Insulin‐like growth factor II mRNA‐binding protein 3 expression predicts unfavorable prognosis in patients with neuroblastoma

Abstract

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) has been reported to enhance proliferation and invasion in various cancers. The role of IMP3 on neuroblastoma (NB) is unknown. We aimed to clarify the prognostic significance of IMP3 expression in patients with NB. By microarray analysis, high IMP3 expression was found in patients with poor outcome. IMP3 expression in 90 NB samples was analyzed by immunohistochemical staining to correlate with clinical stages, histology, and patient outcome. Positive IMP3 expression was detected in 52 of 90 patients, and was significantly correlated with undifferentiated histology, advanced stages, MYCN amplification, and poor outcome. In subgroups, positive IMP3 expression could predict an even worse prognosis in patients with advanced disease, with normal MYCN status, or with MYCN amplification (P = 0.005, P = 0.001, and P = 0.033, respectively). The IMP3 expression decreased by induction of differentiation with retinoid acid treatment in SK-N-DZ and SK-N-SH cells in vitro. The invasion ability of NB cells also decreased as IMP3 knockdown by using RNA interference in vitro. In summary, high expression of IMP3 in NB might contribute to the undifferentiated phenotype and invasive behaviors, leading to a poor prognosis. Determining IMP3 expression in NB could help to improve a personalized therapy. (Cancer Sci 2011; 102: 2191-2198 N euroblastoma (NB), a common cancer of early childhood that originates from primitive sympathetic neural precursors, has a remarkable heterogeneity of clinical behaviors ranging from spontaneous regression to rapid progression and death. Therapeutic options are proposed according to the Children's Oncology Group risk stratification criteria based on clinical and biological factors, including clinical stage, MYCN status, age at diagnosis, histology, and ploidy status.(1,2) Treatment strategy, which ranges from observation alone to intensive multimodal therapy, depends on the risk stratification of the patient in one of the three subgroups of low-, intermediate-, and high-risk of death. Although several biological and molecular prognostic factors have been identified, amplification of the MYCN oncogene, which occurs in roughly 20% of primary NB, is one of the most powerful prognostic factors in NB.(3) The co-opting neurotrophin pathways including the neurotrophin receptors (TrkA, TrkB, and TrkC) and their ligands (NGF, BDNF, and neurotrophin-3, respectively), which regulate the differentiation, apoptosis, and growth of neural cells, are also important prognosis-related factors in NB.(4) However, some patients with a normal MYCN copy number still present with clinically aggressive progression similar to those with MYCN-amplified tumors, suggesting that other unfavorable molecules determining inferior survival may exist.(5,6)The insulin-like growth factor II mRNA-binding protein 3 (IMP3), also known as L532S or K homology domain-containing protein overexpressed in cancer (KOC), is a member of the RNA-binding protein family that includes IMP1, IMP2...

Prognostic value of high IMP3 expression in solid tumors: a meta-analysis

“…The 53 studies involved 8,937 patients with different cancer types, including 6 studies of RCC,8,25–29 6 lung cancer,9,30–34 4 oral cancer,10,35–37 4 urothelial carcinoma,38–41 4 ovarian cancer,16,17,42,43 3 hepatocellular carcinoma (HCC),44–46 4 colorectal cancer,12,47–49 3 prostate cancer,14,15,50 3 pancreatic cancer,51–53 2 gastric cancer,11,54 2 intrahepatic cholangiocarcinoma (ICC),55,56 and one study each of tongue cancer,57 thyroid carcinoma,58 sacral chordoma,59 pilocytic astrocytoma and pilomyxoid astrocytoma (PA/PMA),60 neuroblastoma,61 meningioma,62 melanoma,63 breast cancer,64 giant cell tumor,65 bile duct carcinoma,66 esophageal carcinoma,67 and cervical cancer 13. A total of 25 studies involved Caucasians and 28 involved Asians.…”

Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression

“…10,25 Specifically, increased protein expression of IGF2BP3 has been associated with enhanced tumor aggressiveness, metastatic behavior and inferior outcome of various solid cancers. [12][13][14][15][16][17][18] Recently, there has been growing interest in the IGF pathway from a therapeutic perspective, as monoclonal antibodies and small molecules targeting the IGF1 receptor have become available a few years ago and initial, small phase I and II, trials showed encouraging results in individual patients. 25 In this study, we investigated the mRNA expression levels of several molecules involved in IFG signaling in mantle cell lymphoma cell lines and primary mantle cell lymphoma cases.…”

“…11 More recently, increased IGF2BP3 protein expression has been reported in a variety of solid tumors and was found to be associated with a higher histological grade, 12 progression or metastasis 13,14 and with an unfavorable outcome. [15][16][17][18] These data indicate that IGF2BP3 may promote tumor cell proliferation and progression by enhancing signaling via the IGF pathway. In lymphoid cells, IGF2BP3 is physiologically expressed in normal germinal center B cells and an initial study described variable IGF2BP3 protein expression in different types of malignant lymphomas, particularly in those with an association to a germinal center B-cell phenotype.…”

The distribution of IGF2 and IMP3 in osteosarcoma and its relationship with angiogenesis

“…Periosteal osteosarcoma, is an intermediate grade chondroblastic osteosarcoma arising on the surface of bone periosteal osteosarcoma is associated with a better prognosis than conventional osteosarcoma (Fletcher et al 2002). The invasion ability of neuroblastoma cells decreased as IMP3 knock-down by using RNA interference in vitro, and high expression of IMP3 in neuroblastoma may contribute to the undifferentiated phenotype and invasive behaviors, leading to a poor prognosis (Chen et al 2011). In the present study, the parosteal and periosteal osteosarcoma have better prognosis than the conventional osteosarcoma, but the reasons remains unknown except for the histological differentiation (Fletcher et al 2002).…”