Prognostic Value Of miRNAs Research Articles

Diagnostic and Prognostic Values of miRNAs in High-Grade Gliomas: A Systematic Review

Abstract* Background Gliomas, particularly glioblastomas, have grim prognoses, necessitating early diagnostic and prognostic indicators. MicroRNAs (miRNAs), influential in cancer research, show potential as glioma biomarkers. This systematic review aimed to examine the efficacy of miRNAs in the diagnosis and prognosis of high-grade glioma. Methods A comprehensive search was conducted of PubMed, EMBASE, Cochrane Library, and Web of Science for studies published from 2013 to 2023. The eligibility criteria included high-grade glioma, histopathological confirmation, miRNA samples from cerebrospinal fluid or plasma, and relevant outcome data. Studies were excluded if they were experimental or reviews and not in English. Results Of the 1120 initial results, 8 studies involving 660 subjects met the inclusion criteria. Several studies have assessed miRNA expression and its association with diagnosis and prognosis of high-grade gliomas. Overexpression of miR-221, miR-222, miR-210, miR-21, miR-125b, and miR-223 and under-expression of miR-15b and miR-124-3p showed significant potential in differentiating high-grade glioma patients from controls. Additionally, miRNAs are associated with distinct tumorigenic pathways. Conclusion Elevated or depressed expression levels of specific circulating miRNAs hold significant promise as noninvasive biomarkers for the diagnosis and prognosis of high-grade glioma. These miRNAs offer valuable insights into disease progression and patient outcome. Further validation through extensive clinical trials and in-depth mechanistic studies is essential to realize their full clinical utility.

The role of natural products versus miRNA in renal cell carcinoma: implications for disease mechanisms and diagnostic markers.

Natural products are chemical compounds produced by living organisms. They are isolated and purified to determine their function and can potentially be used as therapeutic agents. The ability of some bioactive natural products to modify the course of cancer is fascinating and promising. In the past 50years, there have been advancements in cancer therapy that have increased survival rates for localized tumors. However, there has been little progress in treating advanced renal cell carcinoma (RCC), which is resistant to radiation and chemotherapy. Oncogenes and tumor suppressors are two roles played by microRNAs (miRNAs). They are involved in important pathogenetic mechanisms like hypoxia and epithelial-mesenchymal transition (EMT); they control apoptosis, cell growth, migration, invasion, angiogenesis, and proliferation through target proteins involved in various signaling pathways. Depending on their expression pattern, miRNAs may identify certain subtypes of RCC or distinguish tumor tissue from healthy renal tissue. As diagnostic biomarkers of RCC, circulating miRNAs show promise. There is a correlation between the expression patterns of several miRNAs and the prognosis and diagnosis of patients with RCC. Potentially high-risk primary tumors may be identified by comparing original tumor tissue with metastases. Variations in miRNA expression between treatment-sensitive and therapy-resistant patients' tissues and serum allow for the estimation of responsiveness to target therapy. Our knowledge of miRNAs' function in RCC etiology has a tremendous uptick. Finding and validating their gene targets could have an immediate effect on creating anticancer treatments based on miRNAs. Several miRNAs have the potential to be used as biomarkers for diagnosis and prognosis. This review provides an in-depth analysis of the current knowledge regarding natural compounds and their modes of action in combating cancer. Also, this study aims to give information about the diagnostic and prognostic value of miRNAs as cancer biomarkers and their involvement in the pathogenesis of RCC.

Revisiting miRNA Association with Melanoma Recurrence and Metastasis from a Machine Learning Point of View.

The diagnostic and prognostic value of miRNAs in cutaneous melanoma (CM) has been broadly studied and supported by advanced bioinformatics tools. From early studies using miRNA arrays with several limitations, to the recent NGS-derived miRNA expression profiles, an accurate diagnostic panel of a comprehensive pre-specified set of miRNAs that could aid timely identification of specific cancer stages is still elusive, mainly because of the heterogeneity of the approaches and the samples. Herein, we summarize the existing studies that report several miRNAs as important diagnostic and prognostic biomarkers in CM. Using publicly available NGS data, we analyzed the correlation of specific miRNA expression profiles with the expression signatures of known gene targets. Combining network analytics with machine learning, we developed specific non-linear classification models that could successfully predict CM recurrence and metastasis, based on two newly identified miRNA signatures. Subsequent unbiased analyses and independent test sets (i.e., a dataset not used for training, as a validation cohort) using our prediction models resulted in 73.85% and 82.09% accuracy in predicting CM recurrence and metastasis, respectively. Overall, our approach combines detailed analysis of miRNA profiles with heuristic optimization and machine learning, which facilitates dimensionality reduction and optimization of the prediction models. Our approach provides an improved prediction strategy that could serve as an auxiliary tool towards precision treatment.

