Molecular Profiling of Human Hepatocellular Carcinoma Defines Mutually Exclusive Interferon Regulation and Insulin-Like Growth Factor II Overexpression

Abstract

ABSTRACT

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Although the physiological function of lowlevel IGF-II expression in adult liver has largely remained obscure, there is a large body of evidence for multiple protumorigenic functions during hepatocarcinogenesis such as antiapoptosis, stimulation of proliferation and activation of angiogenesis. IGF-II is overexpressed in 16-40% of human HCCs (Table 1), and possibly even in some premalignant lesions (Cariani et al, 1988;Ng et al, 1998;Aihara et al, 1996;Sohda et al, 1996;Breuhahn et al, 2004), in HCC cell lines (Li et al, 1997;Breuhahn et al, 2004;Lund et al, 2004) and in several HCC animal models (Schirmacher et al, 1991(Schirmacher et al, , 1992Harris et al, 1998). Elevated expression in HCC cells results from transcriptional activation such as loss of promoter-specific imprinting or re-activation of the fetal promoter (P2-P4) pattern (Li et al, 1997;Vernucci et al, 2000).…”

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…Moreover, few studies described elevated IGF-ⅡR levels in HCCs [53,54] . Independent of the underlying molecular mechanism, IGF-Ⅱ overexpression denominates a group of HCCs with fewer tumor infiltrating lymphocytes, a lower apoptosis rate [55] and extrahepatic metastasis [56] . Thus, serum IGF-Ⅱ availability was proposed as a tumor marker discriminating HCC from cirrhosis [57] .…”

“…The pivotal oncogenic function of IGF-Ⅱ-signaling IGF-II 9.2 [117] 22.5 [26] 25.6-60 [118] 66.7 [54] 40 [119] 100 [120] 50 [121] 14 [55] IGF-IR 7-78 [117] 40 [53] IRS-1 46.7 [53] 100 [122] IRS-2 53.3 [53] 86 [123] IRS-4 46.7 [53] in hepatocarcinogenesis is supported by several animal models. Transgenic mice expressing IGF-Ⅱ (20-30-fold increased levels in serum) develop hypoglycemia and many types of malignancies, which are most frequently HCC [67] .…”

Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

“…A significant decrease of IGF-I and IGF-II (Ϫ95% and Ϫ55%, respectively) and an increase of IGF-binding protein-3 (ϩ110%) levels have been observed in conditioned media after treatment with IFN-␣ (10 IU/ml), whereas the IGF-IR and IGF-IIR expression increased in Calu-6 cells during incubation with the cytokine (9). In addition, gene expression analyses showed a mutual exclusivity between IGF-II expression and IFN-induced genes in breast cancer and in hepatocellular carcinoma, suggesting an inverse relationship between both pathways (1,23).…”