MicroRNA-138 Increases Chemo-Sensitivity of Glioblastoma through Downregulation of Survivin

Glioblastoma (GBM) is one of the most deadly cancers and poorly responses to chemotherapies, such as temozolomide (TMZ). Dysregulation of intrinsic signaling pathways in cancer cells are often resulted by dysregulated tumor suppressive microRNAs (miRNAs). Previously, we found miR-138 as one of tumor suppressive miRNAs that were significantly down-regulated in GBM. In this study, we demonstrated that ectopic over-expression of miR-138 sensitizes GBM cells to the treatment of TMZ and increased apoptotic cell death. Mechanistically, miR-138 directly repressed the expression of Survivin, an anti-apoptotic protein, to enhance caspase-induced apoptosis upon TMZ treatment. Using an intracranial GBM xenograft mice model, we also showed that combination of miR-138 with TMZ increases survival rates of the mice compared to the control mice treated with TMZ alone. This study provides strong preclinical evidence of the therapeutic benefit from restoration of miR-138 to sensitize the GBM tumor to conventional chemotherapy.

Non-Genomic Control of Dynamic MYCN Gene Expression in Liver Cancer

Upregulated MYCN gene expression is restricted to specialized cell populations such as EpCAM+ cancer stem cells in liver cancer, regardless of DNA amplification and mutation. Here, we reviewed the role of MYCN gene expression in liver homeostasis, regeneration, and tumorigenesis, and discussed the potential non-genomic mechanisms involved in controlling MYCN gene expression in liver cancer, with a focus on inflammation-mediated signal transduction and microRNA-associated post-transcriptional regulation. We concluded that dynamic MYCN gene expression is an integrated consequence of multiple signals in the tumor microenvironment, including tumor growth-promoting signals, lipid desaturation-mediated endoplasmic reticulum stress adaptation signals, and tumor suppressive miRNAs, making it a potential predictive biomarker of tumor stemness and plasticity. Therefore, understanding and tracing the dynamic changes and functions of MYCN gene expression will shed light on the origin of liver tumorigenesis at the cellular level and the development of novel therapeutic and diagnostic strategies for liver cancer treatment.

miREIA - an immunoassay method in assessment of microRNA levels in tumor tissue-pilot study. The impact of miR-93-5p, miR-142-5p and IFNγ on PD-L1 level in colorectal cancer

Colorectal cancer is the second and third most common cancer in females and males, respectively. The PD-L1/PD-1 immune checkpoint is an important source of immunosuppression in the tumor microenvironment and is associated with IFNγ. Recent studies have revealed that a significant number of tumor suppressive miRNAs can regulate the expression of PD-L1. The objective quantification of selected microRNAs using the miREIA method in CRC tissue was performed. We investigated the roles of miR-93-5p and miR-142-5p expression and the levels of IFNγ in regulating the expression of PD-L1 in tumor and margin tissues of CRC in relation to the histological grade, TNM classification, and tumor localization. 37 samples of tumor and margin tissues from CRC patients were evaluated. MiR-93-5p and miR-142-5p levels were measured by a method for quantitative measurement of human microRNA (miREIA). The concentrations of PD-L1 and IFNγ were determined by the ELISA kit. We found higher concentrations of miR-93-5p, PD-L1 and IFNγ in tumor samples compared to tumor margin samples. A significant correlation was found between PD-L1 and IFNγ in tumor and margin specimens; between miR-142-5p and miR-93-5p levels in tumor and margin specimens. A higher level of miR-93-5p was found in tumor margin tissues on the left side of the colon. Patients with distant metastases were characterized by higher miR-93-5p concentration compared to patients without metastases. CRC is an important source of PD-L1, IFNγ and miR-93-5p expression. Understanding the mechanisms underlying intratumoral PD-L1 expression may open new opportunities for targeted immunotherapy for colorectal cancer.

