Vasoactive intestinal peptide increases apoptosis of hepatocellular carcinoma by inhibiting the <scp>cAMP</scp>/Bcl‐<scp>xL</scp> pathway

Hara, Masaki; Takeba, Yuko; Iiri, Taroh; Ohta, Yuki; Ootaki, Masanori; Watanabe, Minoru; Watanabe, Daiki; Koizumi, Satoshi; Otsubo, Takehito; Matsumoto, Naoki

doi:10.1111/cas.13861

Cited by 29 publications

(26 citation statements)

References 36 publications

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“…KEGG pathway analysis has further clarified the function of MeDEGs. The “cAMP signaling pathway” has been indicated as one of the most critical mechanisms in regulating colon cancer cell apoptosis[36-38]. The term “transcriptional misregulation in cancer” is consistent with the GO enrichment results.…”

Section: Discussionsupporting

confidence: 81%

Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis

Yu¹,

Zhang²,

Dai³

2019

WJG

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BACKGROUND DNA methylation, acknowledged as a key modification in the field of epigenetics, regulates gene expression at the transcriptional level. Aberrant methylation in DNA regulatory regions could upregulate oncogenes and downregulate tumor suppressor genes without changing the sequences. However, studies of methylation in the control of gene expression are still inadequate. In the present research, we performed bioinformatics analysis to clarify the function of methylation and supply candidate methylation-related biomarkers and drivers for colon cancer. AIM To identify and analyze methylation-regulated differentially expressed genes (MeDEGs) in colon cancer by bioinformatics analysis. METHODS We downloaded RNA expression profiles, Illumina Human Methylation 450K BeadChip data, and clinical data of colon cancer from The Cancer Genome Atlas project. MeDEGs were identified by analyzing the gene expression and methylation levels using the edgeR and limma package in R software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in the DAVID database and KEGG Orthology-Based Annotation System 3.0, respectively. We then conducted Kaplan–Meier survival analysis to explore the relationship between methylation and expression and prognosis. Gene set enrichment analysis (GSEA) and investigation of protein-protein interactions (PPI) were performed to clarify the function of prognosis-related genes. RESULTS A total of 5 up-regulated and 81 down-regulated genes were identified as MeDEGs. GO and KEGG pathway analyses indicated that MeDEGs were enriched in multiple cancer-related terms. Furthermore, Kaplan–Meier survival analysis showed that the prognosis was negatively associated with the methylation status of glial cell-derived neurotrophic factor (GDNF) and reelin (RELN). In PPI networks, GDNF and RELN interact with neural cell adhesion molecule 1. Besides, GDNF can interact with GDNF family receptor alpha (GFRA1), GFRA2, GFRA3, and RET. RELN can interact with RAFAH1B1, disabled homolog 1, very low-density lipoprotein receptor, lipoprotein receptor-related protein 8, and NMDA 2B. Based on GSEA, hypermethylation of GDNF and RELN were both significantly associated with pathways including “RNA degradation,” “ribosome,” “mismatch repair,” “cell cycle” and “base excision repair.” CONCLUSION Aberrant DNA methylation plays an important role in colon cancer progression. MeDEGs that are associated with the overall survival of patients may be potential targets in tumor diagnosis and treatment.

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Section: Discussionsupporting

confidence: 81%

Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis

Yu¹,

Zhang²,

Dai³

2019

WJG

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“…Cheng YM et al and Follin-Arbelet V et al showed that cAMP could induce apoptosis in multiple myeloma cells in vitro 43 , 44 . However, Hara M et al showed that vasoactive intestinal peptide could prevent the progression of hepatocellular carcinoma (HCC) by increasing apoptosis through inhibiting cAMP / Bcl-xL pathway 45 . Moreover, Safa M et al proposed that the increase of cAMP could inhibit the As 2 O 3 -induced apoptosis in acute promyelocytic leukemia cells 18 .…”

Section: Resultsmentioning

confidence: 99%

Visualization and bibliometric analysis of cAMP signaling system research trends and hotspots in cancer

Tang¹,

Fan²,

Yu³

et al. 2021

J. Cancer

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Cyclic adenosine monophosphate (cAMP) is an essential second messenger that widely distributed among prokaryotic and eukaryotic organisms. cAMP can regulate various biological processes, including cell proliferation, differentiation, apoptosis and immune functions. Any dysregulation or alteration of cAMP signaling may cause cell metabolic disorder, immune dysfunction and lead to disease or cancer. This study aimed to conduct a scientometric analysis of cAMP signaling system in cancer field, and explored the research trend, hotspots and frontiers from the past decade. Relevant literatures published from 2009 to 2019 were collected in the Web of Science Core Collection database. EndNote X9 was used to remove duplicate articles, and irrelevant articles were manually filtered. Bibliometric analyses were completed by CiteSpace V. A total of 4306 articles were included in this study. The number of related literatures published each year is gradually increasing. Most of them belong to "Biochemistry & Molecular Biology", "Oncology", "Cell Biology", "Pharmacology & Pharmacy" and "Endocrinology & Metabolism" areas. In the past decade, USA, China, and Japan contributed the most to the research of cAMP signaling system in cancer. The frontiers and hotspots of cAMP signaling pathway system related to cancer fields mainly focused on cancer cell apoptosis, metastasis, and multiple tumors occurrence in patients with Carney complex. Intervention of the cAMP metabolic pathway may be a potential and promising therapeutic strategy for controlling clinical cancer and tumor diseases.

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“…In a recent paper, Hara and co-authors [122] found that VIP efficiently blocks the proliferation of the HCC cell model Huh7 through a PKA-independent mechanism. VIP reduced cAMP concentration, ser133-phosphorylation on CREB and CREB protein levels, and significantly triggered apoptosis of Huh7 by inhibiting the cAMP/CREB/Bcl-xL pathway.…”

Section: Role Of Cyclic Amp In Hepatocellular Carcinomamentioning

confidence: 99%

Targeting Cyclic AMP Signalling in Hepatocellular Carcinoma

Massimi

Ragusa

Cardarelli

et al. 2019

Cells

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Hepatocellular carcinoma (HCC) is a major healthcare problem worldwide, representing one of the leading causes of cancer mortality. Since there are currently no predictive biomarkers for early stage diagnosis, HCC is detected only in advanced stages and most patients die within one year, as radical tumour resection is generally performed late during the disease. The development of alternative therapeutic approaches to HCC remains one of the most challenging areas of cancer. This review focuses on the relevance of cAMP signalling in the development of hepatocellular carcinoma and identifies the modulation of this second messenger as a new strategy for the control of tumour growth. In addition, because the cAMP pathway is controlled by phosphodiesterases (PDEs), targeting these enzymes using PDE inhibitors is becoming an attractive and promising tool for the control of HCC. Among them, based on current preclinical and clinical findings, PDE4-specific inhibitors remarkably demonstrate therapeutic potential in the management of cancer outcomes, especially as adjuvants to standard therapies. However, more preclinical studies are warranted to ascertain their efficacy during the different stages of hepatocyte transformation and in the treatment of established HCC.

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Vasoactive intestinal peptide increases apoptosis of hepatocellular carcinoma by inhibiting the cAMP/Bcl‐xL pathway

Cited by 29 publications

References 36 publications

Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis

Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis

Visualization and bibliometric analysis of cAMP signaling system research trends and hotspots in cancer

Targeting Cyclic AMP Signalling in Hepatocellular Carcinoma

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