Diagnostic and Prognostic Value of miRNAs after Coronary Artery Bypass Grafting: A Review.

Simple SummaryCoronary artery bypass graft (CABG) surgery is a procedure in which complex coronary arteries stenosis is treated by bypassing atherosclerotic lesions with venous or arterial grafts. CABG is associated with myocardial damage due to ischemia/reperfusion injury. In addition, postoperative complications, including perioperative myocardial infarction, atrial fibrillation and graft failure, remain important clinical challenges. So far, no reliable diagnostic and prognostic tools to predict outcomes after CABG surgery have been established. MiRNAs are noncoding, 21–24 nucleotide-long RNA particles, expressions of which alter during CABG surgery. Here, we summarize the potential clinical applicability of miRNAs as promising biomarkers to predict post-CABG procedure outcomes. MiRNAs are noncoding, 21–24 nucleotide-long RNA particles that control over 60% of genes. MiRNAs affect gene expression through binding to the 3’-untranslated region of messenger RNA (mRNA), thus inhibiting mRNA translation or inducing mRNA degradation. MiRNAs have been associated with various cardiovascular diseases, including heart failure, hypertension, left ventricular hypertrophy, or ischemic heart disease. In addition, miRNA expression alters during coronary artery bypass grafting (CABG) surgery, which could be used to predict perioperative outcomes. CABG is an operation in which complex coronary arteries stenosis is treated by bypassing atherosclerotic lesions with venous or arterial grafts. Despite a very low perioperative mortality rate and excellent long-term survival, CABG is associated with postoperative complications, including reperfusion injury, graft failure, atrial fibrillation and perioperative myocardial infarction. So far, no reliable diagnostic and prognostic tools to predict prognosis after CABG have been developed. Changes in the perioperative miRNA expression levels could improve the diagnosis of post-CABG myocardial infarction and atrial fibrillation and could be used to stratify risk after CABG. Herein, we describe the expression changes of different subtypes of miRNAs during CABG and review the diagnostic and prognostic utility of miRNAs in patients undergoing CABG.

Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320

BackgroundExtracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating EVs can provide diagnostic and prognostic information. To date, little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer.MethodsPlasma EVs were isolated from 40 cancer-free heavy-smokers classified according to a validated 24-microRNA signature classifier (MSC) at high (MSCpos-EVs) or low (MSCneg-EVs) risk to develop lung cancer. EVs origin and functional properties were investigated using in vitro 3D cultures and in vivo models. The prognostic value of miRNAs inside EVs was assessed in training and in validation cohorts of 54 and 48 lung cancer patients, respectively.ResultsDifferent membrane composition, biological cargo and pro-tumorigenic activity were observed in MSCpos vs MSCneg-EVs. Mechanistically, in vitro and in vivo results showed that miR-126 and miR-320 from MSCpos-EVs increased pro-angiogenic phenotype of endothelial cells and M2 polarization of macrophage, respectively. MSCpos-EVs prompted 3D proliferation of non-tumorigenic epithelial cells through c-Myc transfer. Moreover, hypoxia was shown to stimulate the secretion of EVs containing c-Myc from fibroblasts, miR-126-EVs from endothelial cells and miR-320-EVs from granulocytes. Lung cancer patients with higher levels of mir-320 into EVs displayed a significantly shorter overall survival in training [HR2.96] and validation sets [HR2.68].ConclusionOverall our data provide a new perspective on the pro-tumorigenic role of circulating EVs in high risk smokers and highlight the significance of miR-320-EVs as a new prognostic biomarker in lung cancer patients.

Role of miRNAs in urological cancers

The robustly unfavorable prognostic effect of miR-21 has been highlighted across three urologic cancers in the primary analysis. However, the effect of miR-21 in BCa fluctuated in the further confirmation demonstrating single miRNA still lacks the stability. miRNA panel contribute to a better risk stratification and prognostic prediction which could compensate for the unreliability of individual miRNAs in estimating prognosis. However, larger studies with a standardized methodology that assess both single and multiple miRNAs will offer better insight into the prognostic value of miRNAs in urologic cancer. miRNAs’ main function is to inhibit protein synthesis of protein coding genes, either by inhibition of translation or mRNA degradation. However, the relative contribution of each mechanism to repression was unknown until recently. Besides mRNAs repression, miRNAs have been also reported to activate translation of targeted mRNAs. With the advances in molecular biology, efforts are being made to identify sensitive and specific miRNAs for early diagnosis, treatment and prognosis of various urological malignancies. This research can pave the way for improved lifespan and Quality of life of the patients with cancer.

