TY - JOUR
T1 - Control of PD-L1 expression by miR-140/142/340/383 and oncogenic activation of the OCT4-miR-18a pathway in cervical cancer.
AU - Dong, Peixin
AU - Xiong, Ying
AU - Yu, Jiehai
AU - Chen, Lin
AU - Tao, Tang
AU - Yi, Song
AU - Hanley, Sharon J. B.
AU - Yue, Junming
AU - Watari, Hidemichi
AU - Sakuragi, Noriaki
N1 - Acknowledgements
This research was supported by a grant from the Department of Women’s Health Educational System, JSPS Grant-in-Aid for Scientific Research (C) (15K10697 and 16K11123) and the Science and Technology Planning Project of Guangdong Province, China (2014A020212124). We thank Dr. Zhujie Xu for experimental assistance.
PY - 2018/9/27
Y1 - 2018/9/27
N2 - 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.
AB - 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.
KW - Female
KW - Humans
KW - Animals
KW - B7-H1 Antigen/biosynthesis/genetics
KW - Cell Movement/physiology
KW - Cell Proliferation/physiology
KW - Cell Transformation, Neoplastic/genetics/metabolism/pathology
KW - Gene Expression Regulation, Neoplastic/genetics
KW - Heterografts
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Nude
KW - MicroRNAs/genetics/metabolism
KW - Octamer Transcription Factor-3/genetics/metabolism
KW - Uterine Cervical Neoplasms/genetics/metabolism/pathology
U2 - 10.1038/s41388-018-0347-4
DO - 10.1038/s41388-018-0347-4
M3 - Article
VL - 37
SP - 5257
EP - 5268
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 39
ER -
