• Lung cancer
• Pathogenesis
• Prognosis
• ceRNA
• circRNA

• National Natural Science Foundation of China
• Yunan Ten Thousand Talents Plan Young and Elite Talents Project

• Cancer cell
• Mass tag
• Nanoprobe
• PD-L1
• Platelets
• Signal amplification
• Tumor

• Humans
• B7-H1 Antigen/metabolism
• Blood Platelets/metabolism
• Blood Platelets/chemistry
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Aptamers, Nucleotide/chemistry
• Nanoparticles/chemistry

• EGFR
• TP53
• autophagy
• immune infiltration
• preeclampsia

• Pregnancy
• Female
• Humans
• Pre-Eclampsia/genetics
• Placenta
• Autophagy/genetics
• Computational Biology
• ErbB Receptors

• 2023A1515012741 Natural Science Foundation of Guangdong Province, China
• MF220201 Jinan University Medical Joint Fund Project
• MF220203 Jinan University Medical Joint Fund Project

• P30 CA082103 NCI NIH HHS
• R01 CA225103 NCI NIH HHS
• R01 CA250534 NCI NIH HHS
• S10 OD028511 NIH HHS

• Immune checkpoint inhibitors
• Immune-related adverse events
• Immunooncology
• Receptor activator of nuclear factor kappa-Β ligand
• Regulatory T cells

• Humans
• NF-kappa B
• Neoplasms
• T-Lymphocytes
• Immunotherapy
• CTLA-4 Antigen

• immune checkpoint
• immunotherapy
• lung cancer
• natural product
• traditional medicine

• Humans
• Lung Neoplasms/therapy
• Lung Neoplasms/etiology
• Biological Products/therapeutic use
• Immunotherapy/adverse effects
• Medicine, Traditional

• National Natural Science Foundation of China

• CLL
• PD-L1
• ROS
• immune checkpoint
• immune synapse
• p66Shc

• cancer
• immune checkpoint inhibitors
• molecular farming
• nivolumab
• pembrolizumab

• A0V741 Cancer Association of South Africa
• A0W228 Cancer Association of South Africa
• A0W110 Medical Research Council (South Africa)
• AON074 Struwig Germeshuysen Trust
• AOR984 School of Medicine Research Committee of the University of Pretoria
• N00375 National Research Foundation
• N0059 National Research Foundation

• Hypoxia-inducible factor 1
• Hypoxic signaling pathways
• Non-small cell lung carcinoma
• Programmed death ligand-1

• hepatocellular carcinoma
• immune regulation
• immunotherapy
• lactate metabolism
• lactylation

• PD-1
• PD-L1
• TME
• immunotherapy
• resistance
• time

• Immune therapy
• Lung neoplasms
• Tumor microenvironment

• hepatocellular carcinoma, immune checkpoint inhibitors, angiogenesis, combined therapy

• Angiogenesis Inhibitors/therapeutic use
• Carcinoma, Hepatocellular/pathology
• Humans
• Immunotherapy
• Liver Neoplasms/pathology
• Tumor Microenvironment

Severe COVID-19 patients display dysregulated expression of checkpoint molecules PD-1 and its ligand PD-L1, suggesting that these checkpoint molecules could be considered as prognostic markers and therapeutic targets in severe cases of COVID-19.

• COVID-19
• Innate immune cells
• PD-1
• PD-L1
• SARS-CoV-2
• adaptive immune cells
• immune checkpoint molecules

• Apoptosis
• HIF-1α
• Hepatocellular carcinoma
• LW6
• PD-L1

• Animals
• Bone Marrow
• Cell Line, Tumor
• Extracellular Vesicles/metabolism
• Mice
• Multiple Myeloma
• Programmed Cell Death 1 Receptor/metabolism
• Tumor Microenvironment

