IMP2/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer

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.

Raised CA19–9 and CEA have prognostic relevance in gallbladder carcinoma

“…Overexpression of eIF6s and Insulin growth factor-2 mRNA binding protein, (IMP2) have been significantly correlated with advanced tumor and shorter survival of gallbladder cancer patients. Thus, besides the tumor marker CEA and CA 19–9, eIF6 and IMP2 may be used as a prognostic biomarker for overall survival in GBC patients and might be used as a potential therapeutic approach in future [ 19 , 20 ]. Chronic inflammation is risk factor for gall bladder carcinoma.…”

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer

“…In GC tissues, the positive expression of IGF2BP1 was 72.4%, with the lower expression levels compared to control tissues. Furthermore, IGF2BP1 expression was observed to be related to longer survival and better prognosis [ 38 ]. However, IGF2BP1 expression was found to promote HCC cell proliferation, migration, and invasion [ 39 , 40 ], and correlate with poor survival and prognosis [ 41 – 43 ].…”

Altered glucocorticoid metabolism represents a feature of macroph‐aging

“…H 2 O 2 levels were measured using the homovanillic acid (HVA) assay, as described previously (Kessler et al., 2017). PMs were seeded at a density of approximately 2.5 × 10 5 cells per well into a 24‐well plate.…”

“…Quantitative RT–PCR (qPCR) was performed as described previously (Dembek et al., 2017; Hoppstädter, Dembek, et al., 2019; Hoppstädter, Diesel, et al., 2019; Hoppstädter et al., 2015, 2016; Kessler et al., 2017). Total RNA from cells was isolated using the High Pure RNA Isolation Kit (#11828665001; Roche), following the manufacturer's instructions.…”