Abstract
Overexpression of the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2/IGF2BP2) has been described in different cancer types. Gallbladder carcinoma (GBC) is a rare but highly aggressive cancer entity with late clinical detection and poor prognosis.The aim of this study was to investigate the role of IMP2 in human GBC.Tissue microarrays (TMAs) of an international multi-center GBC sample collection from n = 483 patients were analyzed by immunohistochemistry. IMP2 immunoreactivity was found in 74.3% of the tumor samples on TMA, of which 14.0% showed strong and 86.0% low staining intensity. 72.4% of the tumor samples were IMP1 positive, but IMP1 showed lower expression in tumor tissue compared to control tissues. IMP3 immunoreactivity was observed in 92.7% of all tumors, of which 53.6% revealed strong IMP3 expression. Kaplan-Meier analysis linked high IMP2 expression to shorter survival time (p = 0.033), whereas neither IMP1 nor IMP3 expression was linked to a decreased survival time. Eight different human biliary tract cancer (BTC) cell lines were evaluated for tumor growth kinetics in mouse xenografts. Cell lines with high IMP2 expression levels showed the fastest increase in tumor volumes in murine xenografts. Furthermore, IMP2 expression in these cells correlated with the generation of reactive oxygen species (ROS) and RAC1 expression in BTC cells, suggesting RAC1-induced ROS generation as a potential mechanism of IMP2-promoted progression of GBC.In conclusion, IMP2 is frequently overexpressed in GBC and significantly associated with poor prognosis and growth rates in vivo. IMP2 might therefore represent a new target for the treatment of advanced GBC.
Highlights
Gallbladder carcinoma (GBC) is a lethal malignancy with a 5-year survival depending on tumor stages and being less than 10–20% in advanced tumors
Tumor grade data were available for 402 patients with 16% of GBCs cases were categorized as grade 1 (G = 1), 44% as grade 2 (G = 2), 39% as grade 3 (G = 3), and 1% as grade 4 (G = 4). pT, pN, and M categories were available for 335, 147, and 128 patients, respectively. 15.5% of the cases were classified as pT = 1, 40% as pT = 2, 35% as pT = 3, 8% as pT = 4, and 1.5% as carcinoma in situ. pN categories were distributed as follows: 55% pN0, 13% pN1, and 13% pN2 patients. 81% of the cases were classified as M0 and 19% as M1
Nuclear expression of IMP2/p62 was absent in all cases confirming the expected localization [15]. 25.7% of the cases were negative for IMP2/p62 expression, whereas from 74.3% positive samples 86.0% showed low IMP2/ p62 expression and 14.0% highly expressed IMP2/p62 (Figure 1A) without being frequently mutated: mutations in the IGF2BP2 gene were observed in 1.35% of GBC cases investigated (n = 74) and in 0% of bile duct cancer samples (n = 294) (Sanger Institute COSMIC website, http://www.sanger.ac.uk/cosmic)
Summary
Gallbladder carcinoma (GBC) is a lethal malignancy with a 5-year survival depending on tumor stages and being less than 10–20% in advanced tumors. The median survival time for patients with GBC is limited to one year [1]. This is mostly due to late diagnosis, thereby minimizing chances of cure. If diagnosed at early tumor stages (T1 tumors), GBC can be cured in 61–100% [2]. For unresectable GBC, chemotherapy is the only approved treatment strategy, but is only applied as a palliative therapeutic route with low efficacy. The identification and characterization of markers with diagnostic potential and significance is essential to stratify patients into different risk groups for GBC and to develop new therapeutic strategies
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