Extraordinary cancer epigenomics: thinking outside the classical coding and promoter box

The advent of functional genomics powered by high-throughput sequencing has given us a new appreciation of the genomic sequences that lie outside the canonical promoter-coding sequence box. These regions harbor distant regulatory elements, enhancers, super-enhancers, insulators, alternative promoters, and sequences that transcribe as noncoding RNAs (ncRNAs) such as miRNAs and long ncRNAs. These functional genomics studies have also enabled a clearer understanding of the role of the 3D structure of the genome in epigenetic regulation. Here we review the impact that epigenetic changes, and specifically DNA methylation, have on these extraordinary sequences in driving cancer progression

MicroRNAs in the Functional Defects of Skin Aging

Humankind has always been intrigued by death, as illustrated by the eternal quest for the fountain of youth. Aging is a relentless biological process slowly progressing as life cycle proceeds. Indeed, aging traduces an accumulation of physiological changes over time that render organisms more likely to die. Thus, despite our mastery of advanced technologies and robust medical knowledge, defining the molecular basis of aging to control lifespan is still currently one of the greatest challenges in biology. In mammals, the skin is the ultimate multitasker vital organ, protecting organisms from the world they live in. As a preferential interface with the environment, the skin is reflecting the internal physiological balances. The maintenance of these balances, called homeostasis, depends on the concurrent assimilation of diversified signals at the cellular level. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by mRNAs degradation or translational repression. Their relatively recent discovery in 2000 provided new insights into the understanding of the gene regulatory networks. In this chapter, we focused on the role of three miRNA families, namely miR-30, miR-200, and miR-181, playing a key role in the progression of the skin aging process, with particular input in mechanistic considerations related to autophagy, oxidative stress, and mitochondrial homeostasis

Current Cancer Treatment

This book is a collection of in-depth chapters on many aspects of contemporary cancer treatment. Written by experts worldwide, each chapter provides a detailed summary of the state-of-the art knowledge in the area, with extensive references and clear and informative diagrams. The volume is divided into two sections: “Basic Science” and “Clinical Challenges.” The five chapters in the first section cover MicroRNA, the role of angiogenesis in the tumor microenvironment, microbial metabolites in the gastrointestinal microenvironment, the role of dendritic cells in anti-tumor immunity, and challenges of current cancer biomarkers. The two chapters in the second section cover pediatric CNS tumors and the role of sentinel node biopsy in endometrial cancer. The information in this book is designed for cancer clinicians and interested readers to whom this knowledge is important for focusing research and improving patient outcomes

Oncogene and Cancer

This book describes a course of cancer growth starting from normal cells to cancerous form and the genomic instability, the cancer treatment as well as its prevention in form of the invention of a vaccine. Some diseases are also discussed in detail, such as breast cancer, leucaemia, cervical cancer, and glioma. Understanding cancer through its molecular mechanism is needed to reduce the cancer incidence. How to treat cancer more effectively and the problems like drug resistance and metastasis are very clearly illustrated in this publication as well as some research result that could be used to treat the cancer patients in the very near future. The book was divided into six main sections: 1. HER2 Carcinogenesis: Etiology, Treatment and Prevention; 2. DNA Repair Mechanism and Cancer; 3. New Approach to Cancer Mechanism; 4. New Role of Oncogenes and Tumor Suppressor Genes; 5. Non Coding RNA and Micro RNA in Tumorigenesis; 6. Oncogenes for Transcription Factor

