Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer

Kobayashi, Masayoshi; Matsubara, Nagahide; Nakachi, Yutaka; Okazaki, Yasushi; Uchino, Motoi; Ikeuchi, Hiroki; Song, Jihyng; Kimura, Kei; Yasuhara, Michiko; Babaya, Akihito; Yamano, Tomoki; Ikeda, Masataka; Nishikawa, Hiroki; Matsuda, Ikuo; Hirota, Seiichi; Tomita, Naohiro

doi:10.21873/invivo.11745

Cited by 6 publications

(10 citation statements)

References 48 publications

(59 reference statements)

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“…In silico analysis of CRFR2 methylation status revealed that all the emerged DMCs identified in transcription-related regions were hypermethylated in the CRC tissues compared to the healthy ones. This is in line with recent findings indicating positive correlation of hypermethylated CRFR2 (studied by an Infinium Human Methylation 450K array) with colitis-induced CRC [ 35 ]. Accordingly, the previously reported observations on diminished CRFR2 mRNA and protein expression in CRC cell lines and tissues [ 30 ] may be attributed to CRFR2 hypermethylation.…”

Section: Discussionsupporting

confidence: 92%

“…We recently reported on an association of CRFR1 hypermethylation with the presence of steroid hormone receptors in breast cancer [ 34 ]. In addition, using genome-wide methylation approaches, Kobayashi et al found that hypermethylation of CRFR2 is correlated with colitis-induced CRC [ 35 ]. This is in line with our previous reports indicating that diminished or lost CRFR2 expression in CRC promotes tumor development and aggressiveness, including tumor immunoescape, by regulating molecular circuits involved in sustaining inflammation in the gut [ 30 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Methylation Status of Corticotropin-Releasing Factor (CRF) Receptor Genes in Colorectal Cancer

Παναγοπούλου

Cheretaki

Karaglani

et al. 2021

JCM

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The corticotropin-releasing factor (CRF) system has been strongly associated with gastrointestinal pathophysiology, including colorectal cancer (CRC). We previously showed that altered expression of CRF receptors (CRFRs) in the colon critically affects CRC progression and aggressiveness through regulation of colonic inflammation. Here, we aimed to assess the potential of CRFR methylation levels as putative biomarkers in CRC. In silico methylation analysis of CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2) was performed using methylome data derived by CRC and Crohn’s disease (CD) tissues and CRC-derived circulating cell-free DNAs (ccfDNAs). In total, 32 and 33 differentially methylated sites of CpGs (DMCs) emerged in CRFR1 and CRFR2, respectively, between healthy and diseased tissues. The methylation patterns were verified in patient-derived ccfDNA samples by qMSP and associated with clinicopathological characteristics. An automated machine learning (AutoML) technology was applied to ccfDNA samples for classification analysis. In silico analysis revealed increased methylation of both CRFRs in CRC tissue and ccfDNA-derived datasets. CRFR1 hypermethylation was also noticed in gene body DMCs of CD patients. CRFR1 hypermethylation was further validated in CRC adjuvant-derived ccfDNA samples, whereas CRFR1 hypomethylation, observed in metastasis-derived ccfDNAs, was correlated to disease aggressiveness and adverse prognostic characteristics. AutoML analysis based on CRFRs methylation status revealed a three-feature high-performing biosignature for CRC diagnosis with an estimated AUC of 0.929. Monitoring of CRFRs methylation-based signature in CRC tissues and ccfDNAs may be of high diagnostic and prognostic significance in CRC.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Methylation Status of Corticotropin-Releasing Factor (CRF) Receptor Genes in Colorectal Cancer

Παναγοπούλου

Cheretaki

Karaglani

et al. 2021

JCM

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“…UCN2/CRHR2 signal transduction can hinder the metastatic ability of colon cancer cells and negatively regulate the growth of colon cancer [38], However, the combination of UCN3 and CRHR2 can activate the Src/ERK/FAK pathway, which can promote the migration and invasion of colorectal cancer [39]. Angiogenesis is the basis of tumor occurrence and development, vascular endothelial growth factor VEGF is an effective inducer of angiogenesis.…”

