Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival

David F Schaeffer, Daniel R Owen, Howard J Lim, Andrew K Buczkowski, Stephen W Chung, Charles H Scudamore, David G Huntsman, Sylvia S W Ng, David A Owen, David F Schaeffer, Daniel R Owen, Howard J Lim, Andrew K Buczkowski, Stephen W Chung, Charles H Scudamore, David G Huntsman, Sylvia S W Ng, David A Owen

Abstract

Background: Pancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more aggressive tumors could aid in management decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC) is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2) and ACTB (beta-actin).

Methods: We evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression.

Results: IGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38%) patient samples of tumor grade 1 (n = 24) and 27 (44%) of tumor grade 2 (n = 61) showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42) with 26 (62%) positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8).

Conclusions: Our data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

Figures

Figure 1
Figure 1
Expression of IGF2BP3 and IGF-2 staining. Bar graphs showing the percentages of low and high level positive (overexpression) staining for IGF2BP3 and IGF-2 of grade 1, 2, and 3 pancreatic ductal adenocarcinomata, compared to benign ductal pancreatic tissues. Data was obtained from 127 pancreatic ductal adenocarcinoma cases and 14 benign cases.
Figure 2
Figure 2
Immunohistochemical staining for IGF2BP3 and IGF-2 by tumor grade. Representative tissue microarray cores of pancreatic ductal adenocarcinomata with immunohistochemical staining for IGF2BP3 and IGF-2 by tumor grade. Note the complete lack of immunohistochemical staining for IGF2BP3 in benign pancreatic tissue. While there appears to be positive staining for IGF-2 in the benign cores, this was exclusively acinar staining and not ductal. [Scale bar, 100 μm.]
Figure 3
Figure 3
Evaluation of staining intensity and number of stained cells. IGF2BP3 (a) and IGF-2 (b) with strong and moderate staining intensity in more than 80% of pancreatic ductal adenocarcinoma cells, given a score of 12 and 8, respectively. In comparison weak staining of IGF2BP3 (c) in less than 10% of cells in an example of a grade 1 tumor, given a score of 1. [Scale bar, 200 μm.]
Figure 4
Figure 4
Disease specific Survival Analysis. Kaplan-Meier analysis of disease specific survival in pancreatic ductal adenocarcinoma expressing IGF2BP3 (black line, n = 62) and not expressing IGF2BP3 (grey line, n = 65). P value was calculated using the log-rank test.

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