MiR-16-1-3p and miR-16-2-3p possess strong tumor suppressive and antimetastatic properties in osteosarcoma

Vadim V. Maximov, Rania Akkawi, Saleh Khawaled, Zaidoun Salah, Lina Jaber, Ahlam Barhoum, Omer Or, Marco Galasso, Kyle C. Kurek, Eylon Yavin, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Osteosarcoma (OS) is an aggressive malignancy affecting mostly children and adolescents. MicroRNAs (miRNAs) play important roles in OS development and progression. Here we found that miR-16-1-3p and miR-16-2-3p “passenger” strands, as well as the “lead” miR-16-5p strand, are frequently downregulated and possess strong tumor suppressive functions in human OS. Furthermore, we report different although strongly overlapping functions for miR-16-1-3p and miR-16-2-3p in OS cells. Ectopic expression of these miRNAs affected primary tumor growth, metastasis seeding and chemoresistance and invasiveness of human OS cells. Loss-of-function experiments verified tumor suppressive functions of these miRNAs at endogenous levels of expression. Using RNA immunoprecipitation (RIP) assays, we identify direct targets of miR-16-1-3p and miR-16-2-3p in OS cells. Moreover, validation experiments identified FGFR2 as a direct target for miR-16-1-3p and miR-16-2-3p. Overall, our findings underscore the importance of passenger strand miRNAs, at least some, in osteosarcomagenesis.

Original languageAmerican English
Pages (from-to)3052-3063
Number of pages12
JournalInternational Journal of Cancer
Volume145
Issue number11
DOIs
StatePublished - 1 Dec 2019

Bibliographical note

Funding Information:
Authors thank Dr. Yuval Nevo (Bioinformatics division, Hebrew University-Hadassah Medical School, Jerusalem, Israel) for bioinformatics analyses of RIP experiments. This research work was funded by a grant from the Liddy Shriver Sarcoma Initiative (to RIA) and Yissum seed funds (to RIA and EY). VVM was supported by ICRF postdoctoral grant, Lady Davis fellowship and Israel Ministry of Immigrant Absorption postdoctoral fellowships.

Publisher Copyright:
© 2019 UICC

Keywords

  • FGFR2
  • RIP
  • metastasis
  • miR-16-1
  • miR-16-2
  • miR-16-5p
  • osteosarcoma
  • tumor suppressor

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