Immunohistochemical evaluation of p53, FHIT, and IGF2 gene expression in esophageal cancer

Chava, Srinivas; Mohan, Vasavi; Shetty, Preetha J; Manolla, M. L.; Vaidya, Sireesha; Khan, Imran; Waseem, G. L.; Boddala, Pavani; Ahuja, Y.R.; Hasan, Qurratulain

doi:10.1111/j.1442-2050.2011.01213.x

Cited by 20 publications

(14 citation statements)

References 39 publications

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“…IGF2 is overexpressed in 81% of ESCC (27). The direct regulation of IGF2 by E2F1 demonstrated in the in vitro experiments above led us to postulate that E2F1 expression may be upregulated and positively correlated with IGF2 expression in ESCC.…”

Section: E2f1 and Igf2 Are Overexpressed And Positively Correlated Wimentioning

confidence: 95%

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Guan

et al. 2016

Clinical Cancer Research

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Purpose: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance.Experimental Design: In vitro and in vivo functional assays were performed to study the effects of Id1-E2F1-IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes.Results: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types.Conclusions: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment. Clin Cancer Res; 22(5); 1243-55. Ó2015 AACR.

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Section: E2f1 and Igf2 Are Overexpressed And Positively Correlated Wimentioning

confidence: 95%

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Guan

et al. 2016

Clinical Cancer Research

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“…Nuclear p53 protein accumulation, in most cases, is due to mutations within the gene and a strong association was noted between TP53 mutations and nuclear p53 protein accumulation (25). Mutations in this gene and accumulation of the abnormal p53 protein are frequently associated with malignancy and tumor progression; accumulation of the mutant p53 protein has been associated with a poor prognosis in patients with breast, gastric and colorectal carcinomas (26). It is possible that miR-150 and miR-3940-5p directly or indirectly regulate the p53 expression or degradation.…”

Section: A B C Dmentioning

confidence: 99%

Expression of miR-150 and miR-3940-5p is reduced in non-small cell lung carcinoma and correlates with clinicopathological features

Sun

Zhang

et al. 2012

Oncology Reports

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Abstract. The present study investigated the expression of miR-150 and miR-3940-5p in non-small cell lung carcinoma (NSCLC) and its relationship with clinicopathologic features. Samples included tumor, tumor-adjacent and normal lung parenchyma tissues from 90 NSCLC patients and 17 cases of embryonic lung cDNA. The expression levels of miR-150, miR-18b-5p, miR-643 and miR-3940-5p were detected by real-time PCR; p53, EGFR, Kras and Ki-67 expression in tumor tissues was determined by immunohistochemistry. p53 mRNA expression levels in NSCLC were examined by SYBR-Green real-time PCR. The relationship between the four miRNAs and clinicopathologic features of 90 cases was analyzed. The expression of miR-150 and miR-3940-5p was significantly downregulated in tumor tissues and embryonic lung tissues compared to normal lung tissues. The expression of miR-150 and miR-3940-5p in tumor tissues was also lower than that in the matched tumor-adjacent tissues. miR-150 was downregulated preferentially in subgroups of patients with a tumor diameter more than or equal to 3 cm, in smokers and in stage III and IV tumors. Specifically, miR-150 and miR-3940-5p expression was decreased in nuclear cell proliferation antigen Ki-67-positive NSCLC cases. miR-150 and miR-3940-5p were found to be significantly downregulated in p53 IHC-positive NSCLC cases and were negatively correlated with p53 mRNA. Reduced miR-150 and miR-3940-5p expression in tumor tissues and embryonic lung tissues suggests that these miRs may be involved in the tumorigenesis or de-differentiation of NSCLC. Due to this associaton with the Ki-67 proliferation index in NSCLC, downregulation of miR-150 and miR-3940-5p may contribute to tumor growth and proliferation. miR-150 and miR-3940-5p may affect p53 expression through a direct or indirect pathway.

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“…Elevated expressions of insulin-like growth factortype I receptor (IGF-IR), and its ligands IGF-I and IGF-II, had been reported in human cancers, including ESCC, and were found to be correlated with advanced tumor stage and metastasis (13,14), but treatment efficacy of IGF-IR blockade in ESCC remains to be evaluated. The feasibility of targeting the IGF-II-IGF-IR axis as potential treatment options for ESCC was investigated in this study in vitro, as well as in vivo using tumorigenesis and cancer metastasis mouse models.…”

Section: Introductionmentioning

confidence: 99%

Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance—Implications for IGF-II and IGF-IR–Targeted Therapy

Tsao

Chan

et al. 2014

Clinical Cancer Research

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Purpose: To investigate the autocrine/endocrine role of Id1-induced insulin-like growth factor-II (IGF-II) in esophageal cancer, and evaluate the potential of IGF-II-and IGF-type I receptor (IGF-IR)-targeted therapies.Experimental Design: Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing esophageal cancer cells. In vitro and in vivo assays were performed to confirm the induction of IGF-II by Id1, and to study the autocrine and endocrine effects of IGF-II in promoting esophageal cancer progression. Human esophageal cancer tissue microarray was analyzed for overexpression of IGF-II and its correlation with that of Id1 and phosphorylated AKT (p-AKT). The efficacy of intratumorally injected IGF-II antibody and intraperitoneally injected cixutumumab (fully human monoclonal IGF-IR antibody) was evaluated using in vivo tumor xenograft and experimental metastasis models.Results: Id1 overexpression induced IGF-II secretion, which promoted cancer cell proliferation, survival, and invasion by activating AKT in an autocrine manner. Overexpression of IGF-II was found in 21 of 35 (60%) esophageal cancer tissues and was associated with upregulation of Id1 and p-AKT. IGF-II secreted by Id1-overexpressing esophageal cancer xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells. Targeting IGF-II and IGF-IR had significant suppressive effects on tumor growth and metastasis in mice. Cixutumumab treatment enhanced the chemosensitivity of tumor xenografts to fluorouracil and cisplatin.

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Immunohistochemical evaluation of p53, FHIT, and IGF2 gene expression in esophageal cancer

Cited by 20 publications

References 39 publications

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

Expression of miR-150 and miR-3940-5p is reduced in non-small cell lung carcinoma and correlates with clinicopathological features

Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance—Implications for IGF-II and IGF-IR–Targeted Therapy

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