Abstract
Purpose
Increasing evidence suggested that microRNA plays an important role in ovarian cancer. In this study, the role of miR-92 in ovarian cancer was investigated.
Methods
In this study, miR-92 expression in clinical sample was evaluated, role of miR-92 was investigated in vitro, and underlying mechanism was investigated using Chip, co-IP, and western blot.
Results
In this study, we show that miR-92 is overexpressed in ovarian cancer tissue compared with normal cancer tissue. Transfection of miR-92 increased proliferation of ovarian cancer cell, and increased migration capacity and colony formation were observed after miR-92 transfection; we found that expression of LATS2 was decreased by miR-92, and this was further confirmed by luciferase assay, which proved that miR-92 is targeting 3′ of the endogenous LATS2 gene. Downregulation of LATS2 resulted in increased translocation of YAP1 and upregulation of PD-L1, which subsequently suppressed NK cell function and promoted T cell apoptosis. Moreover, co-transfection of YAP1-targeted shRNA could relieve miR-92-induced immune suppression effect. Mechanically, immunoprecipitation (IP) was used to show that LATS2 interacted with YAP1 and subsequently limited nuclear translocation of YAP1; chromatin immunoprecipitation (ChIP) was used to confirm that YAP1 could bind to enhancer region of PD-L1 to enhance transcription activity of PD-L1.
Conclusions
Our data revealed a novel mechanism which finally resulted in immune suppression in ovarian cancer.
Similar content being viewed by others
References
Mohamed Z et al. miR-363 confers taxane resistance in ovarian cancer by targeting the Hippo pathway member, LATS2. Oncotarget. 2018;9.
Ahmed FY, et al. Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol. 1996;14:2968–75.
Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin. 1999;49:8–31.
Hamanishi J, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci. 2007;104:3360.
Wu L, Belasco JG. Let me count the ways: mechanisms of gene regulation by miRNAs and siRNAs. Mol Cell. 2008;29:1–7.
Dahiya N, et al. MicroRNA expression and identification of putative miRNA targets in ovarian cancer. PLoS One. 2008;3:e2436.
Nam EJ, et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 2008;14:2690.
Slack FJ, Weidhaas JB. MicroRNA in Cancer Prognosis. N Engl J Med. 2008;359:2720–2.
Yang C, et al. MicroRNA-766 promotes cancer progression by targeting NR3C2 in hepatocellular carcinoma. FASEB J. 2018;33:1456–67.
Yonemori K, Kurahara H, Maemura K, Natsugoe S. MicroRNA in pancreatic cancer. J Hum Genet. 2017;62:33–40.
Meghani K, et al. Multifaceted impact of MicroRNA 493-5p on genome-stabilizing pathways induces platinum and PARP inhibitor resistance in BRCA2-mutated carcinomas. Cell Rep. 2018;23:100–11.
Qadir MI, Faheem A. miRNA: a diagnostic and therapeutic tool for pancreatic Cancer. Crit Rev Eukaryot Gene Expr. 2017;27(3):197–204.
Paliouras AR, Monteverde T, Garofalo M. Oncogene-induced regulation of microRNA expression: implications for cancer initiation, progression and therapy. Cancer Lett. 2018;421:152–60.
Karimi L, et al. Function of microRNA-143 in different signal pathways in cancer: new insights into cancer therapy. Biomed Pharmacother. 2017;91:121–31.
Rios-Colon L, Deep G, Kumar D. Emerging role of microRNA 628-5p as a novel biomarker for cancer and other diseases. Tumor Biol. 2019;41:1010428319881344.
Chen Z-L, et al. microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin. J Biol Chem. 2011;286:10725–34.
Ng EKO, et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009;58:1375–81.
Shin VY, et al. MiR-92 suppresses proliferation and induces apoptosis by targeting EP4/Notch1 axis in gastric cancer. Oncotarget. 2018;9(36):24209–20.
Tanaka M, et al. Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS One. 2009;4:e5532.
Vareki SM, Garrigós C, Duran I. Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol Hematol. 2017;116:116–24.
Furth N, Aylon Y. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ. 2017;24:1488–501.
Oh J-E, et al. Alterations in the NF2/LATS1/LATS2/YAP pathway in Schwannomas. J Neuropathol Exp Neurol. 2015;74:952–9.
Shi Y, et al. LATS2 inhibits malignant behaviors of glioma cells via inactivating YAP. J Mol Neurosci. 2019;68:38–48.
Hoa L, et al. The characterisation of LATS2 kinase regulation in Hippo-YAP signalling. Cell Signal. 2016;28:488–97.
Guo Y, et al. miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance. Oncogene. 2017;36:6336–47.
Nishida N, et al. Microarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clusters. Clin Cancer Res. 2012;18:3054–70.
Volinia S, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103:2257–61.
Hsu P-C, et al. Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma. J Cell Mol Med. 2018;22:3139–48.
Yang L, et al. Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition. Sci Rep. 2017;7:7958.
Author information
Authors and Affiliations
Contributions
S.F. and W.Z. conceived and designed the study. S.F. and H.T. did the main experiments. S.F. analyzed and interpreted the data. H.T. was responsible for reagents and materials. S.F. drafted the article. W.Z. and H.T. revised the article critically. All authors had final approval of the submitted versions.
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest.
Ethical approval
This work has been approved by the ethical committees at Soochow University.
Informed consent
All patients provided written informed consent.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Feng, S., Sun, H. & Zhu, W. MiR-92 overexpression suppresses immune cell function in ovarian cancer via LATS2/YAP1/PD-L1 pathway. Clin Transl Oncol 23, 450–458 (2021). https://doi.org/10.1007/s12094-020-02439-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-020-02439-y