High expression of insulin‐like growth factor binding protein‐3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma

Abstract

H epatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors worldwide. The longterm prognosis of HCC patients has remained unsatisfactory due to the high incidence of intrahepatic recurrence, which depends on portal venous invasion and the high incidence of intrahepatic metastasis, as well as multicentric development of new tumors.(1,2) Moreover, our understanding of the molecular mechanisms underlying the progression of HCC and the development of effective therapeutic targets remain to be studied in further detail.One candidate among the many growth factors that are closely associated with growth of HCC cells is insulin-like growth factor (IGF).(3) The biological effects of IGF are mediated via type 1 IGF receptor (IGF-1R), which leads to activation of the mitogenactivated protein kinase (MAPK) signaling pathway involved in cell growth and metabolism.(4,5) Mutation of another type 2 receptor (M6P/IGF-2R) and upregulation of IGF-II are expected to be responsible for the early stages of human hepatocarcinogenesis. (6,7) However, it remains unclear how the IGF system is involved in the progression of HCC. IGF are known to bind to IGF binding proteins (IGFBP), which regulate activity and function of IGF. (8) IGFBP-3 is the most abundant IGFBP that is present in non-cancerous liver tissues and serves as a negative regulator of cell proliferation in human HCC.(9-12) IGFBP-3 is also known to regulate cell growth independently of its effects on IGFstimulated growth in other types of malignancy. (13)(14)(15)(16) In our present study, we investigated how IGFBP-3 exerts its antiproliferative effects on HCC cell lines in culture, and using immunohistochemical analyses we further examined whether or not the expression of IGFBP-3 in human clinical samples is associated with the clinicopathological characteristics of HCC. We discuss plausible roles of IGFBP-3 in the IGF-dependent and -independent cell proliferation of HCC, and also the clinical significance of IGFBP-3 in patients with HCC.

Serum IGFBP-3 is a more effective predictor than IGF-1 and IGF-2 for the development of hepatocellular carcinoma in patients with chronic HCV infection

“…In agreement with these results, Aishima et al (20) showed an insignificant negative correlation between HCC staging and serum IGFBP-3 and IGF-1 levels. Moreover, in the present study, IGFBP-3 levels significantly discriminated between cirrhosis and HCC at a sensitivity of 87%, specificity of 80% and a cut-off value of <682.6 ng/ml.…”

Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer

“…Santosh et al (33) reported that IGFBP-3 overexpression in tumor tissues was an independent predictor of reduced survival rate in patients with newly diagnosed glioblastoma. By contrast, Aishima et al (34) identified that high expression levels of IGFBP-3 were independently associated with an improved survival rate in patients with hepatocellular carcinoma. In patients with squamous cell carcinoma of the tongue, IGFBP-3 expression was associated with favorable outcomes (35).…”

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

“…In breast cancer tissue, high IGFBP-3 expression has been associated in some studies with markers of poor prognosis, and/or worse overall survival (Rocha, et al 1996;SheenChen, et al 2009;Vestey, et al 2005). However, a relationship with overall or disease-free survival has not always been seen in breast (Ren, et al 2007) or other cancers (Katsaros, et al 2001), and there is evidence that in some cancers, for example head and neck (Papadimitrakopoulou, et al 2006) and hepatoma (Aishima, et al 2006), low tissue IGFBP-3 expression is associated with poorer patient outcome. Clearly, tissue IGFBP-3 expression is only one of a multitude of factors that might influence the survival of cancer patients, but it is of interest that a Kaplan-Meier plot (Györffy, et al 2010) for women with basal-type breast cancers (that typically have high IGFBP-3 expression) shows a significantly lower probability of recurrence-free survival for patients whose tumors have high IGFBP-3 mRNA expression (n=478, hazard ratio= 1.6, logrank P=0.001) (Fig.…”