.org/10.3390/jcm4081566 - 6 Aug 2015

Cited by 37 | Viewed by 6389

Abstract

MiR-221 and miR-222 (miR-221/222) are well-studied oncogenic microRNAs that are frequently upregulated in several types of human tumors, such as esophageal adenocarcinoma, gastric adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma. In these cancers, silencing miR-221/222 could represent a novel [...] Read more.

MiR-221 and miR-222 (miR-221/222) are well-studied oncogenic microRNAs that are frequently upregulated in several types of human tumors, such as esophageal adenocarcinoma, gastric adenocarcinoma, colorectal adenocarcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma. In these cancers, silencing miR-221/222 could represent a novel anti-tumor approach to inhibit tumor growth and metastasis. On the other hand, miR-221/222 also play onco-suppressive roles in cholangiocarcinoma and gastrointestinal stromal tumors (GISTs). Here we will review the roles of miR-221/222 in digestive systems and their possibility as prognostic and therapeutic tools. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)

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