The Oncogenic Functions of Insulin-like Growth Factor 2 mRNA-Binding Protein 3 in Human Carcinomas

Author(s): Peng-Fei Wang, Xiaoyu Wang, Min Liu, Zheng Zeng, Caiji Lin, Wenwen Xu, Wenqing Ma, Jiali Wang, Qian Xiang, Randal N. Johnston, Huidi Liu*, Shu-Lin Liu*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 32 , 2020

Become EABM
Become Reviewer
Call for Editor


IGF2BP3 (also known as IMP3, KOC), a member of the insulin-like growth factor mRNA-binding protein family (IMPs), has been a research target in recent studies of promoting embryo development and exacerbating cancer. IGF2BP3 is ubiquitously expressed in early embryogenesis stages but limited in postembryonic stages, which is important in many physiological aspects such as stem cell renewal, morphological development and metabolism. A large number of studies show that IGF2BP3 interacts with many kinds of non-coding RNAs and proteins to promote cancer cell proliferation and metastasis and inhibit cancer cell apoptosis. As IGF2BP3 is highly expressed in advanced cancers and associated with poor overall survival rates of patients, it may be a potential molecular marker in cancer diagnosis for the detection of cancerous tissues and an indicator of cancer stages. Therefore, anti-IGF2BP3 drugs or monoclonal antibodies are expected as new therapeutic methods in cancer treatment. This review summarizes recent findings among IGF2BP3, RNA and proteins in cancer processes, with a focus on its cancer-promoting mechanisms and potential application as a new biomarker for cancer diagnosis and treatment.

Keywords: IGF2BP3, function, malignancy, mechanisms, carcinoma, biomarker.

Bell JL, Wächter K, Mühleck B, et al. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression? Cell Mol Life Sci 2013; 70(15): 2657-75. []. [PMID: 23069990].
Carmel MS, Kahane N, Oberman F, et al. A novel role for vickz proteins in maintaining epithelial integrity during embryogenesis. PLoS One 2015; 10(8)e0136408 [].
He X, Li W, Liang X, et al. IGF2BP2 overexpression indicates poor survival in patients with acute myelocytic leukemia. Cell Physiol Biochem 2018; 51(4): 1945-56. []. [PMID: 30513526].
Barghash A, Helms V, Kessler SM. Overexpression of IGF2 mRNA-Binding Protein 2 (IMP2/p62) as a feature of basal-like breast cancer correlates with short survival. Scand J Immunol 2015; 82(2): 142-3. []. [PMID: 25916626].
Huang X, Zhang H, Guo X, Zhu Z, Cai H, Kong X. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer. J Hematol Oncol 2018; 11(1): 88. []. [PMID: 29954406].
Gong Y, Woda BA, Jiang Z. Oncofetal protein IMP3, a new cancer biomarker. Adv Anat Pathol 2014; 21(3): 191-200. []. [PMID: 24713990].
Wan B-S, Cheng M, Zhang L. Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer. World J Gastroenterol 2019; 25(40): 6063-76. []. [PMID: 31686763].
Yang J, Gong X, Yang J, et al. Suppressive role of microRNA-29 in hepatocellular carcinoma via targeting IGF2BP1. Int J Clin Exp Pathol 2018; 11(3): 1175-85. [PMID: 31938212].
Hamilton KE, Chatterji P, Lundsmith ET, et al. Loss of stromal IMP1 promotes a tumorigenic microenvironment in the colon. Mol Cancer Res 2015; 13(11): 1478-86. []. [PMID: 26194191].
Wang G, Huang Z, Liu X, et al. IMP1 suppresses breast tumor growth and metastasis through the regulation of its target mRNAs. Oncotarget 2016; 7(13): 15690-702. []. [PMID: 26910917].
Huang H, Wang D, Guo W, Zhuang X, He Y. Correlated low IGF2BP1 and FOXM1 expression predicts a good prognosis in lung adenocarcinoma. Pathol Res Pract 2019; 215(7)152433 []. [PMID: 31085008].
