Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma

Kate, Fiebo J. C. ten; Suzuki, Lucia; Dorssers, Lambert C. J.; Dinjens, Winand N.M.; Jones, David; Nieboer, Daan; Doukas, Michael; Lanschot, J. Jan B. van; Wijnhoven, Bas P. L.; Looijenga, Leendert H. J.; Biermann, Katharina

doi:10.18632/oncotarget.22021

Cited by 8 publications

(5 citation statements)

References 48 publications

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“…MdM4, which mediates p53-independent activities, is abnormally expressed in various cancer cells and contributes to the development of cancer (36)(37)(38). Gilkes et al (39) noted that MdM4 is overexpressed in human colon tumors; consistent with these findings, the present results also revealed overexpressed MdM4 in human colon cancer tissues and cells.…”

Section: Discussionsupporting

confidence: 88%

miR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4

Fan

Wang

2020

Mol Med Rep

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colon cancer is one of the most frequent malignant tumors, and microrna (mir)-205 is involved in the tumor progression. The present study aimed to explore the effects of mir-205 on human colon cancer and its targeting mechanism. The levels of mir-205 and mouse double minute 4 (MdM4) were determined via reverse transcription-quantitative (rT-q) Pcr and western blot analysis. a luciferase activity assay was performed to analyze the association between mir-205 and MdM4. cell viability, migration and invasion were determined via cell counting Kit-8, wound healing and Transwell assays, respectively. The levels of epithelial-mesenchymal transition (eMT)-associated factors were determined by rT-qPcr and western blot analysis. It was identified that MDM4 was overexpressed in colon cancer tissues and cells, and that there was a negative correlation between mir-205 and MdM4 expression in colon cancer. Similarly, mir-205 inhibited MdM4 expression by binding to its 3'untranslated region. in addition, mir-205 directly targeted MdM4, accompanied by suppressed proliferation, migration and invasion of HcT116 cells. eMT processes were suppressed in mir-205-overexpressed cells; upregulation of e-cadherin, and downregulation of n-cadherin, vimentin, matrix metalloproteinase (MMP)2 and MMP9 were observed. collectively, mir-205 conspicuously depressed the viability, migration, invasion and eMT process of human colon cancer cells via targeting MdM4. mir-205 could be potentially used in the treatment of human colon cancer.

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Section: Discussionsupporting

confidence: 88%

miR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4

Fan

Wang

2020

Mol Med Rep

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“…Complete loss of Tp53 in Lgr5 cells did not induce other chromosomal alteration, as demonstrated in CNV analysis in organoids and GEJ tissue. Nevertheless, TP53 is most commonly mutated in dysplastic BE patients, and we did not study a Tp53 mutated model, which could have a different outcome[29]. Rb1 is downstream of p16 INK4A in the CDKN2A signalling pathway, and while we disrupted p16 signalling by conditional knockout of Rb1 , this on its own was insufficient to induce invasive cancer or chromosomal aberrations or alter organoid growth.…”

Section: Discussionmentioning

confidence: 99%

KRas, in addition to Tp53 is a driver for early carcinogenesis and a molecular target in a mouse model of invasive gastro-esophageal adenocarcinoma

Anand,

Schömig,

Lange

et al. 2024

Preprint

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Objective: The incidence of gastro-esophageal adenocarcinoma (GEAC) has increased dramatically and is associated with Barrett's Esophagus (BE). Gastric cardia progenitors are the likely origin for BE and GEAC. Here we analyze p53, Rb1 and Kras alterations in Lgr5 progenitor cells during carcinogenesis. Design: We introduced single and combined genetic alterations (p53, Rb1 and Kras) in Lgr5-expressing progenitor cells at the inflamed gastroesophageal junction in the L2-IL1b (L2) mouse model crossed to Lgr5-CreERT mice. For in-vitro treatment we utilized mouse and human 3D organoids. Results: Inactivation of Tp53 or Rb1 alone (L2-LP and L2-LR mice) resulted in metaplasia, and mild dysplasia, while expression of KrasG12D (L2-LK) accelerated dysplasia in L2-IL1b mice. Dual induction of genetic alteration in L2-LPR, L2-LKP and L2-LKR mice confirmed the accelerating role of mutant Kras, with the development of invasive cancer in mice with combined Tp53 and Kras alteration. All three genetic events in cardia progenitor cells generated invasive cancer at 6 months of age, with chromosomal instability (CNV). The dominant role of Kras prompted us to treat with a SHP2 inhibitor in combination with an ERK or MEK inhibitor, leading to reduced growth in Kras mutant organoids. SHP2 and MEK inhibition in-vivo reduced Kras-dependent tumor formation. Conclusion: In the first invasive GEAC mouse model, Kras mutation in combination with loss of tumor suppressor genes Tp53 or Rb1 emerges as a key player in GEAC and with the importance of p53 and Rb1 in promoting metaplasia. Targeting this SHP2/MEK/KRAS pathway represents a promising therapeutic option for Kras-altered GEAC.

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“… 57 Esophageal Carcinoma Esophageal Adenocarcinoma The incidence of esophageal adenocarcinoma may be associated with the abnormal amplification of p53 and MDM2, MDM4. 80 Kidney Cancer Renal Cell Cancer The expression level of MDM4 was significantly increased in renal cell cancer. 81 Ovarian Cancer Serous Ovarian Cancer The MDMX SNP34091AC/CC genotype is associated with an increased risk of serous ovarian cancer, particularly high-grade serous ovarian cancer.…”

Section: Phosphorylationmentioning

confidence: 99%

“…The incidence of esophageal adenocarcinoma may be associated with the abnormal amplification of p53 and MDM2, MDM4. 80…”

Section: Esophageal Carcinoma Esophageal Adenocarcinomamentioning

confidence: 99%

MDMX in Cancer: A Partner of p53 and a p53-Independent Effector

Lin,

Yan,

Huang

et al. 2024

BTT

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The p53 tumor suppressor protein plays an important role in physiological and pathological processes. MDM2 and its homolog MDMX are the most important negative regulators of p53. Many studies have shown that MDMX promotes the growth of cancer cells by influencing the regulation of the downstream target gene of tumor suppressor p53. Studies have found that inhibiting the MDMX-p53 interaction can effectively restore the tumor suppressor activity of p53. MDMX has growth-promoting activities without p53 or in the presence of mutant p53. Therefore, it is extremely important to study the function of MDMX in tumorigenesis, progression and prognosis. This article mainly reviews the current research progress and mechanism on MDMX function, summarizes known MDMX inhibitors and provides new ideas for the development of more specific and effective MDMX inhibitors for cancer treatment.

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Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma

Cited by 8 publications

References 48 publications

miR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4

miR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4

KRas, in addition to Tp53 is a driver for early carcinogenesis and a molecular target in a mouse model of invasive gastro-esophageal adenocarcinoma

MDMX in Cancer: A Partner of p53 and a p53-Independent Effector

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