Characterization of the IGF System and Analysis of the Possible Molecular Mechanisms Leading to IGF-II Overexpression in a Mesothelioma

Abstract

The expression of members of the IGF system in a mesothelioma from a patient suffering from hypoglycemia, in term placenta and HT29 colon adenocarcinoma cells were compared. Very high levels of IGF-II mRNA and protein were detected in the mesothelioma. Moreover, half of the IGF-II protein took the high-molecular-weight form. We also analyzed the parental imprinting status and the promoter usage of the IGF-II gene. Our results showed loss of imprinting (LOI) in the mesothelioma while the imprinting was maintained in HT29 cells, expressing moderate levels of the transcript. Promoter P4 was active in the three tissues we analyzed, whereas IGF-II mRNA transcription from promoter P3 was only detected in the mesothelioma and the placenta, expressing comparably high levels of the transcript. IGF-II gene structure was identical in the analyzed tissues and cells. The type-I receptor mRNA expression was very low in the tumor. IGFBP-2, -4 and -5 mRNAs were detected in the mesothelioma, while IGFBP-2, -3 and -5 transcripts were detected in the placenta. IGFBP-1 and -6 transcripts were not detected.

Aberrant promoter methylation of insulin‐like growth factor binding protein‐3 gene in human cancers

“…In addition, IGFBP-3 was more overexpressed in MM cell lines and primary tumors than in a nonmalignant mesothelial cell line, 38 despite the report by Hodzic et al showing that IGFBP-3 was downregulated in MM. 34 One explanation for the overexpression of IGFBP-3 in malignancies is that IGFBP-3 may inhibit tumor cell proliferation via a negative feedback mechanism. 37,[39][40][41][42] Another possibility is that unknown defects in IGFBP-3 receptor function may lead to IGFBP-3 overexpression in these tumors.…”

Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases

“…IGF-II gene overexpression is more widespread than first thought and appears to occur in various malignancies, albeit to a variable extent (Hodzic et al 1997, van der Ven et al 1997. Nowadays it is generally accepted that IGF-II is involved in oncogene-induced tumorigenesis (Khandwala et al 2000, Samani et al 2007).…”

“…Overexpression of IGF-II in tumours has been mainly attributed to either a loss of imprinting or mutations in tumour suppressor genes (Drummond et al 1992, Christofori et al 1995, Khandwala et al 2000. The mechanisms leading to IGF-II mRNA overexpression in NICTH have rarely been studied (Hodzic et al 1997, Bertherat et al 2000. Hodzic et al (1997) reported loss of imprinting of the IGF-II gene in a mesothelioma causing hypoglycaemia.…”

Targeting the epigenome in malignant pleural mesothelioma

“…Presently, limited information is available regarding mechanisms and clinical relevance of DNA hypomethylation in MPM. For instance, with the exception of a single report of LOI of IGF-II in (58), this phenomenon has not been described in MPM. Similarly, expression of endogenous retroviral sequences has not been evaluated in MPM.…”