Diagnostic and prognostic value of miRNAs on salivary gland tumors: a systematic review and meta-analysis.

Different levels of miRNA expression have been described in salivary gland tumors as a potential diagnostic marker and predictor of survival. We systematically reviewed the literature to assess the diagnostic and prognostic value of miRNAs on salivary gland tumors. An electronic search was conducted in PubMed, Scopus, Embase, Cochrane, and Web of Science databases. In the meta-analysis, we assumed random-effects model with adjusted hazard ratio (HR) and 95% confidence intervals (95% CI). For prognostic studies, the risk of bias was assessed by Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) and Quality Assessment Tool for Diagnostic Accuracy Studies-2 (QUADAS-2) was utilized for diagnostic studies. Gathered data from 1.131 patients in seven studies demonstrated that different levels of miRNA expression presented diagnostic and prognostic in SGTs. The meta-analysis showed that altered miRNA expression were associated with shortened survival (HR, 2.35, 95% CI, 1.77-3.10, P < .00001). For diagnostic meta-analysis, the overall pooled results for specificity and sensibility were 0.87-0.97 (95% CI, 0.72-1) and 0.68-0.91 (95% CI, 0.51-0.96), respectively. MicroRNAs may be useful in prognostication of patients with SGTs; however, the diagnostic value of miRNAs in SGTs is still limited.

Abstract 1413: Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study

Abstract Background Abiraterone acetate is registered for treatment of metastatic prostate cancer, including those with castration-resistant disease (mCRPC). Although it improves overall survival and progression free survival (PFS), treatment response differs between patients. Biomarkers to predict treatment response are lacking. Liquid biopsies containing microRNAs (miRNAs) are a promising source of prognostic biomarkers in mCRPC patients. Furthermore, the exposure to abiraterone in plasma is highly variable and subtherapeutic exposure might contribute to the variability in response to therapy. We explored the prognostic value of microRNAs and drug exposure in mCRPC patients treated with abiraterone. Methods In a prospective multi-center observational study, 53 patients with mCRPC were included who started pre-chemotherapy abiraterone treatment. Blood was drawn at baseline, 1, 3 and 6 months after start of treatment. The following predefined miRNAs were selected; miR-21, miR-141, miR-200a, miR-200c, miR-375, miR-3687 and abiraterone concentrations were measured. MiRNA-levels in 30 healthy individuals served as controls. Relative miRNA-levels were calculated by the ΔΔCt method. If the geometric mean of a miRNA was more than 2-fold higher in patients versus healthy controls, they were included for survival analysis. Ctrough levels after 1, 3 and 6 months of therapy were measured. The average Ctrough level per patient was used for further analysis. The prognostic value of miRNAs and drug exposure for PFS (radiographic, biochemical or clinical progression) was analyzed with Kaplan-Meier (KM) analysis and tested with a log-rank test. Cut-off values for miRNAs in KM analysis were calculated using maximally selected rank statistics and for the relation with abiraterone Ctrough the earlier defined threshold of 8.4ng/ml was used. Results Of the miRNAs analyzed, miR-375 was more than 2-fold higher in mCRPC patients versus healthy controls. Patients with more than 2.16 fold higher miR-375 compared to healthy controls showed a trend towards shorter PFS, median 352 vs. 456 days (p=0.076). No PFS benefit was shown for patients with a mean abiraterone Ctrough concentration ≥8.4ng/ml compared to patients below this threshold, median 411 vs. 409 days (p=0.81). Conclusion High levels of miR-375 might be a prognostic biomarker for PFS in patients with mCRPC treated with abiraterone. The prognostic value of this miRNA should be further explored in a larger cohort of patients. Additionally, the functionality of miR-375 should be further elucidated. The beneficial effect of higher abiraterone exposure levels could not be confirmed in this study for this patient population. Citation Format: Emmy Boerrigter, Guillemette E. Benoist, Inge M. van Oort, Gerald W. Verhaegh, Onno van Hooij, Levi Groen, Frank Smit, Irma M. Oving, Pieter de Mol, Tineke J. Smilde, Diederik M. Somford, Niven Mehra, Jack A. Schalken, Nielka P. van Erp. Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1413.

Prognostic Value of MiRNAs in Patients with Laryngeal Cancer: A Systematic Review and Meta-Analysis.

