A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling

Oncogene. 2017 Sep 21;36(38):5407-5420. doi: 10.1038/onc.2017.139. Epub 2017 May 22.

Abstract

Kaposi's sarcoma (KS) as the most common AIDS-associated malignancy is etiologically caused by KS-associated herpesvirus (KSHV). KS is a highly disseminated and vascularized tumor. KSHV encodes 12 pre-microRNAs that yield 25 mature microRNAs (miRNAs), but their roles in KSHV-induced tumor metastasis and angiogenesis remain largely unclear. KSHV-encoded miR-K12-6 (miR-K6) can generate two mature miRNAs, miR-K6-5p and miR-K6-3p. Recently, we have shown that miR-K6-3p induced cell migration and angiogenesis via directly targeting SH3 domain binding glutamate-rich protein (SH3BGR). Here, by using mass spectrometry, bioinformatics analysis and luciferase reporter assay, we showed that miR-K6-5p directly targeted the coding sequence of CD82 molecule (CD82), a metastasis suppressor. Ectopic expression of miR-K6-5p specifically inhibited the expression of endogenous CD82 and strongly promoted endothelial cells invasion and angiogenesis. Overexpression of CD82 significantly inhibited cell invasion and angiogenesis induced by miR-K6-5p. Mechanistically, CD82 directly interacted with c-Met to inhibit its activation. MiR-K6-5p directly repressed CD82, relieving its inhibition on c-Met activation and inducing cell invasion and angiogenesis. Lack of miR-K6 abrogated KSHV suppression of CD82 resulting in compromised KSHV activation of c-Met pathway, and KSHV induction of cell invasion and angiogenesis. In conclusion, our data show that by reducing CD82, KSHV miR-K6-5p expedites cell invasion and angiogenesis by activating the c-Met pathway. Our findings illustrate that KSHV miRNAs may be critical for the dissemination and angiogenesis of KSHV-induced malignant tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Down-Regulation
  • HEK293 Cells
  • Herpesvirus 8, Human / genetics*
  • Heterografts
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Kangai-1 Protein / biosynthesis
  • Kangai-1 Protein / genetics*
  • Kangai-1 Protein / metabolism
  • Male
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction
  • Transfection
  • Xeroderma Pigmentosum / blood supply*
  • Xeroderma Pigmentosum / genetics
  • Xeroderma Pigmentosum / metabolism
  • Xeroderma Pigmentosum / virology

Substances

  • CD82 protein, human
  • Kangai-1 Protein
  • MicroRNAs
  • MET protein, human
  • Proto-Oncogene Proteins c-met