Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5

Cell Physiol Biochem. 2018;47(5):2126-2135. doi: 10.1159/000491523. Epub 2018 Jul 5.


Background/aims: MicroRNAs (miRNAs) regulate the expressions of cancer-related genes, and are involved in the development and progression of various human cancers. Here, we performed further analyses to determine whether let-7d is functionally linked to Jab1 in breast cancer.

Methods: In situ hybridization and immunohistochemical analyses were used to determine the level of let-7d and Jab1 in breast cancer clinical specimens and its correlation with clinicopathological data. Let-7d overexpressing breast cancer cell lines combined with mouse models bearing cell-derived xenografts were used to assess the functional role of let-7d both in vitro and in vivo.

Results: In this study, we found that let-7d was downregulated in breast cancer tissues, coupled with the elevations of Jab1 protein expressions, compared with paired adjacent noncancerous breast tissues. Let-7d overexpression significantly suppressed the proliferation and invasion in MCF-7 and MDA-MB-231 cells. Dual luciferase reporter assay indicated that Jab1 was the direct target of let-7d. Stepwise studies from in vitro and in vivo experiments indicated that let-7d overexpression inhibited cell growth and decreased Jab1 expressions in breast cancer cells and nude mice tumor tissues. Statistical analyses demonstrated that breast cancer patients with low levels of let-7d or high levels of Jab1 had a significant correlation with worse prognosis.

Conclusion: These findings provide novel insights into molecular mechanism of let-7d and Jab1 in tumor development and progression of breast cancer, and thus let-7d/Jab1 are novel potential therapeutic targets for breast cancer patients.

Keywords: Biomarker; Breast cancer; COPS5; CSN5; Jab1; Let-7d.

MeSH terms

  • Aged
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • COP9 Signalosome Complex / genetics
  • COP9 Signalosome Complex / metabolism*
  • Female
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Neoplasm
  • mirnlet7 microRNA, human
  • Peptide Hydrolases
  • COPS5 protein, human
  • COP9 Signalosome Complex