Downregulated long noncoding RNA LINC00313 inhibits the epithelial-mesenchymal transition, invasion, and migration of thyroid cancer cells through inhibiting the methylation of ALX4

J Cell Physiol. 2019 Nov;234(11):20992-21004. doi: 10.1002/jcp.28703. Epub 2019 May 15.


Thyroid cancer represents one of the prevalent endocrine cancer with relatively high incidence rate around the world, accompanied by unchanged fatality rate. We probe into the specific role of LINC00313 in mediation of cellular processes of thyroid cancer including proliferation, migration, and invasion through the methylation of aristaless-like homeobox 4 (ALX4). Thyroid cancer-related long noncoding RNAs (lncRNAs) and genes were analyzed by microarray-based analysis. The antitumor effect of LINC00313 was examined with the gain- and loss-of-function experiments. In addition, the binding of LINC00313 and the promoter region of ALX4, and the interaction of LINC00313 with methylation-related proteins were detected. Later, xenograft tumors in nude mice were induced expecting to dig out the modulatory function of LINC00313 in tumor growth of thyroid carcinoma. The microarray-based analysis manifested that LINC00313 was overexpressed, whereas ALX4 was downregulated in thyroid cancer, the results of which were also verified in thyroid cancer tissues. Besides, our results demonstrated that LINC00313 bound to the ALX4 promoter region, and LINC00313 recruited DNMT1 and DNMT3B proteins to promote the methylation of ALX4 promoter region, thus suppressing the ALX4 expression. Finally, the downregulation of LINC00313 and upregulation of ALX4 repressed the AKT/mTOR signaling axis, thus inhibiting proliferative, migratory, invasive abilities as well as epithelial-to-mesenchymal transition (EMT) of thyroid cancer cells. Collectively, downregulated LINC00313 suppresses cell proliferation, migration, as well as invasion of thyroid cancer by inhibiting the methylation of ALX4 and increasing its expression by inactivation of the AKT/mTOR signaling pathway.

Keywords: AKT/mTOR signaling pathway; aristaless-like homeobox 4; long intergenic non-protein coding RNA 313; proliferation; thyroid cancer.

MeSH terms

  • Animals
  • Cell Movement / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Regulation, Neoplastic / genetics*
  • Heterografts
  • Humans
  • Male
  • Methylation
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness / genetics
  • RNA, Long Noncoding / genetics*
  • Signal Transduction / physiology
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology*
  • Transcription Factors / metabolism*


  • ALX4 protein, human
  • DNA-Binding Proteins
  • RNA, Long Noncoding
  • Transcription Factors