Many studies have explored the relationship between the expression level of miRNAs and the prognosis of patients with laryngeal cancer (LC). However, the prognostic value of miRNA in LC patients has not been comprehensively evaluated. PubMed, Web of Science, Embase, and Cochrane Database of Systematic Reviews were extensively searched for all studies published before the end of February 2020 that investigated the correlation between miRNA expression level and clinical prognosis in patients with LC. Twenty-one studies involving 1784 patients were included in our meta-analysis. The survival endpoints of OS and DFS were 1.69 (95% CI 1.45-1.98; p < 0.05) and 3.62 (95% CI 2.34-5.62; p < 0.05), respectively. Both OS and DFS results were statistically significant. Subgroup analyses were performed by evaluating the effects of miR-196b, miR-375, and miR-21 on OS and the effects of miR-34c-5p on DFS. The results obtained for miR-196b and miR-34c-5p were statistically significant. The results indicate that miRNAs, as prognostic biomarkers for LC, play an important role in clinical value. In particular, miR-196b and miR-34c-5p have the potential to be used as prognostic biomarkers. However, further large-scale cohort studies based on these miRNAs are urgently needed to validate their clinical value and help determine the direction of future clinical work in the area.

Prognostic Value of miRNAs in Head and Neck Cancers: A Comprehensive Systematic and Meta-Analysis

Head and Neck Cancer (HNC) is the sixth most common type of cancer across the globe, with more than 300,000 deaths each year, globally. However, there are currently no standardised molecular markers that assist in determining HNC prognosis. The literature for this systematic review and meta-analysis were sourced from multiple bibliographic databases. This review followed PRISMA guidelines. The Hazard Ratio (HR) was selected as the effect size metric to independently assess overall survival (OS), disease-free survival (DFS), and prognosis. Subgroup analysis was performed for individual highly represented miRNA. A total of 6843 patients across 50 studies were included in the systematic review and 34 studies were included in the meta-analysis. Studies across 12 countries were assessed, with China representing 36.7% of all included studies. The analysis of the survival endpoints of OS and DFS were conducted separately, with the overall pooled effect size (HR) for each being 1.825 (95% CI 1.527–2.181; p < 0.05) and 2.596 (95% CI 1.917–3.515; p < 0.05), respectively. Subgroup analysis was conducted for impact of miR-21, 200b, 155, 18a, 34c-5p, 125b, 20a and 375 on OS, and miR-21 and 34a on DFS. The pooled results were found to be statistically significant for both OS and DFS. The meta-analysis indicated that miRNA alterations can account for an 82.5% decrease in OS probability and a 159.6% decrease in DFS probability. These results indicate that miRNAs have potential clinical value as prognostic biomarkers in HNC, with miR-21, 125b, 34c-5p and 18a, in particular, showing great potential as prognostic molecular markers. Further large scale cohort studies focusing on these miRNAs are recommended to verify the clinical utility of these markers individually and/or in combination.

Circulating microRNAs as biomarkers for Sepsis secondary to pneumonia diagnosed via Sepsis 3.0

BackgroundSepsis biomarkers have limited specificity and sensitivity. Few studies have investigated microRNA (miRNA) biomarkers for sepsis secondary to pneumonia. This study aims to investigate the diagnostic and prognostic values of miRNAs in sepsis secondary to pneumonia.MethodsSepsis 3.0 was used to diagnose sepsis. Screening was performed through the Agilent miRNA chip technology by using the following criteria: p < 0.05, fold ≥2 or < 0.5, or copy number > 50 change. This study recruited 52 patients with pneumonia, including 31 males (59.6%) and 21 females (40.4%), 44 patients with sepsis secondary to pneumonia were diagnosed via Sepsis 3.0 (34 [77.3%] males and 10 [22.7%] females), and 21 healthy controls were used for miRNA verification. The miRNA levels were detected through fluorescence real-time quantitative polymerase chain reaction (qRT-PCR). Results: Fluorescence qRT-PCR detection showed that the miR-7110-5p and miR-223-3p expression levels in both patient groups were upregulated compared with those in the healthy controls. The expression levels differed between patients with pneumonia and those with sepsis secondary to pneumonia. The sensitivity and specificity of miR-7110-5p to differentiate sepsis from healthy controls were 84.2 and 90.5%, whereas those of miR-223-3p were 82.9 and 100%, respectively. Multivariate analysis of variance suggested that the presence of sepsis affected the miR-223-3p level (p = 0.041), whereas the presence of sepsis (p = 0.000) and the underlying disease (p = 0.025) influenced the miR-7110-5p level.ConclusionsMiR-223-3p could be utilized to predict sepsis secondary to pneumonia.

