Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1

Our plain-English summary of Insulin-Like Growth Factor 2 mRNA Binding Protein 3 Promotes Cell Proliferation of Malignant Mesothelioma Cells by Downregulating p27Kip1, by I. Endo, V.J. Amatya, K. Kushitani, et al (Frontiers in Oncology, 2021).

The study

• Authors: I. Endo, V.J. Amatya, K. Kushitani, T. Kambara, T. Nakagiri, Y. Fujii, Y. Takeshima
• Journal: Frontiers in Oncology
• Published: 2021;11:795467
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is a tumor with a poor prognosis, mainly caused by asbestos exposure and with no adequate treatment yet. To develop future therapeutic targets, we analyzed the microarray dataset GSE 29370 of malignant mesothelioma and reactive mesothelial hyperplasia, downloaded from the Gene Expression Omnibus (GEO) database. We identified insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) as one of the significantly upregulated genes in malignant mesothelioma. IGF2BP3 functions as an oncoprotein in many human cancers; however, to our knowledge, this is the first study on the biological function of IGF2BP3 in malignant mesothelioma cells. The knockdown of IGF2BP3 in malignant mesothelioma cells resulted in the suppression of cell proliferation with an increase in the proportion of cells in the G1 phase of the cell cycle. Furthermore, knockdown of IGF2BP3 inhibited cell migration and invasion. We focused on the cell cycle assay to investigate the role of IGF2BP3 in cell proliferation in malignant mesothelioma. Among the various proteins involved in cell cycle regulation, the expression of p27 Kip1 (p27) increased significantly upon IGF2BP3 knockdown. Next, p27 siRNA was added to suppress the increased expression of p27. The results showed that p27 knockdown attenuated the effects of IGF2BP3 knockdown on cell proliferation and G1 phase arrest. In conclusion, we found that IGF2BP3 promotes cell proliferation, a critical step in tumorigenesis, by suppressing the expression of p27 in malignant mesothelioma.

Copyright © 2022 Endo, Amatya, Kushitani, Kambara, Nakagiri, Fujii and Takeshima.

In plain English

This was a laboratory study of cancer cells. The authors analyzed public gene-activity data (dataset GSE29370) comparing 11 malignant mesothelioma samples (seven tissues and four cell lines) with 2 tissue samples of reactive mesothelial hyperplasia, a non-cancerous condition. The gene IGF2BP3 was about twice as active on average in the mesothelioma samples. The authors then used small RNA molecules (siRNA) to reduce IGF2BP3 in two human malignant pleural mesothelioma cell lines, ACC-MESO1 and CRL-5915. Compared with control-treated cells, growth after 72 hours was lower by 47.2% and 47.5%. More cells were held in the G1 phase of the cell cycle, and cell migration and invasion were reduced. Levels of the protein p27 rose by 424.2% and 508.2%. When p27 was also reduced, cell growth significantly recovered. The authors concluded that IGF2BP3 is involved in mesothelioma cell proliferation by decreasing p27, and suggested it as a potential treatment target. They noted it is unclear whether this effect is direct or indirect. The study did not examine asbestos exposure and did not study patients directly. Its tissue data came from an existing public dataset.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: analysis of a public microarray (gene-expression) dataset plus experiments in two human mesothelioma cell lines using siRNA to reduce gene activity
• Who was studied: Two human mesothelioma cell lines taken from malignant pleural mesothelioma: ACC-MESO1 (fibroblast-like type) and CRL-5915 (epithelioid type). Also, from the public dataset GSE29370, 11 malignant mesothelioma samples (seven tissues and four cell lines) and 2 reactive mesothelial hyperplasia tissue samples.
• Exposure: No asbestos exposure was studied. The experimental treatment was siRNA that reduced IGF2BP3, p27, or both, compared with a negative control siRNA.
• Main results:
  • In the dataset (11 malignant mesothelioma vs 2 reactive mesothelial hyperplasia samples), the mean IGF2BP3 transcript level in mesothelioma was approximately 2-fold higher
  • All seven mesothelioma tissues and four mesothelioma cell lines in the dataset showed high IGF2BP3 expression compared with the two reactive mesothelial hyperplasia tissues
  • The dataset analysis found 378 upregulated and 256 downregulated transcripts with more than 1.5-fold change in malignant mesothelioma compared with reactive mesothelial hyperplasia
  • IGF2BP3 siRNA reduced IGF2BP3 mRNA by 86.9% in ACC-MESO1 cells and 85.7% in CRL-5915 cells, compared with control siRNA
  • Reducing IGF2BP3 lowered cell proliferation by 47.2% in ACC-MESO1 and 47.5% in CRL-5915 after 72 hours, compared with control siRNA
  • The proportion of cells in G1 phase was 69.9% (ACC-MESO1) and 75.4% (CRL-5915) with IGF2BP3 siRNA, versus 57.3% and 62.5% with control siRNA
  • Reducing IGF2BP3 lowered cell migration by 23.9% (ACC-MESO1) and 36.0% (CRL-5915) compared with control siRNA
  • Reducing IGF2BP3 lowered the number of invading cells by 16.0% (ACC-MESO1) and 36.5% (CRL-5915) compared with control siRNA
  • In both cell lines, reducing IGF2BP3 increased p27 and decreased CDK2, cyclin E1 and phospho-RB compared with control siRNA
  • p27 protein rose by 424.2% in ACC-MESO1 cells after IGF2BP3 knockdown
  • p27 protein change in CRL-5915 cells after IGF2BP3 knockdown was 508.2%
  • In ACC-MESO1 cells, reducing both IGF2BP3 and p27 increased cell proliferation by 31.8% and 30.4% (at 72 and 96 hours) compared with reducing IGF2BP3 alone
  • In CRL-5915 cells, reducing both IGF2BP3 and p27 increased cell proliferation by 43.8% (72 hours) and 48.8% (96 hours) compared with reducing IGF2BP3 alone
  • Reducing p27 alone produced no significant change in cell proliferation compared with control siRNA
  • With both IGF2BP3 and p27 reduced, the percentage of cells in G1 phase was reduced by 18.0% in ACC-MESO1 and 7.6% in CRL-5915, compared with IGF2BP3 siRNA alone
• The authors' conclusion: The authors concluded that IGF2BP3 is involved in the proliferation of mesothelioma cells by decreasing p27 expression, and that the study highlights IGF2BP3's potential as a therapeutic target for malignant mesothelioma
• Limitations the authors state:
  • It is not clear whether IGF2BP3's effect on p27 works through its RNA-binding function or some other way, or whether it acts directly or indirectly. Further investigation is needed.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Prognosis, Asbestos Exposure, Reactive Mesothelial Hyperplasia, Tumorigenesis.

Related studies

• Practical utility of insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1, and epithelial membrane antigen for distinguishing malignant mesotheliomas from benign mesothelial proliferations — S. Chang, M.H. Oh, et al. (2014)
• CD146 and insulin-like growth factor 2 mRNA-binding protein 3 predict prognosis of asbestos-induced rat mesothelioma — Y. Okazaki, H. Nagai, et al. (2013)
• The use of insulin like-growth factor II messenger RNA binding protein-3 in diagnostic pathology — J.J. Findeis-Hosey, H. Xu (2011)
• Insulin-like growth factor II messenger RNA-binding protein 3 expression in gastrointestinal mesenchymal tumors — H. Yamamoto, K. Arakaki, et al. (2014)
• Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression — A.W. Langerak, K.A. Williamson, et al. (1995)
• Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages — P.W. Noble, F.R. Lake, et al. (1993)

Browse more research in Frontiers in Oncology, or return to medical research.