TY - JOUR
T1 - The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer
AU - Fujita, Yu
AU - Yagishita, Shigehiro
AU - Hagiwara, Keitaro
AU - Yoshioka, Yusuke
AU - Kosaka, Nobuyoshi
AU - Takeshita, Fumitaka
AU - Fujiwara, Tomohiro
AU - Tsuta, Koji
AU - Nokihara, Hiroshi
AU - Tamura, Tomohide
AU - Asamura, Hisao
AU - Kawaishi, Makoto
AU - Kuwano, Kazuyoshi
AU - Ochiya, Takahiro
N1 - Funding Information:
We thank Luc Gailhouste for carefully reading the manuscript. This work was supported in part by a grant-in-aid for the Third-Term Comprehensive 10-Year Strategy for Cancer Control of Japan including Awardee of Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan). National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan. T.O., Y.F., M.K., and K.K. conceived the idea and coordinated the project. Y.F., K.H., and Y.Y. performed a significant amount of the experimental work. S.Y., H.N., and T.T. analyzed the clinical data. K.T. and H.A. provided tumor specimens. T.O., Y.F., S.Y., Y.Y., and N.K. wrote the manuscript and prepared the figures and tables. The authors have declared that no conflict of interest exists.
Publisher Copyright:
© 2015 The American Society of Gene & Cell Therapy.
PY - 2015/4/10
Y1 - 2015/4/10
N2 - Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1 high drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.
AB - Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1 high drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.
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U2 - 10.1038/mt.2015.10
DO - 10.1038/mt.2015.10
M3 - Article
C2 - 25597412
AN - SCOPUS:84927005034
SN - 1525-0016
VL - 23
SP - 717
EP - 727
JO - Molecular Therapy
JF - Molecular Therapy
IS - 4
ER -
