HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5‐FU resistance by a p53‐dependent pathway

Han, Yang; Song, Chenlong; Wang, Jianying; Tang, Huamei; Peng, Zhihai; Lu, Su

doi:10.1002/mc.22793

Cited by 46 publications

(33 citation statements)

References 45 publications

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“…DHRS2 is originally cloned from hepatocellular carcinoma cells (HepG2) and associates closely with the inhibition of cell proliferation, migration and quiescence [22,[24][25][26]. In HepG2 cells, DHRS2 is upregulated accompanied by cell G1 phase arrest induced by the treatment of sodium butyrate, a histone deacetylase inhibitor [27].…”

Section: Introductionmentioning

confidence: 99%

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DHRS2 mediates cell growth inhibition induced by Trichothecin in nasopharyngeal carcinoma

Zhao

Liao

et al. 2019

J Exp Clin Cancer Res

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Background: Cancer is fundamentally a deregulation of cell growth and proliferation. Cancer cells often have perturbed metabolism that leads to the alteration of metabolic intermediates. Dehydrogenase/reductase member 2 (DHRS2) belongs to short-chain alcohol dehydrogenase/reductase (SDR) superfamily, which is functionally involved in a number of intermediary metabolic processes and in the metabolism of lipid signaling molecules. DHRS2 displays closely association with the inhibition of cell proliferation, migration and quiescence in cancers. Methods: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), 5-ethynyl-2′deoxyuridine (EdU) and colony formation assays were applied to evaluate the proliferative ability of nasopharyngeal carcinoma (NPC) cells. We performed lipid metabolite profiling using gas chromatography coupled with mass spectrometry (GC/MS) to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA sequencing technique combined with differentially expressed genes analysis was applied to identify the expression of genes responsible for the anti-tumor effect of trichothecin (TCN), a natural sesquiterpenoid compound isolated from an endophytic fungus. Results: Our current findings reveal that DHRS2 affects lipid metabolite profiling to induce cell cycle arrest and growth inhibition in NPC cells. Furthermore, we demonstrate that TCN is able to induce growth inhibition of NPC in vitro and in vivo by up-regulating DHRS2. Conclusions: Our report suggests that activating DHRS2 to reprogram lipid homeostasis may be a target for the development of targeted therapies against NPC. Moreover, TCN could be exploited for therapeutic gain against NPC by targeting DHRS2 and it may also be developed as a tool to enhance understanding the biological function of DHRS2.

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Section: Introductionmentioning

confidence: 99%

“…DHRS2 can act as negative regulator of murine double minute 2 (MDM2), subsequently promote p53 stabilization and accumulation [24]. Down-regulation of DHRS2 contributes to gastric carcinogenesis through interacting with MDM2 and confers insensitivity to 5-FU therapy through a p53-dependent pathway [25].…”

Section: Introductionmentioning

confidence: 99%

DHRS2 mediates cell growth inhibition induced by Trichothecin in nasopharyngeal carcinoma

Zhao

Liao

et al. 2019

J Exp Clin Cancer Res

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“…Interestingly, our analyses showed 13 out of 39 cluster members of the Homeobox (HOX) genes: HOXA3, HOXA4, HOXA5, HOXA7, HOXA9, HOXA10, HOXC8, HOXD3, HOXD4, HOXD8, HOX11AS, HOXA11, and HOXD13 hypermethylated in HCC. HOX genes are a family of transcription factors that show deregulated expression in a variety of cancers . Saha reported that HOXA10 and HOXB13 were associated with the process of epithelial–mesenchymal transition in cervical cancer .…”

Section: Discussionmentioning

confidence: 99%

“…HOX genes are a family of transcription factors that show deregulated expression in a variety of cancers. [25][26][27] Saha reported that HOXA10 and HOXB13 were associated with the process of epithelial-mesenchymal transition in cervical cancer. 28 Aberrant expression of HOX cluster genes is integral to a network of regulatory mechanisms involved in normal adult tissue homeostasis, and maintenance and activation of stem cell self-renewal process, crucial to malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

Epigenomic profiling of DNA methylation for hepatocellular carcinoma diagnosis and prognosis prediction

