Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2021 | Colorectal Cancer | Research

RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA

Authors: Meng Zhang, Senlin Zhao, Cong Tan, Yanzi Gu, Xuefeng He, Xiang Du, Dawei Li, Ping Wei

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

MEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism.

Methods

To investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays.

Results

We find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3′-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover, IMP3^−/− mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo.

Conclusion

Our study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.

Available only for authorised users

Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93. https://doi.org/10.3322/caac.21395.CrossRefPubMed

Schoumacher M, Hurov KE, Lehar J, Yan-Neale Y, Mishina Y, Sonkin D, et al. Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling. Cancer Res. 2014;74(12):3294–305. https://doi.org/10.1158/0008-5472.CAN-14-0138-T.CrossRefPubMed

Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009;6(9):519–27. https://doi.org/10.1038/nrclinonc.2009.111.CrossRefPubMed

Xue Z, Vis DJ, Bruna A, Sustic T, van Wageningen S, Batra AS, et al. MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell Res. 2018 Jul;28(7):719–29. https://doi.org/10.1038/s41422-018-0044-4.CrossRefPubMedPubMedCentral

Prahallad A, Bernards R. Opportunities and challenges provided by crosstalk between signalling pathways in cancer. Oncogene. 2016;35(9):1073–9. https://doi.org/10.1038/onc.2015.151.CrossRefPubMed

Sugiura R, Kita A, Shimizu Y, Shuntoh H, Sio SO, Kuno T. Share. Feedback regulation of MAPK signalling by an RNA-binding protein. Nature. 2003;424(6951):961–5. https://doi.org/10.1038/nature01907.CrossRefPubMed

Pereira B, Billaud M, Almeida R. RNA-binding proteins in Cancer: old players and new actors. Trends in Cancer. 2017;3(7):506–28. https://doi.org/10.1016/j.trecan.2017.05.003.CrossRefPubMed

Gerstberger S, Hafner M, Tuschl T. A census of human RNA-binding proteins. Nat Rev Genet. 2014;15(12):829–45. https://doi.org/10.1038/nrg3813.CrossRefPubMed

Hong S. RNA binding protein as an emerging therapeutic target for Cancer prevention and treatment. Journal of Cancer Prevention. 2017;22(4):203–10. https://doi.org/10.15430/JCP.2017.22.4.203.CrossRefPubMedPubMedCentral

10.

Bell JL, Wächter K, Mühleck B, Pazaitis N, Köhn M, Lederer M, 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. https://doi.org/10.1007/s00018-012-1186-z.CrossRefPubMed

11.

Fadare O, Liang SX, Crispens MA, Jones HW, Khabele D, Gwin K, et al. Expression of the oncofetal protein IGF2BP3 in endometrial clear cell carcinoma: assessment of frequency and significance. Hum Pathol. 2013;44(8):1508–15. https://doi.org/10.1016/j.humpath.2012.12.003.CrossRefPubMedPubMedCentral

12.

Degrauwe N, Suva ML, 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;30:2459–74.CrossRef

13.

Samanta S, Guru S, Elaimy AL, Amante JJ, Ou J, Yu J, et al. IMP3 stabilization of WNT5B mRNA facilitates TAZ activation in breast Cancer. Cell Rep. 2018;23(9):2559–67. https://doi.org/10.1016/j.celrep.2018.04.113.CrossRefPubMedPubMedCentral

14.

Glisovic T, Bachorik JL, Yong J, Dreyfuss G. RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett. 2008;582(14):1977–86. https://doi.org/10.1016/j.febslet.2008.03.004.CrossRefPubMedPubMedCentral

15.

Vikesaa J, Hansen TV, Jonson L, Borup R, Wewer UM, Christiansen J, et al. RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J. 2006;25(7):1456–68. https://doi.org/10.1038/sj.emboj.7601039.CrossRefPubMedPubMedCentral

16.

Jonson L, Christiansen J, Hansen TV, Vikesa 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. https://doi.org/10.1016/j.celrep.2014.03.015.CrossRefPubMed

17.

Palanichamy JK, Tran TM, Howard JM, Contreras JR, Fernando TR, Sterne-Weiler T, et al. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation. J Clin Invest. 2016;126(4):1495–511. https://doi.org/10.1172/JCI80046.CrossRefPubMedPubMedCentral

18.

Zhang M, Weng W, Zhang Q, Wu Y, Ni S, Tan C, et al. The lncRNA NEAT1 activates Wnt/beta-catenin signaling and promotes colorectal cancer progression via interacting with DDX5. J Hematol Oncol. 2018;11(1):113. https://doi.org/10.1186/s13045-018-0656-7.CrossRefPubMedPubMedCentral

19.

Wang E, Lu SX, Pastore A, Chen X, Imig J, Chun-Wei Lee S, et al. Targeting an RNA-binding protein network in acute myeloid leukemia. Cancer Cell. 2019;35(3):369–84. https://doi.org/10.1016/j.ccell.2019.01.010.CrossRefPubMedPubMedCentral

20.

Wang J, Choi JM, Holehouse AS, Lee HO, Zhang X, Jahnel M, et al. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell. 2018;174(3):688–99. https://doi.org/10.1016/j.cell.2018.06.006.CrossRefPubMedPubMedCentral

21.

Hodson DJ, Screen M, Turner M. RNA-binding proteins in hematopoiesis and hematological malignancy. Blood. 2019 May 30;133(22):2365–73. https://doi.org/10.1182/blood-2018-10-839985.CrossRefPubMedPubMedCentral

22.