Abstract 1958: Developing an online tool to validate survival-associated miRNAs utilizing expression data from 2,061 breast cancer patients

Abstract Background. MicroRNAs (miRNAs) are small non-coding RNAs capable of simultaneously regulating multiple gene networks, and affecting breast cancer patients’ outcome. Here we present the development of an online tool for the real-time meta-analysis of published miRNA datasets to identify novel prognostic biomarkers in breast cancer. Methods. First, a comprehensive database was set up by searching GEO, TCGA, and PubMed repositories to identify datasets with published miRNA expression and clinical data. Due to platform differences, each dataset was processed separately. Kaplan-Meier and Cox regression analyses were performed to investigate the prognostic value of a set of dysregulated miRNAs in breast cancer. The complete analysis tool can be accessed online at: www.kmplot.com/mirna. Results. Overall, 2,061 samples from four independent datasets were integrated into the tool including the expression signature of 1,302 distinct miRNAs. In addition to overall survival data, ER status (n = 2,039), histological grade (n = 1,396) and lymph node status (n = 1,933) are also available. By using our online tool, we demonstrated the prognostic value of some of the previous reported miRNAs implicated in breast cancer. For instance, miR-29c, miR-34c, miR-101, miR-125, and miR-190b, showed a consistent prognostic value in at least three out of four breast cancer datasets. Discussion. In summary, we established the first online integrated platform for the rapid identification of the prognostic value of miRNAs in breast cancer. Citation Format: Balázs Győrffy, András Lánczky, Giulia Bottai, Ádám Nagy, András Szabó, Libero Santarpia. Developing an online tool to validate survival-associated miRNAs utilizing expression data from 2,061 breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1958.

Micro-RNAs in stage II colorectal cancer: Is there any role?

566 Background: Patients with stage II CRC have a varying survival outcome. Therefore, it is critical to identify new prognostic biomarkers that can help to identify more aggressive forms of the disease. The aim of this study was to identify the potential prognostic value of miRNAs in patients with stage II CRC. Methods: The study included 124 patients with stage II CRC who attended the NCI - Medical Oncology clinics, received treatment and followed-up during the period from January 2004 to December 2014. The expression levels of the five studied miRNAs were examined by qRT-PCR analysis. Additionally, blood samples were drawn from 41 patients recruited in the study in the last 3 years of recruitment to assess the level of miRNAs in blood. Results: In tumor tissues of 124 patients, miR-137, miR-145 and miR-320 were significantly under-expressed in 39.5%, 38.4% and 52.4% of cases, respectively while miR-21 and miR-498 were significantly over-expressed in 48.4% and 40.3%, respectively. On the other hand, assessment of these miRNAs in the blood of 41 cases revealed that miR-137, miR-145 and miR-320 were significantly under-expressed in 46.3%, 46.3% and 51.2% of cases, respectively while miR-21 and miR-498 were significantly over-expressed in 46.3% and 43.9%, respectively. The concordance between tissue and blood was weak with miR-320 and miR-145 (kappa 40-65%), intermediate with miR-498 and miR-137 (kappa 65-75%) while strong concordance has been achieved with miR-21 (kappa 75-85%). Performance status, over-expression of miR-21 and miR-498 and under-expression of miR-137, miR-145, and miR-320 were associated with significantly inferior DFS and OS in univariate analysis. In a multivariate analysis, deregulated miR-498 and miR-320 were independent prognostic factors for worse DFS, while over-expressed miR-498 and miR-21 were found to be independent prognostic factors for inferior OS. Conclusions: MiRNAs play an important role as prognostic markers in stage II CRC patients. Large-scale collaborative efforts are still absolutely essential to aid in determining the clinical potential of miRNAs as diagnostic, prognostic, and predictive biomarkers in CRC in order to achieve better survival outcomes.

Abstract 4004: Prognostic value of miRNAs in breast cancer varies with patient race and molecular subtype

