Recent Developments in Cancer Systems Biology

This ebook includes original research articles and reviews to update readers on the state of the art systems approach to not only discover novel diagnostic and prognostic biomarkers for several cancer types, but also evaluate methodologies to map out important genomic signatures. In addition, therapeutic targets and drug repurposing have been emphasized for a variety of cancer types. In particular, new and established researchers who desire to learn about cancer systems biology and why it is possibly the leading front to a personalized medicine approach will enjoy reading this book

Role of miRNAs in Cancer

MicroRNAs are the best representatives of the non-coding part of the genome and their functions are mostly linked to their target genes. During the process of carcinogenesis, both dysregulation of microRNAs and their target genes can explain the development of the disease. However, most of the target genes of microRNAs have not yet been elucidated. In this book, we add new information related to the functions of microRNAs in various tumors and their associated targetome

Fecal microRNAs as innovative biomarkers of intestinal diseases and effective players in host-microbiome interactions

Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and for the development of innovative therapeutic applications in several human conditions, including intestinal diseases. In this review, we explored the literature and summarized the role of identified dysregulated fecal miRNAs in intestinal diseases, with particular focus on colorectal cancer (CRC) and celiac disease (CD). The aim of this review is to highlight one fascinating aspect of fecal miRNA function related to gut microbiota shaping and bacterial metabolism influencing. The role of miRNAs as "messenger" molecules for inter kingdom communications will be analyzed to highlight their role in the complex host-bacteria interactions. Moreover, whether fecal miRNAs could open up new perspectives to develop novel suitable biomarkers for disease detection and innovative therapeutic approaches to restore microbiota balance will be discussed

Assessing new prognostic biomarkers in resected colon cancer patients

Colon cancer is a common malignancy. We retrospectively established a biobank including 452 patients operated for colon cancer stage I-III in Northern Norway in the period 1998-2007. Tissue microarrays (TMAs) containing tumor tissue from these patients were constructed, and subsequently biomarker expression assessed by digital pathology. By using in situ hybridization, we assessed the expression of miR-126, miR-17-5p and miR-20a-5p. A high expression of all these miRs was related to improved disease-specific survival for these patients. For miR-17-5p and miR-20a-5p we investigated their functional aspects in select colon cancer cell lines. Over-expression of miR-17-5p and miR-20a-5p did not impact viability or invasion, and mitigated migration, strengthening our results of improved survival upon high expression. Additionally, using immunohistochemistry, we wanted to investigate four proteins thought to be regulated by these miRs; IRS-1, IRS-2, RUNX3 and SMAD4. In our material, a high expression of IRS-1, RUNX3 and SMAD4 was related to a favorable survival. These novel biomarkers could improve risk stratification in colon cancer patients, differentiating patients with a high risk of recurrence vs patients with a low risk of recurrence in the same TNM-stage. This could help the oncologists to choose the appropriate adjuvant treatment. For this to be implemented in clinical practice, the results need to be verified in large prospective trials

Innate immunity, the hepatic extracellular matrix, and liver injury: mathematical modeling of metastatic potential and tumor development in alcoholic liver disease.

The overarching goals of the current work are to fill key gaps in the current understanding of alcohol consumption and the risk of metastasis to the liver. Considering the evidence this research group has compiled confirming that the hepatic matrisome responds dynamically to injury, an altered extracellular matrix (ECM) profile appears to be a key feature of pre-fibrotic inflammatory injury in the liver. This group has demonstrated that the hepatic ECM responds dynamically to alcohol exposure, in particular, sensitizing the liver to LPS-induced inflammatory damage. Although the study of alcohol in its role as a contributing factor to oncogenesis and metastatic progression has not been extensively investigated in basic science, it is clear from numerous clinical reports and meta-analyses that it would be a benefit to patients to understand the complexity of their comorbidities on a molecular level. It is well recognized that intramural research efforts are needed to understand the associated pathologies. Using signatures of liver ECM to predict cell surface integrin binding profile can establish personalized data that can be used clinically to determine therapeutic targets

Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics

Extracellular vesicles (EVs) are particles wrapped in a lipid bilayer membrane and are naturally released from cells. This kind of cargo vessel is a nanostructure that mainly transfers lipids, proteins, various nucleic acid fragments, and metabolic components to neighboring cells or distant parts of the body through the circulatory system. EVs are of great significance to the communication mechanism between cells. This book collects feature articles to enhance our understanding of the biological characteristics of EVs and their potential applications

Prostate intraepithelial neoplasia 와 prostate cancer 에서의 microRNA 발현의 차이와 carcinogenesis 에 관여하는 연관된 전사 인자

의과대학/박사Background: Prostatic intraepithelial neoplasia (PIN), convincingly acceptable precursor lesion of prostate cancer (PCa), is characterized by obvious cytologic atypia in luminal cells with preserved basal cells. However, molecular association between PIN and PCa has been vaguely clarified. We aimed to identify miRNAs and surrogate target mRNA specific to regulate development of PIN and PCa, and to identify clinical implication of PIN as precancerous lesion of PCa. Materials and methods: Among the 388 radical prostatectomy patients, 69.3% harbored PIN, and large PIN was observed in 56 patients. Clinicopathologic analysis was performed based on the PIN status. To anlaysis miRNAs and surrogate target mRNAs, PIN clusters were obtained by macrodisseciton or laser capture microdissection from formalin-fixed paraffin embedded tissue. Using miRNA microarray screening analysis for each PIN or PCa to compare with normal prostatic tissue, top-ranked miRNAs with relatively lower expression were selected. Immunohistochemistry for FGFRL1, BACH1, ephrin-A3, STAT3, and ZEB1was performed, and expression level of the proteins in PCa, PIN, and normal prostatic tissue was analyzed. Results: Patients harbored PIN showed significant less lymphovascular invasion, less lymph node metastasis, lower tumor volume, lower Gleason score, lower death rate, longer overall survival compared to patients without PIN. Significant downregulation of miR-155, miR-210, miR-153, and miR-200c was observed. Subsequent validation step using immunohistochemistry against the candidate gene products revealed significant high expression of STAT3, ephrin-A3 and ZEB1 in PCa compared to PIN and normal prostatic tissue. Significant stepwise increase in expression of STAT3 and ZEB1 was observed from normal prostatic tissue to PCa. Conclusion: More favorable clinicopathologic parameters and longer overall survival in patients with PIN imply disease progression from PIN to PCa. Furthermore, downregulation of cancer-related miRNAs - miR-155, miR-210, miR-153, and miR-200c- in both PIN and PCa and stepwise increased expression of STAT3 and ZEB1 support that PIN is a preceding lesion of PCa and early carcinogenesis starts at the molecular level.ope

Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs

Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction.Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles.Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR.This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms

RNA expression patterns in pancreatic intraepithelial neoplasia

Pancreatic ductal adenocarcinoma (PDAC) is a genetic disease that evolves from precursor lesions, the most common of which are pancreatic intraepithelial neoplasia (PanINs). In this study, we present RNA-sequencing analysis of PanINs. We identify genes subject to differential expression between PanIN and normal pancreatic duct and between low-grade and high-grade PanIN. One novel gene identified as overexpressed in PanIN and invasive pancreatic ductal adenocarcinoma is interleukin-2 receptor subunit gamma (IL2RG) which encodes the common gamma chain. CRISPR-mediated depletion of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice. Additionally, we examine the therapeutic sensitivities of inactivation of Ataxia Telangiectasia Mutated (ATM), a critical DNA repair gene not infrequently mutated in pancreatic cancers. We find that ATM-depleted pancreatic cancer cell lines have no added sensitivity to several chemotherapeutic agents, but are markedly sensitive to radiotherapy. These data contribute new considerations for existing therapeutic candidates and open the door to a new set of potentially-targetable pathways for disease management