miR-140-3p inhibits colorectal cancer progression and its liver metastasis by targeting BCL9 and BCL2

Cancer Med. 2021 May;10(10):3358-3372. doi: 10.1002/cam4.3840. Epub 2021 Apr 10.


Recent studies have identified microRNAs (miRNAs) as a compelling novel class of biomarker in colorectal cancer (CRC) development and metastasis. Here, we demonstrated that the level of plasma exosomal miR-140-3p in CRC patients was lower than that in healthy controls. The decreased miR-140-3p level was also observed in CRC patients with liver metastasis. The expression of miR-140-3p in CRC tissues were significantly lower than that in matched normal tissues. Functionally, miR-140-3p overexpression suppressed proliferation, migration, invasion, and β-catenin nuclear translocation, as well as promoted apoptosis in LoVo cells, while inhibition of miR-140-3p reversed these cellular processes in HCT 116 cells. Notably, BCL9 and BCL2 were recognized as direct targets of miR-140-3p. BCL9 knockdown abrogated miR-140-3p inhibitor-induced effects on HCT 116 cells with decreased proliferation, migration, and invasion. BCL2 knockdown increased apoptosis of miR-140-3p inhibitor-transfected HCT 116 cells. In vivo experiments revealed that miR-140-3p overexpression inhibited tumor growth in LoVo xenograft model and diminished metastatic nodules in nude mice liver. Taken together, this work supports that miR-140-3p exerts as a tumor suppressor in CRC progression via targeting BCL9 and BCL2, and suggests miR-140-3p-BCL9/BCL2 axis may be applied in miRNA-based therapy and prognostication of CRC.

Keywords: BCL2; BCL9; colorectal cancer; metastasis; miR-140-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Gene Expression Regulation, Neoplastic / genetics
  • HCT116 Cells
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Transcription Factors / genetics*
  • beta Catenin / genetics


  • BCL2 protein, human
  • BCL9 protein, human
  • MicroRNAs
  • Mirn140 microRNA, human
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factors
  • beta Catenin