Diethylnitrosamine induces long-lasting re-expression of insulin-like growth factor II during early stages of liver carcinogenesis in mice

Lahm, Harald; Gittner, Katinka; Krebs, Ottheinz; Sprague, Lisa D.; Deml, E.; Oesterle, Doris; Hoeflich, Andreas; Wanke, Rüdiger; Wolf, Eckhard

doi:10.1054/ghir.2002.0261

Cited by 14 publications

(18 citation statements)

References 38 publications

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“…IGF-II has been reported to be upregulated in HCC tissues, and this increase in expression was correlated with cancer cell proliferation and tumor neovascularization (17,18). IGF-1R has also been demonstrated to be upregulated in HCC.…”

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confidence: 98%

Transcriptional activation of the IGF-II/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma

et al. 2015

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Abstract. Hepatocellular carcinoma (HCC) is characterized by the aberrant expression of a number of genes that govern crucial signaling pathways. The insulin-like growth factor (IGF) axis is important in this context, and the precise regulation of expression of members of this axis is known to be lost in HCC. miR-155 is a well-established oncogene in numerous types of cancer. However, to the best of our knowledge, its effect on the regulation of the IGF axis has not been investigated to date. The present study aimed to elucidate the interactions between miR-155 and key components of the IGF axis, in addition to examining its effect on HCC development. Reverse transcription-quantitative polymerase chain reaction was used to measure the expression of miR-155 in HCC and cirrhotic tissues, in addition to HCC cell lines. Furthermore, the effect of the induction of miR-155 expression on the expression of three members of the IGF axis [IGF II, IGF type-1 receptor (IGF-1R) and IGF-binding protein 3 (IGFBP-3)], was analyzed. Finally, the effect of miR-155 on HCC cell proliferation, migration and clonogenicity was also examined. Quantification of the expression of miR-155 demonstrated that it is upregulated in HCC. Induction of the expression of miR-155 in HCC cell lines led to the upregulation of IGF-II and IGF-IR, and the downregulation of IGFBP-3. In addition, the proliferation, migration and clonogenicity of HCC was increased following induction of miR-155 expression. miR-155 is an oncomiR, which upregulates the oncogenes, IGF-II and IGF-IR, and downregulates the tumor suppressor, IGFBP-3, thereby resulting in increased HCC cell carcinogenicity. Therefore, miR-155 may be a therapeutic target in HCC.

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confidence: 98%

Transcriptional activation of the IGF-II/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma

et al. 2015

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“…To distinguish transgenic mice and their non-transgenic littermates animals were genotyped by PCR using the following primers for IGF-II: 5' ATG GGA ATC CCA ATG GGG AAG 3' and 5' CTT GCC CAC GGG GTA TCT GGG 3'. These primers generate a 336 bp product from the transgenic human IGF2 DNA [25]. Genomic DNA was prepared from mouse-tail biopsies.…”

Section: Methodsmentioning

confidence: 99%

“…The reaction was terminated for 5 min at 95°C. The amplification of human and murine IGF-II sequences was performed with species-specific primers as described [25]. Both primer-pairs yielded an amplification product of 499 bp [25].…”

Section: Methodsmentioning

confidence: 99%

“…The amplification of human and murine IGF-II sequences was performed with species-specific primers as described [25]. Both primer-pairs yielded an amplification product of 499 bp [25]. The integrity of cDNA was confirmed by β-actin specific primers 5' GGC ATC GTG ATG GAC TCC G 3' (β-actin: forward), 5' GTC GGA AGG TGG ACA GCG A 3' (β-actin: reverse).…”

Section: Methodsmentioning

confidence: 99%

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Diehl¹,

Oesterle²,

Elmlinger³

et al. 2006

J Carcinog

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In colorectal cancer insulin-like growth factor II (IGF-II) is frequently overexpressed. To evaluate, whether IGF-II affects different stages of tumorigenesis, we induced neoplastic alterations in the colon of wild-type and IGF-II transgenic mice using 1,2-dimethylhydrazine (DMH). Aberrant crypt foci (ACF) served as markers of early lesions in the colonic mucosa, whereas adenomas and carcinomas characterized the endpoints of tumor development. DMH-treatment led initially to significantly more ACF in IGF-II transgenic than in wild-type mice. This increase in ACF was especially prominent for those consisting of ≥three aberrant crypts (AC). Nevertheless, adenomas and adenocarcinomas of the colon, present after 34 weeks in both genetic groups, were not found at different frequency. Tumor volumes, however, were significantly higher in IGF-II transgenic mice and correlated with serum IGF-II levels. Immunohistochemical staining for markers of proliferation and apoptosis revealed increased cell proliferation rates in tumors of IGF-II transgenic mice without significant affection of apoptosis. Increased proliferation was accompanied by elevated localization of β-catenin in the cytosol and cell nuclei and reduced appearance at the inner plasma membrane. In conclusion, we provide evidence that IGF-II, via activation of the β-catenin signaling cascade, promotes growth of ACF and tumors without affecting tumor numbers.

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“…the effects of elevated IGFBP levels in the multi-step process of hepatocellular or colorectal carcinogenesis. A suitable experimental approach would be the chemical induction [49,50] of the respective tumors in IGFBP transgenic models followed by a systematic monitoring of preneoplastic lesions and tumor progression compared with nontransgenic controls.…”

Section: Future Directions Of Researchmentioning

confidence: 99%

Functional consequences of IGFBP excess?lessons from transgenic mice

Wolf

Schneider²,

Zhou³

et al. 2004

Pediatr Nephrol

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The functions of insulin-like growth factor-binding proteins (IGFBPs) have been studied extensively in vitro, revealing IGF-dependent and also IGF-independent effects on cell growth, differentiation, and survival. In contrast, the biological relevance of IGFBPs in vivo is only partially understood. In the past decade, mouse models lacking or overexpressing specific IGFBPs have been generated by transgenic technology. Phenotypic analysis revealed features that are common for most IGFBPs (growth inhibition), but also effects that appear to be specific for some but not all IGFBPs, such as disturbed glucose homeostasis (IGFBP-1 and -3) or impaired fertility (IGFBP-1, -5, and -6). Future systematic comparison of IGFBP functions in transgenic mice will be facilitated by targeted insertion of IGFBP expression vectors and by standardized phenotype assessment. Furthermore, analysis of IGFBP expression in growth-selected mouse lines or pedigrees segregating for growth phenotypes will be important to understand the roles of IGFBPs in multigenic growth regulation.

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Diethylnitrosamine induces long-lasting re-expression of insulin-like growth factor II during early stages of liver carcinogenesis in mice

Cited by 14 publications

References 38 publications

Transcriptional activation of the IGF-II/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma

Transcriptional activation of the IGF-II/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma

Untitled

Functional consequences of IGFBP excess?lessons from transgenic mice

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