Ascites in ovarian cancer: MicroRNA deregulations and their potential roles in ovarian carcinogenesis

Ovarian cancer comprises the most lethal gynecologic malignancy and is accompanied by the high potential for the incidence of metastasis, recurrence and chemotherapy resistance, often associated with a formation of ascitic fluid. The differentially expressed ascites-derived microRNAs may be linked to ovarian carcinogenesis. The article focuses on a number of miRNAs that share a common expression pattern as determined by independent studies using ascites samples and with regard to their functions and outcomes in experimental and clinical investigations. Let-7b and miR-143 have featured as tumor suppressors in ovarian cancer, which is in line with data on other types of cancer. Although two miRNAs, i.e. miR-26a-5p and miR-145-5p, act principally as tumor suppressor miRNAs, they occasionally exhibit oncogenic roles. The performance of miR-95-3p, upregulated in ascites, is open to debate given the current lack of supportive data on ovarian cancer; however, data on other cancers indicates its probable oncogenic role. Different findings have been reported for miR-182-5p and miR-200c-3p; in addition to their presumed oncogenic roles, contrasting findings have indicated their ambivalent functions. Further research is required for the identification and evaluation of the potential of specific miRNAs in the diagnosis, prediction, treatment and outcomes of ovarian cancer patients.

Transcription Factors and Methylation Drive Prognostic miRNA Dysregulation in Hepatocellular Carcinoma

Many dysregulated microRNAs (miRNAs) have been suggested to serve as oncogenes or tumor suppressors to act as diagnostic and prognostic factors for HCC patients. However, the dysregulated mechanisms of miRNAs in HCC remain largely unknown. Herein, we firstly identify 114 disordered mature miRNAs in HCC, 93 of them are caused by dysregulated transcription factors, and 10 of them are driven by the DNA methylation of their promoter regions. Secondly, we find that seven up-regulated miRNAs (miR-9-5p, miR-452-5p, miR-452-3p, miR-1180-3p, miR-4746-5p, miR-3677-3 and miR-4661-5p) can promote tumorigenesis via inhibiting multiple tumor suppressor genes participated in metabolism, which may act as oncogenes, and seven down-regulated miRNAs (miR-99-5p, miR-5589-5p, miR-5589-3p, miR-139-5p, miR-139-3p, miR-101-3p and miR-125b-5p) can suppress abnormal cell proliferation via suppressing a number of oncogenes involved in cancer-related pathways, which may serve as tumor suppressors. Thirdly, our findings reveal a mechanism that transcription factor and miRNA interplay can form various regulatory loops to synergistically control the occurrence and development of HCC. Finally, our results demonstrate that this key transcription factor FOXO1 can activate a certain number of tumor suppressor miRNAs to improve the survival of HCC patients, suggesting FOXO1 as an effective therapeutic target for HCC patients. Overall, our study not only reveals the dysregulated mechanisms of miRNAs in HCC, but provides several novel prognostic biomarkers and potential therapeutic targets for HCC patients.

Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development

Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.

DLK1-DIO3 Region as a Source of Candidate Tumor Suppressor miRNAs in Papil- Lary Thyroid Carcinoma

Background: DLK1-DIO3 genomic region comprises one of the largest microRNA (miRNAs) clusters in human genome. In previous studies we showed the downregulation of several miRNAs from the genomic region in papillary thyroid carcinoma (PTC). Due to the large number of miRNAs within this region the individual contribution of these molecules to PTC development and progression remains unclear. Methods: We used different computational resources to clarify the contribution of DLK1-DIO3-derived miRNAs to PTC. Results: Our analysis suggests that 12 miRNAs from this region cooperate to modulate distinct cancer-relevant biological processes, potentially responding for most of the impact of DLK1-DIO3-derived miRNAs to PTC development and progression. The overexpression of miR-485-5p in two PTC cell lines decreased proliferation and migration, confirming the biological relevance of in silico data. Conclusion: Our results shed light on the role of DLK1-DIO3 region, harboring several tumor suppressor miRNAs in thyroid cancer and open perspectives for the functional exploration of these miRNAs as therapeutic targets for PTC.

Urine miRNA Signature as a Potential Non-invasive Diagnostic and Prognostic Biomarker in Cervical Cancer

MicroRNAs as cancer biomarkers in serum, plasma and other body fluids are often used but analysis of miRNA in urine is limited. We investigated the expression of selected miRNAs in the paired urine, serum, cervical scrape and tumor tissue specimens from the women with cervical precancer and cancer with a view to identify if urine miRNAs could be used as reliable non-invasive biomarkers for an early diagnosis and prognosis of cervical cancer. Expression of three oncomiRs (miR-21, miR-199a, and miR-155-5p) and three tumor suppressors (miR-34a, miR-145, and miR-218) in cervical pre-cancer, cancer and normal controls including cervical cancer cell lines were analyzed using qRT-PCR. The expression of miRNAs was correlated with various clinicopathological parameters, including HPV infection and survival outcome. We observed a significant overexpression of the oncomiRs and the downregulation of tumor suppressor miRNAs. A combination of miR-145-5p, miR-218-5p, and miR-34a-5p in urine yielded 100% sensitivity and 92.8% specificity in distinguishing precancer and cancer patients from healthy controls. The expression of miR-34a-5p and miR-218-5p were found to be independent prognostic factors for overall survival of cervical cancer patients. We conclude that the evaluation of specific miRNA expression in non-invasive urine samples may serve as reliable biomarker for early detection and prognosis of cervical cancer.

Notch Signaling & Micro RNAs - two tumblers of neurogenesis and Gliomas

Gliomas are one of the most annihilating types of brain tumors having a high rate of annual incidence worldwide. Notch signaling is an evolutionary conserved pathway that regulates differentiation and development. Aberrations in Notch signalling pathways lead to severe pathological state such as the Gliomas. MicroRNAs (miRNAs) are the tiny molecules less than 200 bps in length and regulate a myriad of cellular processes. Categorically, miRNAs are divided in to oncogenic and tumor suppressor miRNAs. Accumulating data have identified miRNAs, which positively or negatively regulate Notch signaling in Gliomas. Here, we have assessed status of our understanding of the interplay between miRNA-base regulation of Notch signaling in gliomas, interaction between Notch signaling and other signaling cascades and have also discussed use of natural compounds that will help us get closer to personalized medicine for gliomas. Keywords: Notch signaling; MicroRNA; Therapeutic Targets; Continuous...

MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects?

The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.

Development of MicroRNAs as Potential Therapeutics against Cancer

MicroRNAs (miRNAs) are small noncoding RNAs that function at the posttranscriptional level in the cellular regulation process. miRNA expression exerts vital effects on cell growth such as cell proliferation and survival. In cancers, miRNAs have been shown to initiate carcinogenesis, where overexpression of oncogenic miRNAs (oncomiRs) or reduced expression of tumor suppressor miRNAs has been reported. In this review, we discuss the involvement of miRNAs in tumorigenesis, the role of synthetic miRNAs as either mimics or antagomirs to overcome cancer growth, miRNA delivery, and approaches to enhance their therapeutic potentials.

Potential miRNAs for miRNA-Based Therapeutics in Breast Cancer

MicroRNAs (miRNAs) are small non-coding RNAs that can post-transcriptionally regulate the genes involved in critical cellular processes. The aberrant expressions of oncogenic or tumor suppressor miRNAs have been associated with cancer progression and malignancies. This resulted in the dysregulation of signaling pathways involved in cell proliferation, apoptosis and survival, metastasis, cancer recurrence and chemoresistance. In this review, we will first (i) provide an overview of the miRNA biogenesis pathways, and in vitro and in vivo models for research, (ii) summarize the most recent findings on the roles of microRNAs (miRNAs) that could potentially be used for miRNA-based therapy in the treatment of breast cancer and (iii) discuss the various therapeutic applications.