Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis

Beckers, Johannes; Herrmann, F; Rieger, Sandra; Drobyshev, Alexei L.; Horsch, Marion; Angelis, Martin Hrabé de; Seliger, Barbara

doi:10.1002/ijc.20798

Cited by 54 publications

(41 citation statements)

References 59 publications

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“…Due to the fact that high expression of KLF5 is also observed in breast cancer, we additionally compared KLF5 expression to MCF-7 breast cancer cells and found similar results in terms of a higher expression by pancreatic cancer cells (data not shown; refs. 6,19). Importantly, we found that phosphorylation of MEK did not strongly correlate with KLF5 levels, suggesting that the MEK pathway might not be the critical determinant for KLF5 up-regulation in pancreatic cancer cells (Fig.…”

Section: Expression Of Klf5 In Pancreatic Cancermentioning

confidence: 80%

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk-mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1β or hypoxia. The IL-1 β-mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1α (HIF-1α) and HIF-1α siRNA reduced constitutive KLF5. Similarly, KLF5 siRNA reduced the expression of the HIF-1α target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/ MAPK/Erk signaling, but involves the IL-1β/IL-1R system, p38, and the transcription factor

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Section: Expression Of Klf5 In Pancreatic Cancermentioning

confidence: 80%

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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“…TNFAIP2 has previously been shown to be regulated by interleukin-1b (IL-1b), 23 retinoic acid, 38 erythroblastic leukemia viral oncogene homolog 2 (V-erb-b2), 39 and dioxin. 40 In the clinical setting, the levels of TNFa and IL-1b are known to be elevated in nasopharyngeal carcinoma.…”

Section: Discussionmentioning

confidence: 99%

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

Chen

et al. 2011

Modern Pathology

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Tumor necrosis factor alpha (TNFa) is an inflammatory cytokine that is present in the microenvironment of many tumors and is known to promote tumor progression. To examine how TNFa modulates the progression and metastasis of nasopharyngeal carcinoma, we used Affymetrix chips to identify TNFa-inducible genes that are dysregulated in this tumor. Elevated expression of TNFAIP2, which encodes TNFa-inducible protein 2 and not previously known to be associated with cancer, was found and confirmed by quantitative RT-PCR of TNFAIP2 expression in nasopharyngeal carcinoma and adjacent normal tissues. Immunohistochemical analysis showed that the TNFAIP2 protein was highly expressed in tumor cells. Analysis of 95 nasopharyngeal carcinoma biopsy specimens revealed that high TNFAIP2 expression was significantly correlated with highlevel intratumoral microvessel density (P ¼ 0.005) and low distant metastasis-free survival (P ¼ 0.001). A multivariate analysis further confirmed that TNFAIP2 was an independent prognostic factor for nasopharyngeal carcinoma (P ¼ 0.002). In vitro, TNFa treatment of nasopharyngeal carcinoma HK1 cells was found to induce TNFAIP2 expression, and siRNA-based knockdown of TNFAIP2 dramatically reduced the migration and invasion of nasopharyngeal carcinoma HK1 cells. These results collectively suggest for the first time that TNFAIP2 is a cell migration-promoting protein and its expression predicts distant metastasis. Our data suggest that TNFAIP2 may serve as an independent prognostic indicator for nasopharyngeal carcinoma.

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“…Previous reports have suggested that mouse embryonic fibroblasts and mouse mammary epithelial cells deficient in TIMP3 have increased h-catenin signaling (30). In addition, TIMP3 is normally downregulated by the activated RAS pathway and, notably, ERBB2 overexpression (31). Given our findings suggesting differential p53 pathway activation in LMP and invasive ovarian carcinomas, we examined p53 immunohistochemical staining in LLI samples, for which formalin-fixed, paraffin-embedded (FFPE) tissue was available (five of eight samples).…”

Section: Identification Of Lmp-like Invasive Tumorsmentioning

confidence: 99%

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Anglesio

Arnold²,

George³

et al. 2008

Molecular Cancer Research

113

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Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with f12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2

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Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis

Cited by 54 publications

References 59 publications

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

A novel role for TNFAIP2: its correlation with invasion and metastasis in nasopharyngeal carcinoma

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

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