Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci

We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.This work was supported by CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico – Brasil, Junta de Andalucía, project of Excellence from Junta de Andalucía P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2015-70520-R to FJO and JMRdA, RTICC RD12/0036/0026 and CIBER Cáncer ISCIII CB16/12/00421 to FJO

MicroRNAs as regulators of apoptosis mechanisms in cancer

MicroRNAs or miRNAs are small non-coding RNAs that regulate gene expression. Their discovery has brought new knowledge in biological processes of cancer. Involvement of miRNAs in cancer development includes several major pathways from cell transformation to tumor cell development, metastasis and resistance to treatment. The first part of this review discusses miRNAs function in the intrinsic and extrinsic pathways of apoptosis. Due to the fact that many miRNAs that regulate apoptosis have been shown to play a major role in tumor cell resistance to treatment, in the second part of the review we aim at discussing miRNAs potential in becoming curative molecules

Understanding the Role of Non-Coding RNAs in Bladder Cancer: From Dark Matter to Valuable Therapeutic Targets

The mortality and morbidity that characterize bladder cancer compel this malignancy into the category of hot topics in terms of biomolecular research. Therefore, a better knowledge of the specific molecular mechanisms that underlie the development and progression of bladder cancer is demanded. Tumor heterogeneity among patients with similar diagnosis, as well as intratumor heterogeneity, generates difficulties in terms of targeted therapy. Furthermore, late diagnosis represents an ongoing issue, significantly reducing the response to therapy and, inevitably, the overall survival. The role of non-coding RNAs in bladder cancer emerged in the last decade, revealing that microRNAs (miRNAs) may act as tumor suppressor genes, respectively oncogenes, but also as biomarkers for early diagnosis. Regarding other types of non-coding RNAs, especially long non-coding RNAs (lncRNAs) which are extensively reviewed in this article, their exact roles in tumorigenesis are—for the time being—not as evident as in the case of miRNAs, but, still, clearly suggested. Therefore, this review covers the non-coding RNA expression profile of bladder cancer patients and their validated target genes in bladder cancer cell lines, with repercussions on processes such as proliferation, invasiveness, apoptosis, cell cycle arrest, and other molecular pathways which are specific for the malignant transformation of cells

miR‐181a/b therapy in lung cancer: reality or myth?

Despite substantial progress in oncology, lung cancer remains the number one malignancy in terms of both incidence and mortality rates, and there thus remains an urgent need for new therapeutic alternatives. MicroRNA (miRNA) have an important role in cancer initiation and progression due to their capacity to interfere with transcriptional signaling and regulate key cellular processes. miR‐181a and miR‐181b (miR‐181a/b), which are located on chromosomes 1 and 9, are pathologically expressed in the tumor tissue and plasma of patients diagnosed with lung cancer. The miR‐181a/b regulatory mechanisms are sophisticated and are directly related to different target genes. In recent years, an ever‐increasing number of studies have focused on the biological relevance of miR‐181a/b in key cellular processes. In this paper, we aim to discuss the challenging experimental data related to miR‐181a/b and their potential use for the development of new therapeutic approaches in lung cancer. We will further present the ongoing issues regarding the regulation of their multiple target genes, and their potential use as biomarkers and therapeutic targets in this deadly malignancy

Phytochemicals modulate carcinogenic signaling pathways in breast and hormone-related cancers

Roxana Cojocneanu Petric,1,2 Cornelia Braicu,2 Lajos Raduly,2,3 Oana Zanoaga,2 Nicolae Dragos,1,4 Paloma Monroig,5 Dan Dumitrascu,6 Ioana Berindan-Neagoe2,5,7,81Department of Biology, Babes-Bolyai University, 2Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 3Department of Physiopathology, Faculty of Veterinary Medicine, University of Agricultural Science and Veterinary Medicine, 4Department of Taxonomy and Ecology, Institute of Biological Research, Cluj-Napoca, Romania; 5Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX, USA; 62nd Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 7Department of Functional Genomics and Experimental Pathology, The Oncology Institute “Prof Dr Ion Chiricuţă”, 8Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaAbstract: Over the years, nutrition and environmental factors have been demonstrated to influence human health, specifically cancer. Owing to the fact that cancer is a leading cause of death worldwide, efforts are being made to elucidate molecular mechanisms that trigger or delay carcinogenesis. Phytochemicals, in particular, have been shown to modulate oncogenic processes through their antioxidant and anti-inflammatory activities and their ability to mimic the chemical structure and activity of hormones. These compounds can act not only by influencing oncogenic proteins, but also by modulating noncoding RNAs such as microRNAs and long noncoding RNAs. Although we are only beginning to understand the complete effects of many natural compounds, such as phytochemicals, researchers are motivated to combine these agents with traditional, chemo-based, or hormone-based therapies to fight against cancer. Since ongoing studies continue to prove effective, herein we exalt the importance of improving dietary choices as a chemo-preventive strategy.Keywords: natural compounds, dietary polyphenols, epigallocatechin gallate, curcumin, genistein, noncoding RNA, cance

Comprehensive Analysis of the Expression of Key Genes Related to Hippo Signaling and Their Prognosis Impact in Ovarian Cancer