• HIF
• ROS
• YAP
• notch
• tissue mechanics

• Ministry of Science and Technology, Taiwan
• Academia Sinica

Transmembrane protein 16A (TMEM16A) forms a plasma membrane-localized Ca²⁺-activated Cl- channel. Its gene has been mapped to an area on chromosome 11q13, which is amplified in head and neck squamous cell carcinoma (HNSCC). In HNSCC, TMEM16A overexpression is associated with not only high tumor grade, metastasis, low survival, and poor prognosis, but also deterioration of clinical outcomes following platinum-based chemotherapy. Recent study revealed the interaction between TMEM16A and transforming growth factor-β (TGF-β) has an indirect crosstalk in clarifying the mechanism of TMEM16A-induced epithelial-mesenchymal transition. Moreover, human papillomavirus (HPV) infection can modulate TMEM16A expression along with epidermal growth factor receptor (EGFR), whose phosphorylation has been reported as a potential co-biomarker of HPV-positive cancers. Considering that EGFR forms a functional complex with TMEM16A and is a co-biomarker of HPV, there may be crosstalk between TMEM16A expression and HPV-induced HNSCC. EGFR activation can induce programmed death ligand 1 (PD-L1) synthesis via activation of the nuclear factor kappa B pathway and JAK/STAT3 pathway. Here, we describe an interplay among EGFR, PD-L1, and TMEM16A. Combination therapy using TMEM16A and PD-L1 inhibitors may improve the survival rate of HNSCC patients, especially those resistant to anti-EGFR inhibitor treatment. To the best of our knowledge, this is the first review to propose a biological validation that combines immune checkpoint inhibition with TMEM16A inhibition.

• Ca2+-activated Cl− channel
• EGFR
• HPV
• Head and neck squamous cell carcinoma
• Metastasis
• NF-kB
• PD-L1
• Proliferation
• STAT3
• TGF-β
• TMEM16A

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis have been remarkably successful in inducing tumor remissions in several human cancers, yet a substantial number of patients do not respond to treatment. Because this may be partially due to the mechanisms giving rise to high PD-L1 expression within a patient, it is highly relevant to fully understand these mechanisms. In this study, we conduct a bioinformatic analysis to quantify the relative importance of transcription factor (TF) activity, microRNAs (miRNAs) and mutations in determining PD-L1 (CD274) expression at mRNA level based on data from the Cancer Genome Atlas. To predict individual CD274 levels based on TF activity, we developed multiple linear regression models by taking the expression of target genes of the TFs known to directly target PD-L1 as independent variables. This analysis showed that IRF1, STAT1, NFKB and BRD4 are the most important regulators of CD274 expression, explaining its mRNA levels in 90–98% of the patients. Because the remaining patients had high CD274 levels independent of these TFs, we next investigated whether mutations associated with increased CD274 mRNA levels, and low levels of miRNAs associated with negative regulation of CD274 expression could cause high CD274 levels in these patients. We found that mutations or miRNAs offered an explanation for high CD274 levels in 81–100% of the underpredicted patients. Thus, CD274 expression is largely explained by TF activity, and the remaining unexplained cases can largely be explained by mutations or low miRNA abundance.

• CTLA-4
• EGFR mutations
• EGFR-TKIs
• PD-1
• PD-L1
• immunotherapy
• non-small-cell lung cancer
• resistance
• tumor microenvironment

• Animals
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes
• Cell Line, Tumor
• Colorectal Neoplasms/pathology
• Humans
• Interferon Regulatory Factor-1/metabolism
• Jumonji Domain-Containing Histone Demethylases/metabolism
• Mice
• Receptors, Interferon/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction/genetics
• Interferon gamma Receptor

Programmed cell death 1 ligand 1 (PD-L1) is the ligand for programmed death protein-1 (PD-1), is associated with immunosuppression. Signaling via PD-1/PD-L1 will transmits negative regulatory signals to T cells, inducing T-cell inhibition, reducing CD8⁺ T-cell proliferation, or promoting T-cell apoptosis, which effectively reduces the immune response and leads to large-scale tumor growth. Accordingly, many antibody preparations targeting PD-1 or PD-L1 have been designed to block the binding of these two proteins and restore T-cell proliferation and cytotoxicity of T cells. However, these drugs are ineffective in clinical practice. Recently, numerous of studies have shown that, in addition to the surface of tumor cells, PD-L1 is also found on the surface of extracellular vesicles secreted by these cells. Extracellular vesicle PD-L1 can also interact with PD-1 on the surface of T cells, leading to immunosuppression, and has been proposed as a potential mechanism underlying PD-1/PD-L1-targeted drug resistance. Therefore, it is important to explore the production, regulation and tumor immunosuppression of PD-L1 on the surface of tumor cells and extracellular vesicles, as well as the potential clinical application of extracellular vesicle PD-L1 as tumor biomarkers and therapeutic targets.

