The down-regulation of the CYP2C19 gene is associated with aggressive tumor potential and the poorer recurrence-free survival of hepatocellular carcinoma

Ashida, Ryo; Okamura, Yukiyasu; Ohshima, Keiichi; Kakuda, Yuko; Uesaka, Katsuhiko; Sugiura, Teiichi; Ito, Takaaki; Yamamoto, Yusuke; Sugino, Takashi; Urakami, Kenichi; Kusuhara, Masatoshi; Yamaguchi, Ken

doi:10.18632/oncotarget.25178

Cited by 19 publications

(22 citation statements)

References 41 publications

(39 reference statements)

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“…Although the present result showed no significant changes in Cyp expression in HCA, aberrant CYP expression has been previously reported in hepatocellular tumors (Chen, White, and Eaton 1993; Degawa et al 1995; Wastl et al 1998; Ashida et al 2018). Furthermore, aberrant Cyp expression in hepatocellular tumors has been reported to be involved in status of gene mutation such as β-catenin and Ha-ras (Loeppen et al 2005; Hailfinger et al 2006).…”

Section: Discussioncontrasting

confidence: 81%

Molecular Pathological Differences in Global Gene Expression between Two Sustained Proliferative Lesions, Nodular Regenerative Hepatocellular Hyperplasia and Hepatocellular Adenoma, in Mice

et al. 2018

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Long-term exposure to piperonyl butoxide (PBO) induces multiple nodular masses along with hepatocellular tumors in the liver of mice. The histopathological features of the nodules led to our diagnosis of nodular regenerative hepatocellular hyperplasia (NRH). However, because of the lack of data on the biological characteristics of NRH, whether this lesion is truly nonneoplastic remains unknown. In this study, the molecular characteristics of NRH were compared with those of hepatocellular adenoma (HCA) by global gene expression analysis. Six-week-old male ICR mice were fed a diet containing 6,000 ppm PBO for 43 weeks to induce NRH and HCA development. Complementary DNA microarray analysis was performed using messenger RNA extracted from NRH and HCA frozen sections collected by laser microdissection. Hierarchical cluster analysis showed that all NRH samples clustered together but were separate from the HCA cluster. Pathway analysis revealed activation of the cell cycle and Delta-Notch signaling in both lesions, but the latter was more upregulated in HCA. Downregulation of cytochrome p450 enzymes was observed in NRH, but not in HCA. These results imply that NRH differs from HCA in terms of not only morphological but also molecular characteristics.

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Section: Discussioncontrasting

confidence: 81%

Molecular Pathological Differences in Global Gene Expression between Two Sustained Proliferative Lesions, Nodular Regenerative Hepatocellular Hyperplasia and Hepatocellular Adenoma, in Mice

