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

Daru. 2019 Jun;27(1):1-7. doi: 10.1007/s40199-018-0231-3. Epub 2019 May 10.

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. Graphical abstract 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.

Keywords: Anaplastic thyroid cancer; BI-847325; Cyclin D1; MALAT1; Mcl1; miR-363-3p.

MeSH terms

  • Aniline Compounds / pharmacology*
  • Cell Culture Techniques / methods*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin D1 / genetics
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Indoles / pharmacology*
  • MicroRNAs / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • RNA, Long Noncoding / genetics*
  • Thyroid Carcinoma, Anaplastic / genetics*
  • Thyroid Neoplasms / genetics*

Substances

  • Aniline Compounds
  • BI-847325
  • CCND1 protein, human
  • Indoles
  • MALAT1 long non-coding RNA, human
  • MCL1 protein, human
  • MIRN363 microRNA, human
  • MicroRNAs
  • Myeloid Cell Leukemia Sequence 1 Protein
  • RNA, Long Noncoding
  • Cyclin D1