TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation

Yatagai, Noboru; Saito, Tsuyoshi; Akazawa, Yoichi; Hayashi, Takuo; Yanai, Yuka; Tsuyama, Sho; Ueyama, Hiroya; Murakami, Takashi; Watanabe, Sumio; Nagahara, Akihito; Yao, Takashi

doi:10.1007/s00428-018-2508-9

Cited by 20 publications

(24 citation statements)

References 31 publications

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“…3 Previous studies have revealed that TET1-mediated demethylation was involved in the acquisition of aggressive behavior in gastric adenocarcinoma with enteroblastic differentiation. 4 Moreover, TET2 affects malignant cell activity through RASSF1A methylation in GC. 5 More recently, the down-regulation of TET3 expression and loss of 5hmC levels have also been demonstrated in GC.…”

Section: Introductionmentioning

confidence: 99%

<p>Chrysin Induced Cell Apoptosis and Inhibited Invasion Through Regulation of TET1 Expression in Gastric Cancer Cells</p>

Zhong

Liu

Jiang

et al. 2020

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Ten-eleven translocation (TET) enzymes that oxidize a 5-methylcytosine (5mC) to yield 5-hydroxymethylcytosine (5hmC) have been responsible for fine-tuning methylation patterns and exhibit role in epigenetic modifications. Chrysin, a natural flavone frequently present in honey, has been recognized to exhibit anti-tumor properties. In this study, we investigated the effects of Chrysin in the expression pattern of TET proteins in gastric cancer (GC) cells. Materials and Methods: Using qRT-PCR and Western blot analysis, we analyzed the expression of TET1 in GC cells in vitro following treatment with Chrysin. Immunofluorescence staining detected the expression levels of 5mC and 5hmC. Flow cytometry, wound healing, and Matrigel invasion assays were performed to determine cell proliferation, cell cycle, apoptosis, and migration and invasion of GC cells following treatment with Chrysin, si-TET1, and TET1-KO. Furthermore, a xenograft model was developed to analyze the expression pattern of TET1 on tumor development in vivo. Results: qRT-PCR and Western blot assays indicated that treatment with Chrysin significantly promoted the expression of TET1 in GC cells. Immunofluorescence study further confirmed that TET1 and 5hmC levels were significantly enhanced following treatment with Chrysin in MKN45 cells. Moreover, our results suggested that Chrysin could noticeably induce cell apoptosis and inhibit cell migration and invasion. Further, knockdown and overexpression of TET1 were conducted to investigate whether TET1 expression affected cell apoptosis, and cell migration and invasion in MKN45 cells. The results indicated that overexpression of TET1 markedly promoted cell apoptosis and inhibited cell migration and invasion. Furthermore, the TET1 gene knocked out was generated using the CRISPR/Cas9 system. Our data suggested that TET1 expression was associated with GC tumor growth in vivo. Conclusion: This study indicated that Chrysin exerted anti-tumor effects through the regulation of TET1 expression in GC and presented TET1 as a novel promising therapeutic target for GC therapy.

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Section: Introductionmentioning

confidence: 99%

<p>Chrysin Induced Cell Apoptosis and Inhibited Invasion Through Regulation of TET1 Expression in Gastric Cancer Cells</p>

Zhong

Liu

Jiang

et al. 2020

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“…4,5 We and others have shown that GAED exhibits aggressive behaviour characterised by frequent vascular invasion and liver metastasis. 3,[6][7][8] However, the GAED counterpart, colorectal adenocarcinoma with enteroblastic differentiation (CAED), has been reported only in a single case or few cases. [9][10][11][12] CAED has been described as colorectal carcinoma (CRC) with clear cytoplasm and expression of enteroblastic markers, such as AFP, GPC3 and SALL-4.…”