et al. 2018

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“…Enriched genes such as CYP1A2 [Biazi et al 2017], ADH4 [Wei et al 2012], ACSL1 [Cui et al 2014], UGT2B4 [Wijayakumara et al 2017], ALDH1A1 [Yan et al 2016], PON1 [Shu et al 2017], ASS1 [Frulio et al 2019], AKR1D1 [Nikolaou et al 2019], PTGS2 [Chen et al 2019], NNMT (nicotinamide N-methyltransferase) [Kim et al 2009], GPT (glutamic--pyruvic transaminase) [Shimokawa et al 1977], NNT (nicotinamide nucleotide transhydrogenase) [Lu et al 2017] and PCK1 [Xiang et al 2020] were linked with metabolic activity in hepatocellular carcinoma, but these genes may be involved in metabolic activity in hepatoblastoma. Low expression of enriched genes such as CYP2C19 [Ashida et al 2018], ABAT (4-aminobutyrate aminotransferase) [Jansen et al 2015], ACOX1 [Chen et al 2018], ACSM3 [Ruan et al 2017], FBP1 [Liu et al 2018], ST3GAL6 [Souady et al 2011], AGXT (alanine--glyoxylate and serine-- pyruvate aminotransferase) [Sun et al 2019], ALDOB (aldolase, fructose-bisphosphate B) [Tao et al 2015], ALDH6A1 [Shin et al 2020], XDH (xanthine dehydrogenase) [Chen et al 2017], OGDHL (oxoglutarate dehydrogenase like) [Jiao et al 2019], CYP2C8 [Li et al 2019], CYP2C9 [Yu et al 2015], CYP3A5 [Jiang et al 2015], BHMT (betaine--homocysteine S-methyltransferase) [Jin et al 2016], TAT (tyrosine aminotransferase) [Fu et al 2010], SLC27A5 [Gao et al 2020], GYS2 [Chen et al 2019], GLYAT (glycine-N-acyltransferase) [Matsuo et al 2012], CES3 [Quiroga et al 2016], MASP2 [Ding et al 2014], C7 [Seol et al 2016] and F11 [Du et al 2019] were involved in progression of hepatocellular carcinoma, but decrease expression these genes may be identified with growth of hepatoblastoma. Enriched genes such as SULT1A2 [Fernandez-Santander et al 2013], PIK3C2G [Li et al 2015], AGL (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) [Richmond et al 2018], UGT2B10 [Lu et al 2018], CTH (cystathionine gamma-lyase) [Xu et al 2020] and CYP26A1 [Osanai and Lee, 2015] were involved in metabolic activity of various cancer types, but these genes may liable for metabolic activity of in hepatoblastoma.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential core genes in hepatoblastoma via bioinformatics analysis

Vastrad¹,

Vastrad²,

Kotturshetti³

2020

Preprint

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Hepatoblastoma is the childhood liver cancer. Profound efforts have been made to illuminate the pathology, but the molecular mechanisms of hepatoblastoma are still not well understood. To identify the candidate genes in the carcinogenesis and progression of hepatoblastoma, microarray dataset GSE131329 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and pathway and Gene Ontology (GO) enrichment analysis were performed. The protein-protein interaction network (PPI), module analysis, target gene - miRNA regulatory network and target gene - TF regulatory network were constructed and analyzed. A total of 996 DEGs were identified, consisting of 499 up regulated genes and 497 down regulated genes. The pathway and Gene Ontology (GO) enrichment analysis of the DEGs include proline biosynthesis, superpathway of tryptophan utilization, chromosome organization and organic acid metabolic process. Twenty-four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell cycle, chromosome organization, lipid metabolic process and oxidation-reduction process. Validation of hub genes showed that TP53, PLK1, AURKA, CDK1, ANLN, ESR1, FGB, ACAT1, GOT1 and ALAS1 may be involved in the carcinogenesis, invasion or recurrence of hepatoblastoma. In conclusion, DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the carcinogenesis and progression of hepatoblastoma, and provide candidate targets for diagnosis and treatment of hepatoblastoma.

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“…(CYP) pathway, which is responsible for drug response and the survival of PDAC patients [32][33][34]. We therefore explored its intervention with anti-PDAC drugs contained in the standard chemotherapeutic regimens FOLFIRINOX (folinic acid-fluorouracil-irinotecan-oxaliplatin) and gemcitabine plus nab-paclitaxel [35,36].…”

Section: Pdacmentioning

confidence: 99%

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Wang

Zhang

et al. 2020

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. Methods: The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. Results: Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. Conclusion: The present study has identified a novel functional signature for PDAC and it is like to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a potential linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation.

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The down-regulation of the CYP2C19 gene is associated with aggressive tumor potential and the poorer recurrence-free survival of hepatocellular carcinoma

Cited by 19 publications

References 41 publications

Molecular Pathological Differences in Global Gene Expression between Two Sustained Proliferative Lesions, Nodular Regenerative Hepatocellular Hyperplasia and Hepatocellular Adenoma, in Mice

Molecular Pathological Differences in Global Gene Expression between Two Sustained Proliferative Lesions, Nodular Regenerative Hepatocellular Hyperplasia and Hepatocellular Adenoma, in Mice

Identification of potential core genes in hepatoblastoma via bioinformatics analysis

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

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