Section: The Relationship Between Crh and Various Tumorsmentioning

confidence: 99%

The role of corticotropin-releasing hormone (CRH) family in tumor

Liao

et al. 2021

neo

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The corticotropin-releasing hormone (CRH) family is widely distributed among the central nervous system and peripheral tissues, such as the digestive, cardiovascular, immune, reproductive, endocrine systems. The CRH family members are widely involved in the regulation of human cell biological processes, immune response, and regulation of inflammatory processes that can affect the occurrence and development of tumors. At present, CRH family members and their receptors can be detected in many tumor tissues, and some people think that members of the CRH fa mily may be potential tumor treatment targets as they can affect cellular processes, such as proliferation, migration, invasion, and apoptosis. However currently, there is no systematic introduction to the relationship between the CRH family and various tumors. This review introduces the molecular regulation of the CRH family in tumor formation and seeks further targeted therapy.

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“…Furthermore, regarding the CRHR2 gene, a recent study indicates higher levels of hypermethylation of the gene in patients with z colitis-associated CRC versus non-tumorous mucosa, which could be used in screening, prognostics, as well as evaluation of therapy outcomes in patients with UC-associated CRC [267]. These studies could also determine that hypermethylation of CRHR2 may be responsible (similarly as in the case of SM) for lowered tissue expression of this protein [96], but also cell spreading, being a high metastasis risk factor in CRC [98].…”

Section: Genetic and Epigenetic Changes Of Selected Nps And Crc Liver Metastasismentioning

confidence: 99%

The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management

Kasprzak

Adamek

2020

IJMS

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Colorectal cancer (CRC), classified as the third most prevalent cancer worldwide, remains to be a clinical and research challenge. It is estimated that ~50% of CRC patients die from distant metastases, with treatment of this complication still posing significant difficulties. While liver metastasis (LM) cascade is known in the literature, its mechanisms are still unclear and remain studied in different research models. A connection is suggested between nervous system dysfunctions and a range of Neurotransmitters (Nts) (including Neuropeptides, NPs), Neurotrophins (Ntt) and their receptors (Rs) in CRC liver metastasis development. Studies on the role of NP/NP-Rs in the progression and metastasis of CRC, show the complexity of brain–tumor interactions, caused by their different forms of release to the extracellular environment (endocrine, autocrine, paracrine and neurocrine). Many stages of LM are connected to the activity of pro-inflammatory, e.g., Corticotropin-releasing Hormone Receptor 1 (CRHR1), Neuropeptide Y (NPY) and Neurotensin (NT), anti-inflammatory, e.g., Calcitonin Gene-related Peptide (CGRP), CRHR2 and Vasoactive Intestinal Polypeptide (VIP) or dual role neuropeptides, e.g., Substance P (SP). The regulation of the local immunological profile (e.g., CRH/CRHRs), dysfunctions of enteroprotective role of NPs on epithelial cells (e.g., NT/NT-R), as well as structural-functional changes in enteric nervous system innervation of the tumor are also important. More research is needed to understand the exact mechanisms of communication between the neurons and tumor cells. The knowledge on the mechanisms regulating tumor growth and different stages of metastasis, as well as effects of the action of a numerous group of Nts/NPs/Ntt as growth factors, have implications for future therapeutic strategies. To obtain the best treatment outcomes, it is important to use signaling pathways common for many NPs, as well to develop a range of broad-spectrum antagonists. This review aims to summarize the current knowledge on the importance of neuroactive molecules in the promotion of the invasion-metastasis cascade in CRC, as well as the improvements of clinical management of CRC liver metastasis.

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Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer

Cited by 6 publications

References 48 publications

Methylation Status of Corticotropin-Releasing Factor (CRF) Receptor Genes in Colorectal Cancer

Methylation Status of Corticotropin-Releasing Factor (CRF) Receptor Genes in Colorectal Cancer

The role of corticotropin-releasing hormone (CRH) family in tumor

The Neuropeptide System and Colorectal Cancer Liver Metastases: Mechanisms and Management

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