Kapoor S. IMP3: a new and important biomarker of systemic malignancies 2008.
Ren F, Lin Q, Gong G, et al. Igf2bp3 maintains maternal RNA stability and ensures early embryo development in zebrafish. Commun Biol 2020; 3(1): 94. []. [PMID: 32127635].
Bao G, Huang J, Pan W, Li X, Zhou T. Long noncoding RNA CERS6-AS1 functions as a malignancy promoter in breast cancer by binding to IGF2BP3 to enhance the stability of CERS6 mRNA. Cancer Med 2020; 9(1): 278-89. []. [PMID: 31701672].
Kim HY, Ha Thi HT, Hong S. IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor. Cancer Lett 2018; 415: 30-9. []. [PMID: 29217458].
Sheen YS, Liao YH, Lin MH, et al. IMP-3 promotes migration and invasion of melanoma cells by modulating the expression of HMGA2 and predicts poor prognosis in melanoma. J Invest Dermatol 2015; 135(4): 1065-73. []. [PMID: 25380351].
Zhao W, Lu D, Liu L, et al. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability. Oncotarget 2017; 8(55): 93672-87. []. [PMID: 29212181].
Li M, Zhang L, Ge C, et al. An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma. Oncotarget 2015; 6(28): 25149-60. []. [PMID: 26327240].
Müeller-Pillasch F, Lacher U, Wallrapp C, et al. Cloning of a gene highly overexpressed in cancer coding for a novel KH-domain containing protein. Oncogene 1997; 14(22): 2729-33. []. [PMID: 9178771].
Dai N, Christiansen J, Nielsen FC, Avruch J. mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts. Genes Dev 2013; 27(3): 301-12. []. [PMID: 23388827].
Git A, Allison R, Perdiguero E, Nebreda AR, Houliston E, Standart N. Vg1RBP phosphorylation by Erk2 MAP kinase correlates with the cortical release of Vg1 mRNA during meiotic maturation of Xenopus oocytes. RNA 2009; 15(6): 1121-33. []. [PMID: 19376927].
Hentze MW. Determinants and regulation of cytoplasmic mRNA stability in eukaryotic cells. Biochim Biophys Acta 1991; 1090(3): 281-92. []. [PMID: 1954250].
Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge CB. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 2008; 320(5883): 1643-7. []. [PMID: 18566288].
van Kouwenhove M, Kedde M, Agami R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 2011; 11(9): 644-56. []. [PMID: 21822212].
Legendre M, Ritchie W, Lopez F, Gautheret D. Differential repression of alternative transcripts: A screen for miRNA targets. PLOS Comput Biol 2006; 2(5)e43 []. [PMID: 16699595].
Liao B, Hu Y, Herrick DJ, Brewer G. The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells. J Biol Chem 2005; 280(18): 18517-24. []. [PMID: 15753088].
Suvasini R, Shruti B, Thota B, et al. Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2. J Biol Chem 2011; 286(29): 25882-90. []. [PMID: 21613208].
Liu Y, Yu C, Wu Y, et al. CD44+ fibroblasts increases breast cancer cell survival and drug resistance via IGF2BP3-CD44-IGF2 signalling. J Cell Mol Med 2017; 21(9): 1979-88. []. [PMID: 28523716].
Vikesaa J, Hansen TV, Jønson L, et al. RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J 2006; 25(7): 1456-68. []. [PMID: 16541107].
Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers (Basel) 2014; 6(3): 1769-92. []. [PMID: 25198391].
Hsu KF, Shen MR, Huang YF, et al. Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer. Br J Cancer 2015; 113(3): 414-24. []. [PMID: 26158423].
Nielsen FC, Nielsen J, Kristensen MA, Koch G, Christiansen J. Cytoplasmic trafficking of IGF-II mRNA-binding protein by conserved KH domains. J Cell Sci 2002; 115(Pt 10): 2087-97. [PMID: 11973350].
