Alternative titles; symbols
HGNC Approved Gene Symbol: IGF2BP3
Cytogenetic location: 7p15.3 Genomic coordinates (GRCh38) : 7:23,310,209-23,470,491 (from NCBI)
From a pancreatic cancer tumor screen, Mueller-Pillasch et al. (1997) identified a novel cDNA, which they termed KOC. The deduced 580-amino acid protein has a molecular mass of approximately 65 kD and contains 4 K-homologous (KH) domains. The transcript was highly overexpressed in pancreatic cancer cell lines and in pancreatic cancer tissue compared to normal pancreas and chronic pancreatitis tissue, as well as in tissues of other human tumors. Mueller-Pillasch et al. (1997) noted that the KH domain has been shown to be involved in the regulation of RNA synthesis and metabolism.
By Northern blot analysis, Monk et al. (2002) detected expression of a 4.4-kb IMP3 transcript in placenta and limb fetal tissue. PCR showed that IMP3 is expressed ubiquitously during fetal development and in multiple adult tissues, suggesting a role in normal growth and development. Imprinting studies showed that IMP3 is biallelically expressed.
Nielsen et al. (1999) noted that the IMP3 protein contains 2 functional RNA recognition motifs (RRM) in addition to the 4 KH domains. By Northern blot analysis, they found that IMP3 is expressed in multiple fetal tissues in both humans and mice, with a burst of expression at embryonic day 12.5 followed by a decline towards birth. IMP3 mRNA was not detected in several adult mouse tissues.
Monk et al. (2002) determined that the IGF2BP3 gene contains 15 exons.
By FISH analysis, Monk et al. (2002) mapped the IGF2BP3 gene to human chromosome 7p15. They mapped the mouse Igf2bp3 gene to a region of chromosome 6 that shares homology of synteny with human chromosome 7p15.
Nielsen et al. (1999) found that the IMP3 protein associates specifically with the 5-prime UTR of the human 6.0-kb insulin-like growth factor II (IGF2; 147470) leader-3 mRNA, suggesting a role for IMP3 in the physiologic regulation of IGF2 production.
Jiang et al. (2006) found that IMP3 tumor expression was greatly was associated with metastasis in clear cell renal cell carcinoma (RCC; 144700). Among 371 patients with localized clear cell renal cell carcinoma, those with IMP3 tumor expression had a much lower 5-year metastasis-free survival than those with IMP3-negative tumors (44% vs 98% for stage I; 41% vs 94% for stage II; and 16% vs 62% for stage III). IMP3 expression was also associated with reduced 5-year overall survival. These findings were replicated by Hoffmann et al. (2008) who studied 716 clear cell RCC specimens and found that 213 (29.8%) of 716 tumors expressed IMP3, which was associated with advanced stage and grade of primary tumors as well as other adverse features, including coagulative tumor necrosis and sarcomatoid differentiation. After multivariate adjustment, positive IMP3 expression was still associated with a 42% increase in the risk of death from RCC. Among those with initially localized disease, positive IMP3 expression was associated with a 4.71-fold increased risk of distant metastases.
Jiang et al. (2008) found that 40 (12%) of 334 RCCs, including 254 papillary and 80 chromophobic tumors, expressed IMP3. Positive IMP3 expression was significantly associated with later tumor stage and higher tumor grade. An analysis of patient outcomes showed that 28 of 317 with initially localized disease progressed to metastasis. Fifteen (45.5%) of the 33 patients with IMP3-positive tumors developed metastases compared to only 13 (4.6%) of the 284 patients with IMP3-negative tumors. Statistical analysis showed that those with initially localized IMP3-positive tumors were over 10 times more likely to have metastasis (risk ratio of 11.38; p less than 0.001), and were nearly twice as likely to die compared to patients with localized IMP3-negative tumors. The 5-year metastasis-free and overall survival rates were 64% and 58% for patients with IMP3-positive localized papillary and chromophobe RCCs compared to 98% and 85% for patients with IMP3-negative tumors, respectively. Jiang et al. (2008) concluded that IMP3 expression can be used as a prognostic biomarker for metastasis in all subtypes of renal cell carcinoma.
Exclusion Studies
Although the location and putative function of IMP3 suggested a possible role in Silver-Russell syndrome (see SRS2, 618905), Monk et al. (2002) found no IMP3 mutations in 25 affected patients.
The IMP3 gene described here is distinct from the IMP3 gene described in 608238.
Hoffmann, N. E., Sheinin, Y., Lohse, C. M., Parker, A. S., Leibovich, B. C., Jiang, Z., Kwon, E. D. External validation of IMP3 expression as an independent prognostic marker for metastatic progression and death for patients with clear cell renal cell carcinoma. Cancer 112: 1471-1479, 2008. [PubMed: 18260086] [Full Text: https://doi.org/10.1002/cncr.23296]
Jiang, Z., Chu, P. G., Woda, B. A., Rock, K. L., Liu, Q., Hsieh, C.-C., Li, C., Chen, W., Duan, H. O., McDougal, S., Wu, C.-L. Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell carcinoma: a retrospective study. Lancet Oncol. 7: 556-564, 2006. [PubMed: 16814207] [Full Text: https://doi.org/10.1016/S1470-2045(06)70732-X]
Jiang, Z., Lohse, C. M., Chu, P. G., Wu, C.-L., Woda, B. A., Rock, K. L., Kwon, E. D. Oncofetal protein IMP3: a novel molecular marker that predicts metastasis of papillary and chromophobe renal cell carcinomas. Cancer 112: 2676-2682, 2008. [PubMed: 18412154] [Full Text: https://doi.org/10.1002/cncr.23484]
Monk, D., Bentley, L., Beechey, C., Hitchins, M., Peters, J., Preece, M. A., Stanier, P., Moore, G. E. Characterisation of the growth regulating gene IMP3, a candidate for Silver-Russell syndrome. (Letter) J. Med. Genet. 39: 575-581, 2002. [PubMed: 12161597] [Full Text: https://doi.org/10.1136/jmg.39.8.575]
Mueller-Pillasch, F., Lacher, U., Wallrapp, C., Micha, A., Zimmerhackl, F., Hameister, H., Varga, G., Friess, H., Buchler, M., Beger, H. G., Vila, M. R., Adler, G., Gress, T. M. Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein. Oncogene 14: 2729-2733, 1997. [PubMed: 9178771] [Full Text: https://doi.org/10.1038/sj.onc.1201110]
Nielsen, J., Christiansen, J., Lykke-Andersen, J., Johnsen, A. H., Wewer, U. M., Nielsen, F. C. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Molec. Cell. Biol. 19: 1262-1270, 1999. [PubMed: 9891060] [Full Text: https://doi.org/10.1128/MCB.19.2.1262]