Section: Introductionmentioning

confidence: 99%

Molecular and clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation

et al. 2020

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Background Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colorectal malignancy with expression of enteroblastic markers (glypican 3, SALL4, AFP); however, the clinicopathological and epidemiological features are not fully elucidated. Aims The aims of this study were to elucidate and establish the molecular and clinicopathological characteristics of CAED. Materials and Methods In addition to three cases recently diagnosed as CAED, colorectal carcinoma (CRC) with expression of enteroblastic markers were selected by using immunohistochemistry (IHC) on tissue microarrays of 988 advanced CRC. We employed next‐generation sequencing (NGS) and Sanger sequencing for the detection of genetic alterations. IHC for p53 and HER2, HER2‐FISH and MSI status was also investigated. Survival analyses for clinicopathological parameters were performed using Kaplan–Meier methods. Results Thirty‐nine cases (4.0%) were positive for at least one enteroblastic marker. Histological evaluation of the total of 42 cases revealed that 10 contained tumour cells with clear cytoplasm. Enteroblastic marker‐positive cases had aggressive behaviour and poor prognosis. NGS revealed TP53 as the most frequently mutated gene. The rate of HER2‐positive cases and MSI‐H cases was 9.5% (four of 42) and 12.2% (five of 41), respectively. Among these 42 cases, there were no molecular and clinicopathological differences according to the presence of tumour cells with clear cytoplasm. Conclusions Enteroblastic marker‐positive CRC could be grouped together as CAED regardless of clear cell cytoplasm. Using this definition, the frequency of CAED is 4.0% and has a poorer prognosis than that for conventional CRCs. HER2 targeted therapy would be a meaningful treatment for CAED, and CAEDs contain both MSI‐H and MSI‐stable CRCs, although the MSS phenotype is dominant.

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“…The majority of adenocarcinoma with enteroblastic differentiation cases have been reported to occur in the stomach . Compared with conventional gastric adenocarcinoma, gastric adenocarcinoma with enteroblastic differentiation shows aggressive behaviour characterised by frequent lymphovascular invasion, lymphatic and liver metastases, and is associated with a poor prognosis …”

Section: Introductionmentioning

confidence: 99%

“…The majority of adenocarcinoma with enteroblastic differentiation cases have been reported to occur in the stomach. 2,[12][13][14] Compared with conventional gastric adenocarcinoma, gastric adenocarcinoma with enteroblastic differentiation shows aggressive behaviour characterised by frequent lymphovascular invasion, lymphatic and liver metastases, and is associated with a poor prognosis. 2,12 Immunohistochemically, in addition to AFP, oncofetal proteins such as glypican-3 (GPC3) and spalt-like transcription factor 4 4 are reportedly associated with gastric adenocarcinoma with enteroblastic differentiation.…”

Section: Introductionmentioning

confidence: 99%

“…2,12 Immunohistochemically, in addition to AFP, oncofetal proteins such as glypican-3 (GPC3) and spalt-like transcription factor 4 4 are reportedly associated with gastric adenocarcinoma with enteroblastic differentiation. 2,13,14 GPC3, a cell-surface heparan sulphate proteoglycan, is present in fetal liver and hepatocellular carcinoma or hepatoblastoma. [15][16][17] SALL4 is a member of the SALL gene family and acts as a zinc finger transcription factor.…”

Section: Introductionmentioning

confidence: 99%

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Colorectal adenocarcinoma with enteroblastic differentiation: a clinicopathological study of five cases

et al. 2019

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Aims Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare malignancy, and its clinicopathological characteristics have not yet been fully elucidated. This study aimed to elucidate the clinicopathological features of CAED through immunostaining of enteroblastic lineage markers alpha‐fetoprotein (AFP), glypican‐3 (GPC3), and spalt‐like transcription factor 4 (SALL4). Methods and results We identified five CAED cases (0.3%) from 1666 colorectal carcinomas, analysed the clinicopathological characteristics and performed immunostaining for AFP, GPC3 and SALL4. Three patients were male and two were female. All cases were located in the sigmoid colon or rectum. Histologically, all cases showed adenocarcinoma composed of cuboidal or columnar cells, with clear cytoplasm resembling the primitive gut; one case exhibited a partial hepatoid pattern. The depth of invasion was T2 and T3 in two and three cases, respectively. Lymphatic/venous invasion was found in all cases (100%), lymph node metastases in four of five cases (80%) and distant metastases in three of five cases (60%) (liver, two cases; lung, one case). Two patients died as a result of their disease during follow‐up. Immunohistochemically, SALL4 and GPC3 were each positive in four of five cases, whereas one case with a hepatoid component was positive for AFP. All three CAED cases with distant metastases were GPC3‐positive. Conclusions CAED was frequently located in the sigmoid colon or rectum, showed aggressive behaviour, such as lymph node metastasis and distant metastasis, and had a dismal prognosis. In addition, CAED was immunoreactive to AFP, GPC3 or SALL4, indicating that these markers may be characteristic of CAED.

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TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation

Cited by 20 publications

References 31 publications

<p>Chrysin Induced Cell Apoptosis and Inhibited Invasion Through Regulation of TET1 Expression in Gastric Cancer Cells</p>

<p>Chrysin Induced Cell Apoptosis and Inhibited Invasion Through Regulation of TET1 Expression in Gastric Cancer Cells</p>

Molecular and clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation

Colorectal adenocarcinoma with enteroblastic differentiation: a clinicopathological study of five cases

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