Samanta S, Sun H, Goel HL, et al. IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene 2016; 35(9): 1111-21. []. [PMID: 25982283].
Piva M, Domenici G, Iriondo O, et al. Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med 2014; 6(1): 66-79. []. [PMID: 24178749].
Zhang B, Ma XT, Zheng GG, Li G, Rao Q, Wu KF. Expression of IL-18 and its receptor in human leukemia cells. Leuk Res 2003; 27(9): 813-22. []. [PMID: 12804640].
Ko CY, Wang WL, Li CF, et al. IL-18-induced interaction between IMP3 and HuR contributes to COX-2 mRNA stabilization in acute myeloid leukemia. J Leukoc Biol 2016; 99(1): 131-41. []. [PMID: 26342105].
Mizutani R, Imamachi N, Suzuki Y, et al. Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA. Oncogene 2016; 35(27): 3495-502. []. [PMID: 26522719].
Chiappetta G, Avantaggiato V, Visconti R, et al. High level expression of the HMGI (Y) gene during embryonic development. Oncogene 1996; 13(11): 2439-46. [PMID: 8957086].
Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer 2007; 7(12): 899-910. []. [PMID: 18004397].
Jønson L, Christiansen J, Hansen TVO, Vikeså J, Yamamoto Y, Nielsen FC. IMP3 RNP safe houses prevent miRNA-directed HMGA2 mRNA decay in cancer and development. Cell Rep 2014; 7(2): 539-51. []. [PMID: 24703842].
Costa FF. Non-coding RNAs: Meet thy masters. BioEssays 2010; 32(7): 599-608. []. [PMID: 20544733].
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281-97. []. [PMID: 14744438].
Wang Z, Tong D, Han C, et al. Blockade of miR-3614 maturation by IGF2BP3 increases TRIM25 expression and promotes breast cancer cell proliferation. EBioMedicine 2019; 41: 357-69. []. [PMID: 30797711].
Huang QD, Zheng SR, Cai YJ, et al. IMP3 promotes TNBC stem cell property through miRNA-34a regulation. Eur Rev Med Pharmacol Sci 2018; 22(9): 2688-96. [PMID: 29771420].
Zhou Y, Huang T, Siu HL, et al. IGF2BP3 functions as a potential oncogene and is a crucial target of miR-34a in gastric carcinogenesis. Mol Cancer 2017; 16(1): 77. []. [PMID: 28399871].
Kouhkan F, Mobarra N, Soufi-Zomorrod M, et al. MicroRNA-129-1 acts as tumour suppressor and induces cell cycle arrest of GBM cancer cells through targeting IGF2BP3 and MAPK1. J Med Genet 2016; 53(1): 24-33. []. [PMID: 26510428].
Fawzy IO, Hamza MT, Hosny KA, Esmat G, El Tayebi HM, Abdelaziz AI. miR-1275: A single microRNA that targets the three IGF2-mRNA-binding proteins hindering tumor growth in hepatocellular carcinoma. FEBS Lett 2015; 589(17): 2257-65. []. [PMID: 26160756].
Fawzy IO, Hamza MT, Hosny KA, Esmat G, Abdelaziz AI. Abrogating the interplay between IGF2BP1, 2 and 3 and IGF1R by let-7i arrests hepatocellular carcinoma growth. Growth Factors 2016; 34(1-2): 42-50. []. [PMID: 27126374].
Carpenter S, Aiello D, Atianand MK, et al. A long noncoding RNA mediates both activation and repression of immune response genes. Science 2013; 341(6147): 789-92. []. [PMID: 23907535].
Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013; 495(7441): 384-8. []. [PMID: 23446346].
Chen G, Wang Q, Yang Q, et al. Circular RNAs hsa_circ_0032462, hsa_circ_0028173, hsa_circ_0005909 are predicted to promote CADM1 expression by functioning as miRNAs sponge in human osteosarcoma. PLoS One 2018; 13(8)e0202896 []. [PMID: 30153287].
Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell 2015; 160(6): 1125-34. []. [PMID: 25768908].
Yang Y, Gao X, Zhang M, et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst 2018; 110(3): 304-15. []. [PMID: 28903484].
Li Z, Zhang J, Liu X, et al. The LINC01138 drives malignancies via activating arginine methyltransferase 5 in hepatocellular carcinoma. Nat Commun 2018; 9(1): 1572. []. [PMID: 29679004].
Chen LT, Lin LJ, Zheng LL. The correlation between insulin-like growth factor II mRNA binding protein 3 expression in hepatocellular carcinoma and prognosis. Hepatogastroenterology 2013; 60(123): 553-6. [PMID: 23159356].
Jiang W, Cheng X, Wang T, Song X, Zheng Y, Wang L. LINC00467 promotes cell proliferation and metastasis by binding with IGF2BP3 to enhance the mRNA stability of TRAF5 in hepatocellular carcinoma. J Gene Med 2020; 22(3)e3134 []. [PMID: 31656043].
Jin P, Huang Y, Zhu P, Zou Y, Shao T, Wang O. CircRNA circHIPK3 serves as a prognostic marker to promote glioma progression by regulating miR-654/IGF2BP3 signaling. Biochem Biophys Res Commun 2018; 503(3): 1570-4. []. [PMID: 30057315].
Hong Y, Qin H, Li Y, et al. FNDC3B circular RNA promotes the migration and invasion of gastric cancer cells via the regulation of E-cadherin and CD44 expression. J Cell Physiol 2019; 234(11): 19895-910. []. [PMID: 30963578].
Yin T, Wang G, He S, Liu Q, Sun J, Wang Y. Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells. Cell Immunol 2016; 300: 41-5. []. [PMID: 26677760].
Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol 2018; 11(1): 64. []. [PMID: 29747682].
Hu S, Wu X, Zhou B, et al. IMP3 combined with CD44s, a novel predictor for prognosis of patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2014; 140(6): 883-93. []. [PMID: 24647926].
Eddy RJ, Weidmann MD, Sharma VP, Condeelis JS. Tumor cell invadopodia: Invasive protrusions that orchestrate metastasis. Trends Cell Biol 2017; 27(8): 595-607. []. [PMID: 28412099].
Murphy DA, Courtneidge SA. The ‘ins’ and ‘outs’ of podosomes and invadopodia: Characteristics, formation and function. Nat Rev Mol Cell Biol 2011; 12(7): 413-26. []. [PMID: 21697900].
Friedl P, Alexander S. Cancer invasion and the microenvironment: Plasticity and reciprocity. Cell 2011; 147(5): 992-1009. []. [PMID: 22118458].
Karasawa T, Steyger PS. An integrated view of cisplatin-induced nephrotoxicity and ototoxicity. Toxicol Lett 2015; 237(3): 219-27. []. [PMID: 26101797].
van Dijk EL, Sussenbach JS, Holthuizen PE. Kinetics and regulation of site-specific endonucleolytic cleavage of human IGF-II mRNAs. Nucleic Acids Res 2001; 29(17): 3477-86. []. [PMID: 11522816].
Dai N, Rapley J, Angel M, Yanik MF, Blower MD, Avruch J. mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes Dev 2011; 25(11): 1159-72. []. [PMID: 21576258].
Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol 1999; 19(2): 1262-70. []. [PMID: 9891060].
Liao B, Patel M, Hu Y, Charles S, Herrick DJ, Brewer G. Targeted knockdown of the RNA-binding protein CRD-BP promotes cell proliferation via an insulin-like growth factor II-dependent pathway in human K562 leukemia cells. J Biol Chem 2004; 279(47): 48716-24. []. [PMID: 15355996].
Liao B, Hu Y, Brewer G. RNA-binding protein insulin-like growth factor mRNA-binding protein 3 (IMP-3) promotes cell survival via insulin-like growth factor II signaling after ionizing radiation. J Biol Chem 2011; 286(36): 31145-52. []. [PMID: 21757716].
