Abstract
The relationship between circular RNA (circRNA) and cancer stem cells (CSCs) is uncertain. We have investigated the combined influence of CSCs, circRNA (hsa_circ_0003222), and immune checkpoint inhibitors in NSCLC progression and therapy resistance. We constructed lung CSCs (LCSCs; PC9 and A549). The effects of hsa_circ_0003222 in vitro were determined by cell counting, colony and sphere formation, and Transwell assays. A tumor xenograft model of metastasis and orthotopic model were built for in vivo analysis. We found that hsa_circ_0003222 was highly expressed in NSCLC tissues and LCSCs. Higher levels of hsa_circ_0003222 were associated with the stage, metastasis, and survival rate of patients with NSCLC. Reduced levels of hsa_circ_0003222 decreased tumor cell proliferation, migration, invasion, stemness-like properties, and chemoresistance. The silencing of hsa_circ_0003222 was found to downregulate PHF21B expression and its downstream, β-catenin by relieving the sponging effect of miR-527. Moreover, silencing hsa_circ_0003222 alleviated NSCLC resistance to anti-programmed cell death-ligand 1 (PD-L1)-based therapy in vivo. Our data demonstrate the significant role of hsa_circ_0003222 in NSCLC cell stemness-like properties. The manipulation of circRNAs in combination with anti-PD-L1 therapy may alleviate NSCLC stemness and progression.
Highlights
Lung cancer encompasses 11.6% of all diagnosed cancer and contributes to 18.4% of deaths related to cancer worldwide [1,2,3]
Despite current advances in the therapy of cancer with immune checkpoint inhibitors, nonsmall cell lung carcinoma (NSCLC) remains a leading cause of cancer fatality, partly owing to drug resistance and metastasis caused by stem cells [31, 32]
We have concentrated on suppressing the role of lung cancer stem cells (LCSCs) in drug resistance and metastasis by exploiting the regulatory characteristics of circRNA
Summary
Lung cancer encompasses 11.6% of all diagnosed cancer and contributes to 18.4% of deaths related to cancer worldwide [1,2,3]. The majority of lung cancers (~85%) have been classified as nonsmall cell lung carcinoma (NSCLC) by the World Health Organization [4]. Several approaches using combination therapies have been used to overcome these barriers, including immune checkpoint inhibitors such as programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) [10, 11]. To reduce the primary drug resistance rate of tumors, immunotherapy can be combined with chemotherapy or new drugs [13]. Many researched confirmed that PD-L1 is combined with other treatments (such as chemotherapy, EGFR-TKI, and VEGF inhibitors) [14, 15]. For cancer stem cells (CSCs), whether PD-L1 combined with other treatments have the same benefits requires further research
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