Abstract
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-L1high 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.
Highlights
Lung cancer is the leading cause of cancer-related deaths
We further demonstrated that a novel signaling pathway, the miR-197/CDC28 protein kinase regulatory subunit 1B (CKS1B)/STAT3 axis, has the ability to promote cancer progression in chemoresistant non-small-cell lung cancer (NSCLC)
Our data demonstrated that miR-197 regulates lung cancer drug resistance and tumor progression by directly targeting the cyclin-dependent kinase CKS1B as well as by indirectly targeting the transcription factor STAT3
Summary
70% of all newly diagnosed patients present with local advanced or metastatic disease and require systemic chemotherapy.[1] Patients with non-small-cell lung cancer (NSCLC) are typically treated with platinum-based chemotherapy. Despite the development of novel targeted therapies, the prognosis of lung cancer remains poor due to drug resistance and tumor recurrence. Understanding the critical molecular mechanisms underlying the development of chemoresistance in NSCLC is an important issue for developing novel and effective therapeutic strategies. MicroRNAs (miRNAs), a family of short endogenous noncoding RNAs, play critical roles in cell growth, differentiation, and the development of various solid and hematological malignancies.[2] Recently, miRNAs have emerged in NSCLC as both diagnostic and prognostic biomarkers.[3] These findings suggest that miRNAs are a promising technology for the development of therapeutic targets for lung cancer.
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