Role of FOXM1 in ovarian cancer tumorigenesis and chemoresistance

Ovarian carcinoma is the most lethal gynecological malignancy. The high relapse and mortality rates are attributable to late diagnosis and development of drug resistance. Identifying novel prognostic and therapeutic targets for ovarian carcinoma is crucial for improving patients' long-term survival rate. Forkhead box protein M1 (FOXM1), which is a widely studied member of the FOX superfamily of proteins, participates in cell proliferation and apoptosis affecting the developmental function of many organs. Recently, there has been emerging evidence supporting the biological significance of FOXM1 in carcinogenesis. Overexpression of FOXM1 has been reported in multiple human malignancies including primary breast cancer, lung cancer, prostate cancer, etc. However, whether FOXM1 participates in the development of ovarian cancer, with emphasis on the association with clinicopathological parameters and chemoresistance, remains unknown. This study aims at elucidating the functional role of FOXM1 in the tumorigenesis of ovarian cancer. Immunohistochemical study showed higher nuclear FOXM1 expression was significantly associated with advanced stages of ovarian cancer (P=0.035). Though not reaching statistical significance, FOXM1 overexpression displayed association with serous histologic subtype, high grade cancers (poor differentiation) and chemoresistance. Patients with a low FOXM1 level had a significantly longer overall (P=0.019) and disease-free survival (P=0.014) than those with high FOXM1 expression. Multivariate progression analysis established high expression of FOXM1, advanced cancer stages and poor histological differentiation (high grade) as independent prognostic factors for short overall and disease-free survival. Consistently, in vitro Transwell assays demonstrated transient knockdown of FOXM1 was capable of reducing SKOV-3 migration and invasion. Furthermore, paclitaxel treatment down-regulated FOXM1 expression in the sensitive cell line but not the resistant one. Immunofluorescence and flow cytometric analyses demonstrated FOXM1 knockdown could enhance paclitaxel-mediated mitotic catastrophe in ovarian cancer cells. Recent attention has been drawn to the oncogenic roles of kinesin-like protein KIF2C and p21-activated kinase 4 (PAK4) in human cancers. Interestingly, the expressions of KIF2C and PAK4 altered in a similar pattern to FOXM1 expression upon paclitaxel treatment by displaying down-regulation only in the paclitaxel sensitive cell line but not the resistant one. FOXM1 silencing, qPCR, luciferase reporter assay and chromatin immunoprecipitation confirmed KIF2C and PAK4 to be novel transcriptional targets of FOXM1. Clonogenic assay showed KIF2C knockdown could re-sensitize resistant cell line to paclitaxel treatment. Flow cytometry demonstrated KIF2C silencing was able to increase the number of cells blocked at G2/M cell cycle phase in sensitive cell line and raise the number of apoptotic cells in resistant cell line. Up-regulations of miR-590 and miR-370 were also observed in a panel of drug resistant ovarian and breast cancer cell lines. While ectopic expression of miR-590 reduced FOXM1 expression, FOXM1 also seemed to be able to regulate the expression of miR-590. In summary, this study showed overexpression of FOXM1 in ovarian cancer correlated with poor survival of patients and paclitaxel resistance. KIF2C and PAK4 were identified as novel transcriptional targets of FOXM1 implicated in chemoresistance.Open Acces

Causes of genome instability: the effect of low dose chemical exposures in modern society.

Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis

Differential microRNA and metabolic expressions in neuroendocrine and cervical carcinomas

MicroRNAs (miRNAs) are important regulators of many biological processes involved in cancer development and progression. However, the functional roles of miRNAs in some cancer types are still poorly understood. The aim of this thesis was to investigate the expressions, targets and functions of specific miRNAs in cervical, adrenocortical and Merkel cell carcinoma. In Paper I, we characterized the functional roles of miR-944, a miRNA with higher expression in cervical cancer. We showed that miR-944 promotes cell proliferation, migration and invasion. Using Ago2 PAR-CLIP sequencing, we identified 58 candidate targets of miR-944 and validated HECW2 and S100PBP as direct targets of miR-944 by luciferase reporter assays. This study reveals the oncogenic role and novel targets of miR-944 in human cervical cancer cells, suggesting its important role in cervical cancer development and its potential implications as a biomarker of cervical carcinoma or as a therapeutic target. In Paper II, we showed that the IGF2-H19 locus was consistently deregulated in adrenocortical carcinoma (ACC). We used available proteomic data, to identify a subset of proteins inversely correlated to miRNAs of the IGF2-H19 locus. Interestingly, several of the proteins are involved in mitochondrial respiration, such as NDUFC1, a subunit of mitochondrial respiratory complex I. NDUFC1 was observed to be down-regulated in our ACC cohort and was a predicted miR-483-5p target. Inhibition of miR-483-5p in ACC cells increased NDUFC1 expression and reduced both glycolysis and mitochondrial respiration, suggesting that miR-483-5p controls major energy metabolism and its high expression is required to fuel cellular activies in ACC cells. In Paper III, we demonstrated that over-expression of miR-375 suppressed cell growth and migration, induced cell cycle arrest and apoptosis in Merkel cell polyomavirus-negative (MCPyV-) Merkel cell carcinoma (MCC). Inhibition of miR-375 suppressed cell growth and increased apoptosis in MCPyV-positive (MCPyV+) MCC. Additionally, we showed that LDHB is a target of miR-375 in MCC as shown by its inverse relationship. Low levels of LDHB are required to maintain cell growth and viability in MCPyV+ MCC, while high levels are required for MCPyV- MCC. In Paper IV, we revealed that MCPyV oncoproteins suppressed LDHB and promoted glycolysis. Intriguingly, LDHB overexpression could revert the growth-promoting effect of sT or truncated LT, indicating that a low LDHB expression is important for maintenance of cell growth and viability in MCPyV+ cells. Inhibition of glycolysis reduced cell growth and induced apoptosis in MCPyV+ MCC cell lines, whereas the MCPyV- MCC cell lines rely on oxidative phosphorylation for cell growth and viability. These data suggest targeting metabolism as a therapeutic strategy in MCC. Taken together, this thesis work provides new insights into the crucial roles of miRNAs in the molecular mechanisms of cervical, adrenocortical and Merkel cell carcinomas

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

Since the publication of the Society for Immunotherapy of Cancer\u27s (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients