An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in human gastric cancer

J Gastroenterol Hepatol. 2021 Feb;36(2):436-445. doi: 10.1111/jgh.15176. Epub 2020 Aug 31.

Abstract

Background and aim: Cancer stem cells (CSCs), a subpopulation of tumor cells, assess the capacity of self-renewal, metastasis, and therapeutic resistance. Regulation of CSCs and their epithelial to mesenchymal transition (EMT) potential is one of the promising strategies to eliminate cancer or to inhibit metastasis. Micro-RNAs (miRNAs) as regulators of several cell properties, such as self-renewal, metastasis, and resistance to the drug, could be proper targets in cancer diagnosis and therapy. The aim of the present study is to select common miRNAs targeting both self-renewal and metastasis in gastric cancer.

Methods: Stemness-related and EMT-related genes were selected by literature mining. The common miRNAs targeting genes were chosen using different databases and r programming language. The expression pattern of selected miRNAs and genes was evaluated in gastrospheres-as a gastric CSC model-and gastric tumor biopsies.

Results: Based on the integrated analysis, six miRNAs common to both stemness and metastasis were identified. miR-200c-3p and miR-520c-3p overexpressed in MKN-45 gastrospheres and grade III tumors. In AGS spheres, however, miR-520c-3p and miR-200c-3p upregulation and miR-34a-5p downregulation were similar to grade II tumors. Interestingly, miR-200c-3p and miR-520c-3p indicated a positive correlation with OCT4 and NOTCH1 expression in grade III tumors and MKN-45 spheres. Protein-protein network revealed that the EMT acquisition can be induced by stemness activation through intermediated core-regulatory genes, including CTNNB1, CTNND1, MAML1, KAT2A, and MAML3.

Conclusion: The upregulation of mir-200c-3p and mir-520c-3p could effect on stemness and metastasis in gastric cancer as well as gastric CSCs. Therefore, they can be used as diagnosis and prognostic factors.

Keywords: gastric cancer stem cell; metastasis; miRNAs; self-renewal.

MeSH terms

  • Cell Self Renewal / genetics*
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • MicroRNAs* / physiology
  • Molecular Targeted Therapy
  • Neoplasm Metastasis / genetics*
  • Prognosis
  • Stomach Neoplasms / diagnosis
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology*
  • Stomach Neoplasms / therapy
  • Up-Regulation

Substances

  • MicroRNAs