Abstract Background: MicroRNAs (miRNAs) may serve as biomarkers for breast cancer (BC) diagnosis and prognosis. Since their clinical value based on race/ethnicity and molecular subtypes has not been studied, we evaluated the prognostic significance of a panel of miRNAs in luminal and triple-negative BCs (TNBCs) of African Americans (AAs) and non-Hispanic Caucasians (CAs). Methods: TaqMan® assays were used to quantify levels of miR-21, miR-106a, miR-206, miR-155, miR-210, and miR-335 in 151 BCs and corresponding normal tissues of 80 AAs (luminal = 24 and TNBCs = 56) and 71 CAs (luminal = 27 and TNBC = 44). Fold changes in levels between tumor-normal pairs were used to categorize the tumors into high- and low-expression groups. The levels of miRNAs were correlated with molecular subtype, patient race/ethnicity, and overall survival by Kaplan-Meier univariate and Cox regression multivariate analyses. Further, the added predictive value of these miRNAs to a baseline prediction model consisting of standard clinical risk factors was evaluated at 2-, 5-, and 8-years post-surgery based on positive predictive curves. Results: In BC tissues, miR-21, miR-106a, miR-155, miR-206, and miR-210 were up-regulated, and miR-335 was down-regulated. For the combined population, univariate and multivariate analyses showed that high levels of miR-21 (adjusted HR = 2.91, 95% CI: 1.27-6.62) and miR-106a (adjusted HR = 2.49, 95% CI: 1.04-5.97) and down-regulation of miR-335 (adjusted HR = 2.97, 95% CI: 1.35-5.54) were associated with poor survival. In multivariate analyses by race, high miR-21 (HR = 7.35, 95% CI: 2.46-21.98) and low miR-335 (HR = 14.13, 95% CI: 2.93-68.13) were indicators of poor survival in only CA patients. Additionally, expression levels of miR-21 aided in identifying risk of death in CA patients with either molecular subtype. In CAs, differences in the area under the positive predictive curve (ΔAUC) between the models with and without miR-21 were 0.077 (95% CI = 0.007-0.154) and 0.053 (95% CI = 0.002-0.128) at 5 and 8 years after surgery, respectively. In TNBCs of both racial groups, addition of miR-106a increased predictive accuracy at 5 (ΔAUC = 0.026, 95% CI = 0.001-0.068) and 8 years (ΔAUC = 0.022, 95% CI = 0-0.061) post-surgery. No miRNA was helpful in identifying patients at high risk of death due to luminal BCs or to AA ethnicity. Conclusions: High levels of miR-106a and miR-21 and low levels of miR-335 are independent prognostic markers of BCs. Furthermore, miR-21 has added predictive value above the standard clinical risk factors for CAs and miR-106a has added predictive value for TNBCs. In evaluation of the clinical utility of miRNAs, patient race and molecular types of BCs should be considered. This work was supported by a pilot grant from UAB Breast SPORE grant of the National Institutes of Health/National Cancer Institute (5P50CA089019). Citation Format: Balananda-Dhurjati Kumar Putcha, Trafina Jadhav, Michael P. Behring, Sejong Bae, Andra R. Frost, Isam-Eldin Eltoum, Li Chen, Heidi L. Weiss, William E. Grizzle, Upender Manne. Prognostic value of miRNAs in breast cancer varies with patient race and molecular subtype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4004. doi:10.1158/1538-7445.AM2015-4004

MicroRNAs Contribute to Hepatocellular Carcinoma

Hepatocellular carcinoma is a leading unnatural death worldwide, and it causes second most common cancer related death. Hepatocellular carcinoma development is distinct from other types of cancer, which is usually based on hepatic cirrhosis resulted from various etiologies including viral hepatitis, non-alcoholic liver diseases and alcohol abuse. MicroRNAs (miRNAs) are a group of small, non-coding sequences with approximate 20~ bp in length, which post-transcriptionally regulates target genes to control multiple biological activities. Recent studies have indicated that miRNAs contribute to hepatocellular carcinoma, indicating that targeting miRNAs might be a novel therapeutic strategy for the management of hepatocellular carcinoma. In this review, we summarized recent advances in the role of miRNAs in hepatocellular carcinoma, and also discussed the potential therapeutic and prognostic values of miRNAs in hepatocellular carcinoma.

Abstract PR5: Prognostic value of miRNAs in breast cancer: Molecular type and patient race