Kelly LM, Liu PS, Zhong S, et al. THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer. Proceedings of the National Academy of Sciences of the United States of America. 2307-12.
Frasca F, Pandini G, Scalia P, et al. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 1999; 19(5): 3278-88. []. [PMID: 10207053].
Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007; 23: 675-99. []. [PMID: 17645413].
Kuo MT, Chen HH, Song IS, Savaraj N, Ishikawa T. The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 2007; 26(1): 71-83. []. [PMID: 17318448].
Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport-an update. AAPS J 2015; 17(1): 65-82. []. [PMID: 25236865].
Samanta S, Pursell B, Mercurio AM. IMP3 protein promotes chemoresistance in breast cancer cells by regulating breast cancer resistance protein (ABCG2) expression. J Biol Chem 2013; 288(18): 12569-73. []. [PMID: 23539627].
Ohashi R, Sangen M, Namimatsu S, et al. Prognostic value of IMP3 expression as a determinant of chemosensitivity in triple-negative breast cancer. Pathol Res Pract 2017; 213(9): 1160-5. []. [PMID: 28756977].
Köbel M, Xu H, Bourne PA, et al. IGF2BP3 (IMP3) expression is a marker of unfavorable prognosis in ovarian carcinoma of clear cell subtype. Mod Pathol 2009; 22(3): 469-75. []. [PMID: 19136932].
Vercellini P, Cribiù FM, Del Gobbo A, Carcangiu ML, Somigliana E, Bòsari S. The oncofetal protein IMP3: A novel biomarker and triage tool for premalignant atypical endometriotic lesions. Fertil Steril 2013; 99(7): 1974-9. []. [PMID: 23473990].
Degrauwe N, Suvà M-L, Janiszewska M, Riggi N, Stamenkovic I. IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. Genes Dev 2016; 30(22): 2459-74. []. [PMID: 27940961].
Jiang Z, Chu PG, Woda BA, et al. Combination of quantitative IMP3 and tumor stage: A new system to predict metastasis for patients with localized renal cell carcinomas. Clin Cancer Res 2008; 14(17): 5579-84. []. [PMID: 18765551].
Chen P, Wang SJ, Wang HB, et al. The distribution of IGF2 and IMP3 in osteosarcoma and its relationship with angiogenesis. J Mol Histol 2012; 43(1): 63-70. []. [PMID: 22042095].
Findeis-Hosey JJ, Xu H. The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology. Hum Pathol 2011; 42(3): 303-14. []. [PMID: 20970161].
Liu H, Zeng Z, Afsharpad M, et al. Overexpression of IGF2BP3 as a potential oncogene in ovarian clear cell carcinoma. Front Oncol 2020; 9(1570): 1570. []. [PMID: 32083017].
Zhang X, Jung IH, Hwang YS. EGF enhances low-invasive cancer cell invasion by promoting IMP-3 expression. Tumour Biol 2016; 37(2): 2555-63. []. [PMID: 26386725].
Campbell NE, Greenaway J, Henkin J, Moorehead RA, Petrik J. The thrombospondin-1 mimetic ABT-510 increases the uptake and effectiveness of cisplatin and paclitaxel in a mouse model of epithelial ovarian cancer. Neoplasia 2010; 12(3): 275-83. []. [PMID: 20234821].
Yorukoglu A, Yalcin N, Avci A, et al. Significance of IMP3, nucleophosmin, and Ki-67 expression in papillary thyroid carcinoma. Int J Surg Pathol 2015; 23(1): 5-12. []. [PMID: 25389240].
Eronat O, Onursever A, Suren D, Yildirim M, Kandemir O, Ali Kahya H. VEGF receptor subtypes may serve as novel prognostic factors and putative indicators for anti VEGF receptor treatment response in renal cell carcinoma cases 2016.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 23 September, 2020
Page: [3939 - 3954]
Pages: 16
DOI: 10.2174/1381612826666200413080936
Price: $65

Article Metrics

PDF: 30