Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors

Hesson, Luke B.; Ng, Benedict; Zarzour, Peter; Srivastava, Sameer; Kwok, Chau To; Packham, Deborah; Nunez, Andrea C.; Beck, Dominik; Ryan, Regina; Dower, Ashraf; Ford, Caroline; Pimanda, John E.; Sloane, Mathew A.; Hawkins, Nicholas J.; Bourke, Michael J.; Wong, Jason; Ward, Robyn L.

doi:10.1158/1541-7786.mcr-16-0175

Cited by 21 publications

(25 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, functional roles for AnkB have been implicated in neuronal disease, diabetes, and cancer. 61–63 AnkB, along with many other cardiac ion channel-related proteins, is also expressed in neurons. AnkB −/− mice are born with severe neurological defects including brain and optical nerve malformation.…”

Section: Future Investigationsmentioning

confidence: 99%

The evolving role of ankyrin-B in cardiovascular disease

Koenig

Mohler

2017

Heart Rhythm

View full text Add to dashboard Cite

Over the last decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression, localization, and regulation of proteins critical for cardiac excitability, cytoskeletal integrity, and signaling. Further, human ANK2 variants that result in ankyrin-B loss-of-function are associated with ‘Ankyrin-B syndrome’, a complex cardiac phenotype that may include bradycardia and heart rate variability, conduction block, atrial fibrillation, QT interval prolongation, and potentially fatal catecholaminergic polymorphic ventricular tachycardia. However, our understanding of the molecular mechanisms underlying ankyrin-B function at baseline and in disease is still not fully resolved due to the complexity of ankyrin-B gene regulation, number of ankyrin-B-associated molecules, multiple roles of ankyrin-B in the heart and other organs that modulate cardiac function, and a host of unexpected clinical phenotypes. Here, we summarize known roles of ankyrin-B in the heart and the impact of ankyrin-B dysfunction in animal models and in human disease, as well as highlight important new findings illustrating the complexity of ankyrin-B signaling.

show abstract

Section: Future Investigationsmentioning

confidence: 99%

The evolving role of ankyrin-B in cardiovascular disease

Koenig

Mohler

2017

Heart Rhythm

View full text Add to dashboard Cite

show abstract

“…This suggests that RGMb acts as a tumor suppressor, possibly by inhibiting SMAD activation. This idea is also supported by the observation that the RGMb gene is inactivated by frame-shift mutations in a subtype of colorectal cancer [67].…”

Section: Box 2 Mutations and Knockouts Of Rgmsmentioning

confidence: 73%

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

View full text Add to dashboard Cite

Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho) biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins. RGMs: A Small Gene Family with Widespread EffectsGuidance molecules, initially observed to direct growing axons during embryogenesis [1], also have crucial roles in the morphogenesis and homeostasis of non-neuronal tissues by controlling a plethora of cellular processes, ranging from cell division and migration to differentiation and death. Figure 1A). Each RGM displays tissuespecific expression, is subjected to distinct biosynthetic and processing steps, and has not only unique, but also shared biological functions [2]. RGMs bind the type 1 transmembrane protein Neogenin ( Figure 1A) and many of the reported biological effects of RGMs rely on Neogenin receptor functions, such as axon guidance or neuronal survival [3,4]. RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin. In this review, we discuss recent highlights in RGM research, from novel structural data to previously unexplored signaling mechanisms and cellular functions. Structural Insight into Ligand-Receptor InteractionsFor many years, RGMs posed a molecular puzzle because of a general lack of structural homologies to any known protein fold. Recent studies have shed light on their 3D structure and identified two ordered and disulfide-stabiliz...

show abstract

“…22 Recent studies suggested epigenetic changes of SLITRK5 may be an early event in colorectal neoplasia. 6 Specifically, we found 4 genes (IRF4, FLI1, KDR and NRG1) within the CGC with hypermethylated DMRs. As illustrated in Supporting Information Figure S2b, methylation levels of FLI1 and KDR, two vascular epithelial growth factor (VEGF) family members, were significantly increased in LST comparing to matched normal samples.…”

Section: Lsts Exhibited Hallmark Dna Methylation Abnormality Around Tsssmentioning

confidence: 74%

“…Some of the differentially methylated sites (CNTN1 and SLITRK5) were reported in previous studies, demonstrating the reliability and robustness of our analysis pipeline. 6 CNTN1 regulates cell surface interactions in the nervous system and participates in the Notch pathway. 19 Previous studies suggest that CNTN1 promotes tumor invasion and metastasis in multiple cancers.…”

Section: Lsts Exhibited Hallmark Dna Methylation Abnormality Around Tsssmentioning

confidence: 99%

Genome‐wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease‐specific epimutations on common pathways

Zhu

Yan

Wang

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Colorectal laterally spreading tumors (LSTs) grow to extremely large size while rarely invade deeply. Also, there is a low tendency to become cancerous. We used the Illumina Human Methylation 450K array to query the main epigenetic difference of LSTs. We built a discovery cohort with 10 matched cases, and a validation cohort with 9 additional matched cases. Our results suggest that LST displays significant decrease in DNA methylation, highlighted by the discovery of 1,018 hypomethylated intergenic regions (IGRs). Comparing to classic differentially methylated probes and regions that overlap transcription starting site and CpG island, IGR-regions were associated more closely with genes involved in functional biological processes and correlated with specific histone modifications. Hypomethylated IGR regions were often annotated as tissue-specific regulatory elements for noncolon tissues and were typically epigenetically silenced in normal colon mucosa. By integration of public data, we defined the commonality and specific epigenetic signatures for adenomas, LSTs and colon adenocarcinomas. Only 435 hypermethylated differentially methylated probes (DMPs) and differentially methylated regions (DMRs) and 517 hypomethylated DMPs and DMRs were shared by the three diseases. However, our pathway-level analysis discovered that genes in four pathways were common target of epimutations in LSTs, adenomas and CRCs. More interestingly, different diseases seem to employ distinct epigenetic insult to disturb specific pathways. Between LST and adenoma, we found eight pathways including Ras signaling and Rap1 signaling pathway were commonly targeted but the epimutation patterns were opposite. Comparison between precancerous conditions and invasive states revealed the key pathways governing the progression to malignancy, including PI3K-Akt pathways.

show abstract

Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors

Cited by 21 publications

References 39 publications

The evolving role of ankyrin-B in cardiovascular disease

The evolving role of ankyrin-B in cardiovascular disease

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Genome‐wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease‐specific epimutations on common pathways

Contact Info

Product

Resources

About