Abstract Background: MicroRNAs (miRNAs) are a class of conserved, non-coding RNAs that are dysregulated in various cancers, including breast cancers. The potential of miRNAs to serve as biomarkers for breast cancer diagnosis and prognosis is being explored, but their clinical value based on race/ethnicity and molecular subtypes (luminal and triple negative breast cancers, TNBCs) has not been examined. Thus, we evaluated expression levels of a panel of miRNAs in luminal (A and B) breast cancers and TNBCs of African Americans (Blacks) and non-Hispanic Caucasians (Whites). We further evaluated the prognostic value of miRNAs based on molecular type of breast cancer and patient race. Methods: TaqMan® miRNA assays were used to quantify expression of miR-181a, miR181b, miR-21, miR-106a, miR-155, miR-210, miR-335, miR-206, and miR-126 in 105 breast cancers (luminal=51 and TNBCs=54) and their corresponding benign/normal tissues. Cancer tissuefrom 48 Blacks (luminal=23 and TNBCs=25) and 57 Whites (luminal=28 and TNBC=29) were analyzed. Fold change in the expression levels between tumor-normal pairs were determined using the 2-∆∆Ct method. A cutoff value for each miRNA was determined by utilizing the Cutoff Finder software application [PLoS ONE 7(12):e51862, 2012]. The cutoff values were used to categorize the tumors into two groups (High expression or positive and low expression or negative). The expression status of tumors was correlated with patient overall survival by univariate Kaplan-Meier analysis. Results: Since the survival probabilities of Blacks and Whites with TNBCs (log rank, p=0.899) were similar, TNBCs from both racial groups were pooled. Similarly, no survival differences were noted in patients of both racial groups with luminal breast cancers (log rank, p=0.178). Therefore, luminal cancers of Blacks and Whites were also pooled together to perform survival analyses based on miRNA expression levels. MiRNA expression profiling studies indicated that, in both the racial groups, miR-181a, miR-181b, miR-21, miR-106a, miR-155, and miR-210 were up-regulated in luminal cancers and TNBCs. In contrast, miR-335, miR-206, and miR-126 were down-regulated in both molecular types. When the prognostic value of miRNAs was evaluated in each molecular type separately, it was found that over-expression of miR-106a (p=0.037) and miR-210 (p=0.039) were associated with poor prognosis of TNBCs. However, none of the evaluated miRNAs were useful in assessing the prognosis of patients with luminal cancers. Conclusions: These findings suggest that increased expression of miR-106a and miR-210 were poor prognostic indicators of TNBCs collected from both Black and White patients. Additionally, our results suggest that in the evaluation of clinical utility of miRNAs molecular types of breast cancer should be considered. This study was funded in part by the National Cancer Institute of the National Institute of Health UAB/TU/MSM Partnership grant (U54 CA118948). This abstract is also presented as Poster C21. Citation Format: Balananda-Dhurjati Kumar Putcha, Trafina Jadhav, Shantel Hebert-Magee, Jeehyun Helen Bae, Andra R. Frost, Isam-Eldin Eltoum, Sejong Bae, Upender Manne. Prognostic value of miRNAs in breast cancer: Molecular type and patient race. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PR5. doi:10.1158/1538-7755.DISP13-PR5

Abstract 108: Diagnostic and Prognostic Biomarker Potential of miR-24 in Abdominal Aortic Aneurysm Disease and Rupture

MicroRNAs (miRNAs) have lately received much attention regarding their suitability and feasibility as biomarkers for cardiovascular diseases. Aim of this current study was to explore the diagnostic and prognostic value of detecting circulating levels of miRNAs in abdominal aortic aneurysms (AAAs). Using a PCR-based array, we profiled the 168 most abundant blood miRNAs in 20 patient plasma samples with AAA disease, undergoing surgical repair of their enlarged aorta vs. 20 samples from a matched screening cohort without aneurysm. We were able to identify a total number of 12 miRNAs that were significantly altered in diseased patient samples as compared to controls. Next we investigated these 12 miRNAs in plasma from ApoE-/- mice with angiotensinII (AngII)-infusion induced AAAs, in order to determine the potential prognostic value of miRNAs being released into circulation. Indeed we were able to detect that the expression of 4 out of the 12 miRNAs (miRs-126 and -668 both increased; miRs-24 and -210 both decreased), was substantially altered in plasma samples drawn from AAA mice immediately before rupture occurred between days 10 and 14 after AngII pump implantation compared to mice with AAA that did not rupture for the remainder of study (28 days), as well as saline-infused controls. The expression of miR-24 was furthermore significantly different in plasma samples from human patients with acutely ruptured AAAs (n=7) compared to patients with non-ruptured AAAs (AA diameter between 55-78 mm; n=7) undergoing surgical repair, as well as un-diseased controls (n=7). Using the AngII model, as well as the elastase infusion model, we were able to show that overexpression of miR-24 protects from aneurysm progression as well as aortic rupture (in the AngII model) by repressing the expression of its target gene chitinase3-like1 (Chi3l1), which regulates macrophage survival and cytokine release in expanding murine AAAs. The present study explores the biomarker potential of miRNAs being released into circulation during initiation, propagation, and ultimately rupture of AAA disease in mice and humans. The identification of miR-24 potentially offers prognostic value to determine which patients present with increased risk of rapid AAA expansion and subsequent rupture.