The Hippo signaling pathway, one of the most conserved in humans, controlling dimensions of organs and tumor growth, is frequently deregulated in several human malignancies, including ovarian cancer (OC). The alteration of Hippo signaling has been reported to contribute to ovarian carcinogenesis and progression. However, the prognostic roles of individual Hippo genes in OC patients remain elusive. Herein we investigated the expression level and prognostic value of key Hippo genes in OC using online databases, followed by a qRT-PCR validation step in an additional patient cohort. Using the GEPIA database, we observed an increased level for TP53 and reduced expression level for LATS1, LATS2, MST1, TAZ, and TEF in tumor tissue versus normal adjacent tissue. Moreover, LATS1, LATS2, TP53, TAZ, and TEF expression levels have prognostic significance correlated with progression-free survival. The qRT-PCR validation step was conducted in an OC patient cohort comprising 29 tumor tissues and 20 normal adjacent tissues, endorsing the expression level for LATS1, LATS2, and TP53, as well as for two of the miRNAs targeting the TP53 gene, revealing miR-25-3p upregulation and miR-181c-5p downregulation. These results display that there are critical prognostic value dysregulations of the Hippo genes in OC. Our data demonstrate the major role the conserved Hippo pathway presents in tumor control, underlying potential therapeutic strategies and controlling several steps modulated by miRNAs and their target genes that could limit ovarian cancer progression

Clinical and pathological implications of miRNA in bladder cancer

Cornelia Braicu,1 Roxana Cojocneanu-Petric,1,2 Sergiu Chira,1 Anamaria Truta,1,3 Alexandru Floares,4 Bogdan Petrut,5,6 Patriciu Achimas-Cadariu,7,8,* Ioana Berindan-Neagoe1,9–11,*1Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania; 3Department of Medical Genetics, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 4Solutions of Artificial Intelligence Applications, Cluj-Napoca, Romania; 5Department of Urology, The Oncology Institute “ Prof Dr. Ion Chiricuta”, Cluj-Napoca, Romania; 6Department of Urology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 7Department of Surgery, The Oncology Institute “ Prof Dr. Ion Chiricuta”, Cluj-Napoca, Romania; 8Department of Surgical Oncology and Gynaecological Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 9Department of Immunology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 10Department of Functional Genomics and Experimental Pathology, The Oncology Institute “ Prof Dr. Ion Chiricuta”, Cluj-Napoca, Romania; 11Department of Experimental Therapeutics M.D. Anderson Cancer Center Houston, TX, USAAbstract: MicroRNAs (miRNAs) are small, noncoding RNA species with a length of 20–22 nucleotides that are recognized as essential regulators of relevant molecular mechanisms, including carcinogenesis. Current investigations show that miRNAs are detectable not only in different tissue types but also in a wide range of biological fluids, either free or trapped in circulating microvesicles. miRNAs were proven to be involved in cell communication, both in pathological and physiological processes. Evaluation of the global expression patterns of miRNAs provides key opportunities with important practical applications, taking into account that they modulate essential biological processes such as epithelial to mesenchymal transition, which is a mechanism relevant in bladder cancer. miRNAs collected from biological specimens can furnish valuable evidence with regard to bladder cancer oncogenesis, as they also have been linked to clinical outcomes in urothelial carcinoma. Therefore, a single miRNA or a signature of multiple miRNAs may improve risk stratification of patients and may supplement the histological diagnosis of urological tumors, particularly for bladder cancer.Keywords: bladder cancer, miRNA, prognostic, diagnosti

Interspecies gene name extrapolation - A new approach

The use of animal models has facilitated numerous scientific developments, especially when employing "omics" technologies to study the effects of various environmental factors on humans. Our study presents a new bioinformatics pipeline suitable when the generated microarray data from animal models does not contain the necessary human gene name annotation. We conducted single color gene expression microarray on duodenum and spleen tissue obtained from pigs which have been exposed to zearalenone and Escherichia coli contamination, either alone or combined. By performing a combination of file format modifications and data alignments using various online tools as well as a command line environment, we performed the pig to human gene name extrapolation with an average yield of 58.34%, compared to 3.64% when applying more simple methods. In conclusion, while online data analysis portals on their own are of great importance in data management and assessment, our new pipeline provided a more effective approach for a situation which can be frequently encountered by researchers in the "omics" era

Differential Effect of Smoking on Gene Expression in Head and Neck Cancer Patients

Smoking is a well-known behavior that has an important negative impact on human health, and is considered to be a significant factor related to the development and progression of head and neck squamous cell carcinomas (HNSCCs). Use of high-dimensional datasets to discern novel HNSCC driver genes related to smoking represents an important challenge. The Cancer Genome Atlas (TCGA) analysis was performed in three co-existing groups of HNSCC in order to assess whether gene expression landscape is affected by tobacco smoking, having quit, or non-smoking status. We identified a set of differentially expressed genes that discriminate between smokers and non-smokers or based on human papilloma virus (HPV)16 status, or the co-occurrence of these two exposome components in HNSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways classification shows that most of the genes are specific to cellular metabolism, emphasizing metabolic detoxification pathways, metabolism of chemical carcinogenesis, or drug metabolism. In the case of HPV16-positive patients it has been demonstrated that the altered genes are related to cellular adhesion and inflammation. The correlation between smoking and the survival rate was not statistically significant. This emphasizes the importance of the complex environmental exposure and genetic factors in order to establish prevention assays and personalized care system for HNSCC, with the potential for being extended to other cancer types