Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis
| Autor: | Tanja Nussbaum, Akmal Khamidjanov, Kai Breuhahn, Xiaolei Yu, Peter Schirmacher, Jana Samarin, Eduard Ryschich, Norbert Gretz, Volker Ehemann, Michaela Bissinger |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Carcinoma Hepatocellular medicine.medical_treatment Transplantation Heterologous Biology medicine.disease_cause Receptor IGF Type 1 Mice Cell Movement Insulin-Like Growth Factor II Internal medicine medicine Tumor Cells Cultured Animals Humans Neoplasm Invasiveness Autocrine signalling Receptor Protein Kinase Inhibitors Podophyllotoxin Hepatology Growth factor Liver Neoplasms Cell migration Up-Regulation Gene Expression Regulation Neoplastic Autocrine Communication Endocrinology Tumor progression Cancer research Disease Progression Picropodophyllin Hepatocyte growth factor Carcinogenesis Neoplasm Transplantation medicine.drug Signal Transduction |
| Zdroj: | Hepatology (Baltimore, Md.). 48(1) |
| ISSN: | 1527-3350 |
| Popis: | The protumorigenic insulin-like growth factor (IGF)-II is highly expressed in a significant fraction of human hepatocellular carcinomas (HCC). However, a functional dissection that clarifies the contribution of IGF-II–binding receptors in tumor progression and a respective molecular characterization of IGF-II signaling has not been performed. Therefore, expression of IGF-II and its receptors IGF-receptor type I (IGF-IR) and insulin receptor (IR) was efficiently blocked using small interfering RNA (siRNA) in HCC cells. Despite functional IR-signaling, oncogenic IGF-II effects such as tumor cell viability, proliferation, and anti-apoptosis were solely transmitted by IGF-IR. Although IGF-II signaling was previously not described in the context of HCC cell migration, the IGF-II–dependent expression profile displayed a high percentage of genes involved in cell motility and adhesion. Indeed, IGF-II overexpression promoted HCC cell migration, especially in synergy with hepatocyte growth factor (HGF). The therapeutic relevance of IGF-II/IGF-IR signaling was tested in vitro and in a murine xenograft transplantation model using the IGF-IR inhibitor picropodophyllin (PPP). IGF-IR inhibition by small molecule treatment efficiently reduced IGF-II–dependent signaling and all protumorigenic properties of the IGF-II/IGF-IR pathway. Conclusion: In human HCC cells, IGF-IR but not IR is involved in oncogenic IGF-II signaling. Autocrine stimulation of IGF-II induces HCC motility by integration of paracrine signals for full malignant competence. Thus, activation of IGF-II/IGF-IR signaling is likely a progression switch selected by function that promotes tumor cell dissemination and aggressive tumor behavior. (HEPATOLOGY 2008.) |
| Databáze: | OpenAIRE |
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