Tumor suppressor miR-139-5p targets Tspan3 and regulates the progression of acute myeloid leukemia through the PI3K/Akt pathway

J Cell Biochem. 2019 Mar;120(3):4423-4432. doi: 10.1002/jcb.27728. Epub 2018 Oct 26.

Abstract

Dysregulation of microRNAs is closely implicated in the initiation and progression of human cancers including acute myeloid leukemia (AML). Though miR-139-5p was reported to be a potent tumor suppressor in adult AML, its underlying molecular mechanism in AML remains to be further defined. Herein, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were conducted to determine the expressions of miR-139-5p and tetraspanin3 (Tspan3) in AML patients and cells. Luciferase reporter assay, qRT-PCR, and Western blot analysis were carried out to detect the interaction between miR-139-5p and Tspan3. Cell proliferation, cell cycle distribution, invasion, and migration were evaluated by cell counting kit-8, flow cytometry, transwell invasion, and migration assays, respectively. Western blot analysis was conducted to determine phosphorylated-protein kinase B (Akt) and Akt levels. We found that a significant reduction in miR-139-5p expression and a prominent increase in Tspan3 expression were observed in AML patients and cells. Tspan3 was confirmed as a direct target of miR-139-5p and was negatively modulated by miR-139-5p. Rescue experiments showed that overexpression of miR-139-5p constrained cell proliferation, invasion and migration capabilities, and induced cell cycle arrest at the S phase in AML cells, which were partially reversed by Tspan3 overexpression. In addition, we found that miR-139-5p suppressed the phosphoinositide 3-kinase (PI3K)/Akt pathway in AML cells by targeting Tspan3. In conclusion, our study concluded that miR-139-5p suppressed the leukemogenesis in AML cells by targeting Tspan3 through inactivation of the PI3K/Akt pathway, providing a better understanding of AML progression.

Keywords: acute myeloid leukemia (AML); leukemogenesis; miR-139-5p; tetraspanin3 (Tspan3); the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation
  • Genes, Tumor Suppressor*
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Signal Transduction*
  • THP-1 Cells
  • Tetraspanins / genetics
  • Tetraspanins / metabolism*
  • U937 Cells

Substances

  • MIRN139 microRNA, human
  • MicroRNAs
  • RNA, Neoplasm
  • Tetraspanins
  • Tspan3 protein, human
  • Proto-Oncogene Proteins c-akt