Different roles for p16<scp><sup>INK</sup></scp><sup>4a</sup>‐<scp>R</scp>b pathway and <scp>INK</scp>4a/<scp>ARF</scp> methylation between adenocarcinomas of gastric cardia and distal stomach

Xue, Liang; Ouyang, Qin; Li, Jie; Meng, Xinxing; Li, Yuehong; Xing, Lingxiao; Wang, Junling; Xia, Yan; Zhang, Xianghong

doi:10.1111/jgh.12547

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…Similar molecular abnormalities also occur in gastric cardia neoplasia (37)(38)(39)(40)(41)(42), supporting the contribution of TP53 and CDKN2A to diverse types of adenocarcinogenesis involving the GEJ region. In agreement with these static observations, our dynamic model establishes that TP53/CDKN2A inactivation directly causes biologic and molecular features consistent with GEJ neoplastic progression.…”

Section: Discussionmentioning

confidence: 59%

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Zhao

Cheng

Kalra

et al. 2022

Preprint

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Inactivation of the tumor suppressor genes TP53 and CDKN2A occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, due to a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have been incompletely characterized. Here we report the development of the first wild-type primary human GEJ organoid model, as well as a CRISPR-edited transformed GEJ organoid model. CRISPR/Cas9 engineering to inactivate TP53 and CDKN2A (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia as well as pro-neoplastic features in vitro and tumor formation in vivo. Notably, lipidomic profiling identified several Platelet-Activating Factors (PTAFs) among the most upregulated lipids in CRISPR-edited organoids; and importantly, PTAF/PTAFR abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) significantly blocked proliferation and other pro-neoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts derived from Eso26, an established esophageal adenocarcinoma (EAC) cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly Forkhead Box M1 (FOXM1). Importantly, FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. In summary, we established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and discovered a potential cancer-therapeutic strategy, while providing insights into pro-neoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia.One Sentence SummaryNovel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model.Graphic Abstract

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Section: Discussionmentioning

confidence: 59%

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Zhao

Cheng

Kalra

et al. 2022

Preprint

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“…Likewise, CDKN2A is inactivated in more than 80% of BE and EAC tissues (34)(35)(36). Similar molecular abnormalities also occur in gastric cardia neoplasia (37)(38)(39)(40)(41)(42), supporting the contribution of TP53 and CDKN2A to diverse types of adenocarcinogenesis involving the GEJ region. In agreement with these static observations, our dynamic model establishes that TP53/CDKN2A inactivation directly causes biologic and molecular features consistent with GEJ neoplastic progression.…”

Section: Discussionmentioning

confidence: 72%

Generation and multiomic profiling of aTP53/CDKN2Adouble-knockout gastroesophageal junction organoid model

et al. 2022

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Inactivation of the tumor suppressor genes tumor protein p53 ( TP53 ) and cyclin-dependent kinase inhibitor 2A ( CDKN2A ) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9–mediated TP53 and CDKN2A knockout ( TP53/CDKN2A KO ) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2A KO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.

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“…An early study showed that about 50% of GC samples were detected with the loss of p16 expression ( 36 ). Interestingly, the expression of p16 in distal gastric carcinomas was higher than that in gastric cardia carcinomas ( 40 ). In GC, abnormal methylation of CpG islands in the promoter region of p16 downregulated p16 ( 47 ).…”

Section: Upstream Regulators Of the Rb-e2f Pathway In Gastric Cancermentioning

confidence: 91%

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer

2021

Front. Oncol.

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Gastric cancer is the most common malignant tumor in the digestive tract, with very high morbidity and mortality in developing countries. The pathogenesis of gastric cancer is a complex biological process mediated by abnormal regulation of proto-oncogenes and tumor suppressor genes. Although there have been some in-depth studies on gastric cancer at the molecular level, the specific mechanism has not been fully elucidated. RB family proteins (including RB, p130, and p107) are involved in cell cycle regulation, a process that largely depends on members of the E2F gene family that encode transcriptional activators and repressors. In gastric cancer, inactivation of the RB-E2F pathway serves as a core transcriptional mechanism that drives cell cycle progression, and is regulated by cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, p53, Helicobacter pylori and some other upstream molecules. The E2F proteins are encoded by eight genes (i.e. E2F1 to E2F8), each of which may play a specific role in gastric cancer. Interestingly, a single E2F such as E2F1 can activate or repress transcription, and enhance or inhibit cell proliferation, depending on the cell environment. Thus, the function of the E2F transcription factor family is very complex and needs further exploration. Importantly, the presence of H. pylori in stomach mucosa may affect the RB and p53 tumor suppressor systems, thereby promoting the occurrence of gastric cancer. This review aims to summarize recent research progress on important roles of the complex RB-E2F signaling network in the development and effective treatment of gastric cancer.

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Different roles for p16^INK^4a‐Rb pathway and INK4a/ARF methylation between adenocarcinomas of gastric cardia and distal stomach

Abstract: There were differences in p16(INK) (4a) -Rb immunotypes and INK4a/ARF methylation between two entities, indicating that cardia adenocarcinoma may be different in cell proliferation, differentiation, and gene biomarkers compared with distal gastric adenocarcinoma.

Cited by 7 publications

References 48 publications

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Generation and multiomic profiling of aTP53/CDKN2Adouble-knockout gastroesophageal junction organoid model

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer

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Different roles for p16INK4a‐Rb pathway and INK4a/ARF methylation between adenocarcinomas of gastric cardia and distal stomach

Abstract: There were differences in p16(INK) (4a) -Rb immunotypes and INK4a/ARF methylation between two entities, indicating that cardia adenocarcinoma may be different in cell proliferation, differentiation, and gene biomarkers compared with distal gastric adenocarcinoma.

Cited by 7 publications

References 48 publications

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Generation and multiomic profiling of aTP53/CDKN2Adouble-knockout gastroesophageal junction organoid model

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer

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Different roles for p16^INK^4a‐Rb pathway and INK4a/ARF methylation between adenocarcinomas of gastric cardia and distal stomach