Kudinov AE, Karanicolas J, Golemis EA, Boumber Y. Musashi RNA-binding proteins as Cancer drivers and novel therapeutic targets. Clin Cancer Res. 2017;23(9):2143–53. https://doi.org/10.1158/1078-0432.CCR-16-2728.CrossRefPubMedPubMedCentral

23.

Chatterji P, Rustgi AK. RNA binding proteins in intestinal epithelial biology and colorectal Cancer. Trends Mol Med. 2018;24(5):490–506. https://doi.org/10.1016/j.molmed.2018.03.008.CrossRefPubMedPubMedCentral

24.

Vasaikar S, Huang C, Wang X, Petyuk VA, Savage SR, Wen B, et al. Proteogenomic analysis of human Colon Cancer reveals new therapeutic opportunities. Cell. 2019;177(4):1035–49. https://doi.org/10.1016/j.cell.2019.03.030.CrossRefPubMedPubMedCentral

25.

Samanta S, Sun H, Goel HL, Pursell B, Chang C, Khan A, et al. IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG. Oncogene. 2016;35(9):1111–21. https://doi.org/10.1038/onc.2015.164.CrossRefPubMed

26.

Burdelski C, Jakani-Karimi N, Jacobsen F, Möller-Koop C, Minner S, Simon R, et al. IMP3 overexpression occurs in various important cancer types and is linked to aggressive tumor features: a tissue microarray study on 8,877 human cancers and normal tissues. Oncol Rep. 2018;39(1):3–12. https://doi.org/10.3892/or.2017.6072.CrossRefPubMed

27.

Pasiliao CC, Chang CW, Sutherland BW, Valdez SM, Schaeffer D, Yapp DT, et al. The involvement of insulin-like growth factor 2 binding protein 3 (IMP3) in pancreatic cancer cell migration, invasion, and adhesion. BMC Cancer. 2015;15(1):266. https://doi.org/10.1186/s12885-015-1251-8.CrossRefPubMedPubMedCentral

28.

Visser NCM, van der Putten LJM, van Egerschot A, Van de Vijver KK, Santacana M, Bronsert P, et al. Addition of IMP3 to L1CAM for discrimination between low- and high-grade endometrial carcinomas: a European network for individualised treatment of endometrial Cancer collaboration study. Hum Pathol. 2019;89:90–8. https://doi.org/10.1016/j.humpath.2019.04.014.CrossRefPubMed

29.

Tschirdewahn S, Panic A, Püllen L, Harke NN, Hadaschik B, Riesz P, et al. Circulating and tissue IMP3 levels are correlated with poor survival in renal cell carcinoma. Int J Cancer. 2019;145(2):531–9. https://doi.org/10.1002/ijc.32124.CrossRefPubMed

30.

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. https://doi.org/10.1016/j.canlet.2017.11.039.CrossRefPubMed

31.

Nguyen LH, Robinton DA, Seligson MT, Wu L, Li L, Rakheja D, et al. Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell. 2014;26(2):248–61. https://doi.org/10.1016/j.ccr.2014.06.018.CrossRefPubMedPubMedCentral

32.

Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81(2):807–69. https://doi.org/10.1152/physrev.2001.81.2.807.CrossRefPubMed

33.

Remenyi A, Good MC, Bhattacharyya RP, Lim WA. The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network. Mol Cell. 2005;20(6):951–62. https://doi.org/10.1016/j.molcel.2005.10.030.CrossRefPubMed

34.

Asai T, Tena G, Plotnikova J, Willmann MR, Chiu WL, Gomez-Gomez L, et al. MAP kinase signalling cascade in Arabidopsis innate immunity. Nature. 2002;415(6875):977–83. https://doi.org/10.1038/415977a.CrossRefPubMed

35.

Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37–40. https://doi.org/10.1038/35065000.CrossRefPubMed

36.

Luettich K, Schmidt C. TGFbeta1 activates c-Jun and Erk1 via alphaVbeta6 integrin. Mol Cancer. 2003;2(1):33. https://doi.org/10.1186/1476-4598-2-33.CrossRefPubMedPubMedCentral

37.

Bian D, Su S, Mahanivong C, Cheng RK, Han Q, Pan ZK, et al. Lysophosphatidic acid stimulates ovarian Cancer cell migration via a Ras-MEK kinase 1 pathway. Cancer Res. 2004;64(12):4209–17. https://doi.org/10.1158/0008-5472.CAN-04-0060.CrossRefPubMed

38.

Cuevas BD, Winter-Vann AM, Johnson NL, Johnson GL. MEKK1 controls matrix degradation and tumor cell dissemination during metastasis of polyoma middle-T driven mammary cancer. Oncogene. 2006;25(36):4998–5010. https://doi.org/10.1038/sj.onc.1209507.CrossRefPubMed

39.

Su F, Li H, Yan C, Jia B, Zhang Y, Chen X. Depleting MEKK1 expression inhibits the ability of invasion and migration of human pancreatic cancer cells. J Cancer Res Clin Oncol. 2009;135(12):1655–63. https://doi.org/10.1007/s00432-009-0612-6.CrossRefPubMed

Title: RNA-binding protein IMP3 is a novel regulator of MEK1/ERK signaling pathway in the progression of colorectal Cancer through the stabilization of MEKK1 mRNA
Authors: Meng Zhang
Senlin Zhao
Cong Tan
Yanzi Gu
Xuefeng He
Xiang Du
Dawei Li
Ping Wei
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01994-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Correction to: Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

circHMGCS1–016 reshapes immune environment by sponging miR-1236-3p to regulate CD73 and GAL-8 expression in intrahepatic cholangiocarcinoma

Correction to: MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer

Modelling hypersensitivity to trastuzumab defines biomarkers of response in HER2 positive breast cancer

An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development

Correction to: The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer