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Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor “BI-847325” on anaplastic thyroid carcinoma

  • Research Article
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Abstract

Background

Anaplastic thyroid carcinoma (ATC) is the most lethal malignancy in thyroid carcinomas. Long non-coding RNAs (lncRNAs) are a member of non-coding RNAs, regulating the expression of gene. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an onco-lncRNA that is overexpressed in several carcinomas including ATC. Evidence showed that MALAT1 has a crucial function in apoptosis, and cell cycle progression.

Objectives

In order to take advantage of 3D cell culture system in cancer investigation, we have used a 3D in vitro ATC model to determine the effect of dual MEK/Aurora kinase inhibitor BI-847325 anticancer drug on the fundamental molecular mechanisms of MALAT1-mediated gene regulation in ATC.

Methods

In this study, ATC cell lines (C643 and SW1736) were grown in alginate scaffold. Encapsulated cells were treated by BI-847325. Changes in expression of MALAT1, Mcl1, miR-363-3p, and cyclinD1 were measured by qRT-PCR.

Results and conclusion

MALAT1 gene expression following BI-847325 treatment was significantly downregulated in C643 and SW1736 cell lines. Reversely, miR-363-3p expression was significantly upregulated by BI-847325 in both ATC cell lines. Mcl1 expression was significantly downregulated after treatment in C643 cell lines. Moreover, the expression of this gene was not significantly reduced following BI-847325 treatment in SW1736 cell line. Additionally, cyclin D1 expression was significantly downregulated after treatment in both ATC cell lines. Altogether, the result of this study was the first report of MALAT1’s molecular function in ATC and suggested that BI-847325 which inhibits both MEK and Aurora kinase family could be effective against ATC by regulating the genes involved in cell cycle and apoptosis including MALAT1and its downstream genes.

Schematic representation of the biological role of MALAT1 in cyclin D1, miR-363-3p and Mcl1 gene regulations. Stimulation of receptor tyrosine kinase (RTK) by growth factors (GFs) phosphorylates RAS that subsequently activates RAF. Then, RAF phosphorylates MEK. Consequently, activated MEK phosphorylates ERK downstream effector, leading to the MALAT1 gene expression. MALAT1 is a negative regulator of Mcl1 mRNA by sponging of miR-363-3p. In addition, MALAT1 leads to Axin1 and APC downregulation and Wnt/β-catenin signaling pathway activation. Stable β-catenin translocates from the cytoplasm to the nucleus and promotes cyclin D1 gene expression.

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Abbreviations

ATC:

anaplastic thyroid carcinoma

EOC:

epithelial ovarian cancer

EZH2:

enhancer of zeste homolog

GFs:

growth factors

hTERT:

human telomerase reverse transcriptase

lncRNAs:

long non-coding RNAs

MALAT1:

metastasis-associated lung adenocarcinoma transcript 1

MAPK:

mitogen-activated protein kinase

miRNA:

micro ribonucleic acid

MMP14:

matrix metallopeptidase 14

NAMA:

non-protein coding RNA associated with MAPK signaling pathway and growth arrest

PTC:

papillary thyroid carcinoma

PVT1:

plasmacytoma variant translocation 1

RTK:

receptor tyrosine kinase

ROR:

regulator of reprogramming

TSHR:

thyroid-stimulating hormone receptor

UCA1:

urothelial carcinoma-associated 1

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Acknowledgements

The authors would like to thank Ms. Resvan Tavakoli and Ms. Zahra Gohari for their technical help and support and Dr. Mahmood Naderi for scientific advice.

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Authors and Affiliations

  1. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

    Hilda Samimi & Shiva Irani

  2. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Vahid Haghpanah

  3. Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Vahid Haghpanah

  4. Molecular Virology Laboratory, Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran

    Ehsan Arefian

  5. Stem Cell Technology Research Center, Tehran, Iran

    Alireza Naderi Sohi

  6. Department of Laboratory Science, Faculty of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran

    Parviz Fallah

  7. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, 14115-111, Iran

    Masoud Soleimani

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  1. Hilda Samimi
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Contributions

MS, the chief instructor of the experiment, and HS performed the experiments, interpreted the data, and wrote the first draft of the manuscript. Other authors contributed to the experimental procedures. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masoud Soleimani.

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Samimi, H., Haghpanah, V., Irani, S. et al. Transcript-level regulation of MALAT1-mediated cell cycle and apoptosis genes using dual MEK/Aurora kinase inhibitor “BI-847325” on anaplastic thyroid carcinoma. DARU J Pharm Sci 27, 1–7 (2019). https://doi.org/10.1007/s40199-018-0231-3

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  • DOI: https://doi.org/10.1007/s40199-018-0231-3

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