Autocrine insulin-like growth factor-II stimulation of tumor cell migration is a progression step in human hepatocarcinogenesis.
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.


CONCLUSIONS
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.
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Tanja
T
Nussbaum
Jana
J
Samarin
Volker
V
Ehemann
Michaela
M
Bissinger
Eduard
E
Ryschich
Akmal
A
Khamidjanov
Xiaolei
X
Yu
Norbert
N
Gretz
Peter
P
Schirmacher
Kai
K
Breuhahn
D000818:Animals; D019898:Autocrine Communication; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D047428:Protein Kinase Inhibitors; C415032:picropodophyllin; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011034:Podophyllotoxin