Longitudinal evaluation of whole blood miRNA expression in firefighters

Background Dysregulated microRNA (miRNA) expression could provide a mechanism linking firefighter exposure to increased cancer risk. Objective To determine if changes in longitudinal miRNA expression in firefighters are associated with occupational exposures. Methods Whole blood MiRNA was evaluated in 52 new recruits prior to live-fire training and 20–37 months later. Linear mixed effects models adjusted for age, ethnicity, BMI, and batch effects were used to determine associations separately for all fires and structure fires only between employment duration, cumulative fire-hours and fire-runs, and time since most recent fire with (1) nine a priori and (2) the full array of 799 miRNAs. Results For multivariable models including all fires, two a priori miRNAs were associated with employment duration and four with time since most recent fire. For multivariable models restricted to structure fires, three a priori miRNAs were associated with employment duration and one with fire-runs. Additional miRNAs from the full array were associated with employment duration for all fires and/or structure fires. In general, tumor suppressive miRNAs decreased and oncogenic miRNAs increased with exposure. Significance Changes in miRNAs may serve as biomarkers of exposure effects and a mechanism for increased cancer risk in firefighters.

6mer Seed Toxicity and Platinum Resistance in Ovarian Cancer

ABSTRACTDevelopment of platinum (Pt) resistance is a major barrier to curing ovarian cancer (OC). 6mer seed toxicity is a novel cancer killing mechanism mediated by tumor suppressive miRNAs with a toxic 6mer seed sequence (positions 2-7) through the RNA-induced silencing complex (RISC). The most toxic 6mer seeds are G-rich and kill cells by targeting the 3′ untranslated region of genes critical for cell survival. We now show that treatment of OC cells with Pt leads to an increase in RISC-bound miRNAs carrying toxic 6mer seeds and a decrease in miRNAs with nontoxic seeds. Pt-resistant cells did not exhibit this Pt induced toxicity shift but retained sensitivity to death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in OC patients revealed that miRNA 6mer seed toxicity ratios were predictive of treatment outcomes. Our results suggest that 6mer seed toxicity can be exploited to treat patients with Pt-resistant OC.

MicroRNAs: New non-invasive diagnostic biomarkers and therapeutic method for cancer treatment

Background: Cancer is a global health problem and the main cause of mortality. Most cancerassociated cases of mortality are the consequences of lack of effective treatment and biomarkers for early diagnosis. New hopes for the improvement of the early diagnosis and treatment of cancer synchronize with the emergence of microRNAs (miRNAs). MicroRNAs are small, noncoding, single-stranded RNAs, the length of which is approximately 18–25 nucleotides and which bind to 3’ untranslated region (3’UTR) of the target messenger RNAs (mRNAs), leading to mRNA degradation or translational inhibition; thereby regulating gene expression posttranscriptionally. Aim: Using microRNAs as promising and potential biomarkers for diagnosis and therapeutic targets. Methods: The microRNA expression changes in peripheral blood and can be assayed using non-invasive, low-cost, precise, and rapid tools. Results: It is noteworthy that miRNAs participate in multiple cancer-related biological processes, including proliferation, apoptosis, angiogenesis, drug resistance, invasion, and metastasis. Interestingly, the identified cancer-associated miRNAs, including over-expressed oncogenic miRNAs (oncomiRs) or underexpressed tumor-suppressive miRNAs, are diverse and specific for different tissues and cancer types. Conclusion: The genetic testing of microRNAs opens up the exciting possibility of early diagnosis and treatment before the onset of metastasis. Keywords: microRNAs, gene silencing, circulating biomarkers, cancer diagnosis, anticancer therapy, miRNAs detection.

Therapeutic Opportunities for Targeting microRNAs in Cancer

MicroRNAs (miRNAs) are small noncoding RNAs that can function as either powerful tumor promoters or suppressors in numerous types of cancer. The ability of miRs to target multiple genes and biological signaling pathways has created intense interest in their potential clinical utility as predictive and diagnostic biomarkers, and as innovative therapeutic agents. Recently, accumulating preclinical studies have illustrated the feasibility of slowing tumor progression by either overexpressing tumor suppressive miRNAs, or by neutralizing the activities of oncogenic miRNAs in cell- and animal-based models of cancer. Here we highlight prominent miRNAs that may represent potential therapeutic targets in human malignancies, as well as review current technologies available for inactivating or restoring miRNA activity in clinical settings.

Involvement of Dual Strands of miR-143 (miR-143-5p and miR-143-3p) and Their Target Oncogenes in the Molecular Pathogenesis of Lung Adenocarcinoma

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease.