Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer.

Peixin Dong, Ying Xiong, Jiehai Yu, Lin Chen, Tang Tao, Song Yi, Sharon J. B. Hanley, Junming Yue, Hidemichi Watari, Noriaki Sakuragi

Research output: Contribution to journalArticlepeer-review

Abstract

PD-L1, a key inhibitory immune receptor, has crucial functions in cancer immune evasion, but whether PD-L1 promotes the malignant properties of cervical cancer (CC) cells and the mechanism by which PD-L1 is regulated in CC remains unclear. We report that PD-L1 is overexpressed in CC, and shRNA-mediated PD-L1 depletion suppresses the proliferation, invasion, and tumorigenesis of CC cells. Loss of miR-140/142/340/383 contributes to PD-L1 upregulation. miR-18a enhances PD-L1 levels by targeting PTEN, WNK2 (ERK1/2 pathway inhibitor), and SOX6 (Wnt/β-catenin pathway inhibitor and p53 pathway activator) to activate the PI3K/AKT, MEK/ERK, and Wnt/β-catenin pathways and inhibit the p53 pathway, and miR-18a also directly suppresses the expression of the tumor suppressors BTG3 and RBSP3 (CTDSPL). miR-18a overexpression in CC cells is triggered by OCT4 overexpression. Our data implicate PD-L1 as a novel oncoprotein and indicate that miR-140/142/340/383 and miR-18a are key upstream regulators of PD-L1 and potential targets for CC treatment.
Original languageEnglish
Pages (from-to)5257-5268
Number of pages12
JournalOncogene
Volume37
Issue number39
Early online date31 May 2018
DOIs
Publication statusPublished - 27 Sep 2018

Keywords

  • Female
  • Humans
  • Animals
  • B7-H1 Antigen/*biosynthesis/genetics
  • Cell Movement/physiology
  • Cell Proliferation/physiology
  • Cell Transformation, Neoplastic/genetics/metabolism/pathology
  • Gene Expression Regulation, Neoplastic/*genetics
  • Heterografts
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs/genetics/metabolism
  • Octamer Transcription Factor-3/genetics/metabolism
  • Uterine Cervical Neoplasms/*genetics/metabolism/pathology

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