Zhang

Wang

et al. 2019

J of Gastro and Hepatol

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Background and Aim DNA hypermethylation has emerged as a novel molecular biomarker for the diagnosis and prognosis prediction of many cancers. We aimed to identify clinically useful biomarkers regulated by DNA methylation in hepatocellular carcinoma (HCC). Methods Genome‐wide methylation analysis in HCCs and paired noncancerous tissues was performed using an Illumina Infinium HumanMethylation 450K BeadChip array. Methylation‐specific polymerase chain reaction and pyrosequencing were used to validate the methylation status of selected genes in 100 paired HCCs and noncancerous samples. Results A total of 97 027 (20.0%) out of 485 577 CpG sites significantly were differed between HCC and noncancerous tissues. Among all the significant CpG sites, 48.8% are hypermethylated and 51.2% are hypomethylated in HCCs. Multiple signaling pathways (AMP‐activated protein kinase, estrogen, and adipocytokine) involved in gene methylation were identified in HCC. FES was selected for further analysis based on its high level of methylation confirmed by polymerase chain reaction and pyrosequencing. The result showed that FES hypermethylation was correlated with tumor size (0.001), serum alpha fetoprotein (0.023), and tumor differentiation (0.006). FES protein was significantly downregulated in 51/100 (51%) HCCs, and 94.12% (48/51) of them were due to promoter hypermethylation. Both FES hypermethylation and protein downregulation were associated with the progression‐free survival and overall survival of HCC patients. Overexpressed and knockdown of FES confirmed its inhibitory effect on the proliferation and migration of HCC cells. Conclusions We identified many new differentially methylated CpGs in HCCs and demonstrate that FES functions as a tumor suppressor gene in HCC and its methylation status could be used as an indicator for prognosis of HCC.

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“…HOXA5 suppresses GC progression by inhibiting the G1/S transition during the cell cycle (17). HOXA13 promotes GC development via TGF-β, ERK1/2, MDM2-p53-MRP1 pathways, and Wnt/β-catenin signalling (23,(41)(42)(43).…”

Section: Publication Biasmentioning

confidence: 99%

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis

Jin

Dai

et al. 2020

Preprint

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Background: An increasing number of studies have described the aberrant expression of homeobox (HOX) proteins in gastric cancer (GC), which is critically associated with the prognosis and clinicopathological characteristics of GC. This study was conducted to investigate the clinical value and action mechanisms of HOX proteins in GC. Methods: A comprehensive search of PubMed, Embase, Web of Science and Cochrane Library was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) and the pooled odds ratio (OR) with its 95% CI were used to assess the effect of HOX protein expression on the prognosis and clinicopathological features of GC, respectively. Results: Nineteen studies containing 3775 patients were selected for this study. Heterogeneity among HRs of overall survival (OS) was markedly high (I2=90.5%, p=0.000). According to the subgroup analysis, increased expression of HOX protein in the downregulated subgroup was associated with a good prognosis for patients with GC (pooled HR: 0.46, 95% CI: 0.36-0.59, I2=3.1%, p=0.377), while overexpression of HOX protein in the upregulated subgroup was correlated with a reduced OS (pooled HR: 2.59, 95% CI: 1.79-3.74, I2=73.5%, p=0.000). The aberrant expression of HOX protein was crucially related to the TNM stage, depth of tumour invasion, tumour size, lymph node metastasis, distant metastasis, vascular invasion, histological differentiation and Lauren classification in patients with GC. In addition, the molecular mechanisms by which HOX proteins regulate tumorigenesis and development of GC were also explored. Conclusions: HOX proteins play vital roles in GC progression, which might serve as prognostic markers and therapeutic targets for GC.

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HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5‐FU resistance by a p53‐dependent pathway

Cited by 46 publications

References 45 publications

DHRS2 mediates cell growth inhibition induced by Trichothecin in nasopharyngeal carcinoma

DHRS2 mediates cell growth inhibition induced by Trichothecin in nasopharyngeal carcinoma

Epigenomic profiling of DNA methylation for hepatocellular carcinoma diagnosis and prognosis prediction

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis

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