MiRNAs in Human Cancers: The Diagnostic and Therapeutic Implications

From chemotherapy and radiotherapy to molecular targeted therapy, in recent decades, we have witnessed the acceleration of cancer treatments. However, nowadays, it has encountered obstacles due to multi-drug resistance, drug-induced toxicity and the insufficient disruption of cancer pathways. Thus, it is required to have more efficient approaches for cancer treatments. MicroRNAs (miRNAs) are perhaps the most researched genes in the last decade. They have been reported to play significant roles in cancers and are considered to be applied in targeted cancer therapies. Here, we will firstly review the implications of miRNAs in clinical use from the aspects of miRNA biogenesis and biological functions, followed by the diagnostic and prognostic values of miRNAs. Furthermore, the application of miRNAs in pre-clinical cancer models and clinical trials regarding miRNAs will also be discussed. Moreover, since miRNA delivery is the biggest challenge for miRNA based therapy, the commonly used delivery methods will then be reviewed. The miRNA combinational therapy with chemotherapy, radiotherapy, molecular targeted therapy and immunotherapy will be reviewed and discussed at last.

The Prognostic Value of MicroRNAs Varies with Patient Race/Ethnicity and Stage of Colorectal Cancer

MicroRNAs (miRNA) have potential prognostic value for colorectal cancers; however, their value based on patient race/ethnicity and pathologic stage has not been determined. The goal was to ascertain the prognostic value of 5 miRNAs with increased expression in colorectal cancers of African American (black) and non-Hispanic Caucasian (white) patients. TaqMan quantitative real-time PCR was used to quantify expression of miR-20a, miR-21, miR-106a, miR-181b, and miR-203 in paired normal and tumor colorectal cancer archival tissues collected from 106 black and 239 white patients. The results were correlated with overall survival based on patient race/ethnicity and pathologic stage. Because decisions about adjuvant therapy are important for stage III colorectal cancers, and because miR-181b seemed to have prognostic value only for stage III black patients, we assessed its prognostic value in a separate cohort of 36 stage III colorectal cancers of blacks. All 5 miRNAs had higher expression in colorectal cancers (>1.0-fold) than in corresponding normal tissues. High expression of miR-203 was associated with poor survival of whites with stage IV colorectal cancers (HR = 3.00; 95% CI, 1.29-7.53), but in blacks it was an indicator of poor survival of patients with stages I and II colorectal cancers (HR = 5.63; 95% CI, 1.03-30.64). Increased miR-21 expression correlated with poor prognosis for white stage IV patients (HR = 2.50; 95% CI, 1.07-5.83). In both test and validation cohorts, high miR-181b expression correlated with poor survival of only black patients with stage III colorectal cancers (HR = 1.94; 95% CI, 1.03-3.67). These preliminary findings suggest that the prognostic value of miRNAs in colorectal cancers varies with patient race/ethnicity and stage of disease.

Abstract 284: microRNAs are Novel Plasma Biomarkers for Diagnosis and Prognosis of Abdominal Aortic Aneurysm Disease

MicroRNAs (miRNAs) have been identified as transcriptional and posttranscriptional inhibitors of gene expression, thought to “fine tune” the translational output of their target mRNAs. Recently, they have received much attention regarding their suitability as biomarkers for disease. Our goal was to explore the diagnostic and prognostic value of miRNAs in abdominal aortic aneurysms (AAAs), a disease for which currently no established biomarker exists. Using a PCR-based array platform, we profiled the 168 most abundant blood miRNAs in 20 patient plasma samples with AAA disease, undergoing surgical repair of their enlarged aorta vs. 20 samples from an age, risk factor, and medication matched control group without aneurysm. We were able to identify a total number of 12 miRNAs being significantly altered in diseased patient samples as compared to controls. We further investigated these 12 miRNAs in plasma (as well as in aortic tissue) from apoE-/- mice with angiotensinII (AngII)-infusion induced AAAs, enabling us to discover a potential prognostic value of miRNAs being released into circulation. Indeed we were able to detect that the expression of 4 out of the 12 miRNAs (miRs-126 and -668 both increased; miRs-24 and -210 both decreased), was substantially modified in plasma samples drawn from mice with AAA immediately before rupture occurred between days 10 and 14 after AngII pump implantation compared to mice with AAA that did not rupture for the remainder of study (28 days), as well as saline-infused controls. Importantly, the expression of miRs-24 and -126 appeared also significantly different in plasma samples from patients with ruptured AAAs (n=7) compared to patients with non-ruptured AAAs (abdominal aortic diameter between 55-78 mm; n=7) and un-diseased controls (n=7). The present study explores the diagnostic and prognostic biomarker potential of miRNAs being released into circulation during initiation, propagation, and ultimately rupture of AAA disease in mice and humans. The identification of miRs-24, -126, -210, and -663 potentially offers great prognostic value to determine which patients present with an increased risk of AAA rupture.