Immunotherapy is currently the backbone of new drug treatments for many cancer patients. CXC chemokine ligand 13 (CXCL13) is an important factor involved in recruiting immune cells that express CXC chemokine receptor type 5 (CXCR5) in the tumor microenvironment and serves as a key molecular determinant of tertiary lymphoid structure (TLS) formation. An increasing number of studies have identified the influence of CXCL13 on prognosis in patients with cancer, regardless of the use of immunotherapy treatment. However, no comprehensive reviews of the role of CXCL13 in cancer immunotherapy have been published to date. This review aims to provide an overview of the CXCL13/CXCR5 signaling axis to summarize its mechanisms of action in cancer cells and lymphocytes, in addition to effects on immunity and cancer pathobiology, and its potential as a biomarker for the response to cancer immunotherapy.

Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. CXC chemokine ligand 13 (CXCL13) exclusively binds CXC chemokine receptor type 5 (CXCR5), which plays a critical role in immune cell recruitment and activation and the regulation of the adaptive immune response. CXCL13 is a key molecular determinant of the formation of tertiary lymphoid structures (TLSs), which are organized aggregates of T, B, and dendritic cells that participate in the adaptive antitumor immune response. CXCL13 may also serve as a prognostic and predictive factor, and the role played by CXCL13 in some ICI-responsive tumor types has gained intense interest. This review discusses how CXCL13/CXCR5 signaling modulates cancer and immune cells to promote lymphocyte infiltration, activation by tumor antigens, and differentiation to increase the antitumor immune response. We also summarize recent preclinical and clinical evidence regarding the ICI-therapeutic implications of targeting the CXCL13/CXCR5 axis and discuss the potential role of this signaling pathway in cancer immunotherapy.

• CXCL13/CXCR5
• immune checkpoint inhibitor
• tertiary lymphoid structure

The purpose of this study was set to investigate the prognostic role of plasmatic levels of heat shock protein 90 alpha (HSP90α) at diagnosis in advanced lung cancer patients treated with Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus chemotherapy.

A total of 137 advanced lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy admitted to the Guangxi Medical University Cancer Hospital were enrolled in this study. Smooth curve fitting was conducted to address the nonlinearity of HSP90α and progression-free survival (PFS) and overall survival (OS). We calculated the inflection point using a recursive algorithm. Kaplan–Meier survival analysis and Cox proportional hazards regression model were used to assess the prognostic value of HSP90α for PFS and OS. Subgroup analysis was performed to evaluate the relationship between high HSP90α and disease progression and death risk.

The average age of patients was 58.6 ± 9.8 years, and 73.7% of them were men. We divided patients according to their plasmatic levels of HSP90α into low (HSP90α <52.7 ng/ml) group and high (HSP90α ≥52.7 ng/ml) group. Kaplan–Meier analysis showed a shorter PFS and OS for the high group with log-rank P < 0.05. Univariate and multivariate analyses indicated that high HSP90α was associated with an increased risk of disease progression and death after fully adjusting potential confounders with hazard ratio (HR) 1.8 (95% CI = 1.0–3.2) and HR 2.4 (95% CI = 1.1–5.1), respectively (P < 0.05). After stratification by subgroup analysis, the relationship between high HSP90α and the risk of disease progression and death was consistent across all patient subgroups.

Plasmatic levels of HSP90α at diagnosis can be considered a potential independent prognostic marker of advanced lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy. A further large-scale prospective validation study is needed to determine whether these results are widely applicable.

• HSP90α
• PD-1/PD-L1 inhibitors
• advanced lung cancer
• chemotherapy
• prognostic marker

Reactive oxygen species (ROS) are critical mediators in many physiological processes including innate and adaptive immunity, making the modulation of ROS level a powerful strategy to augment anticancer immunity. However, current evidences suggest the necessity of a deeper understanding of their multiple roles, which may vary with their concentration, location and the immune microenvironment they are in. Here, we have reviewed the reported effects of ROS on macrophage polarization, immune checkpoint blocking (ICB) therapy, T cell activation and expansion, as well as the induction of immunogenic cell death. A majority of reports are indicating detrimental effects of ROS, but it is unadvisable to simply scavenge them because of their pleiotropic effects in most occasions (except in T cell activation and expansion where ROS are generally undesirable). Therefore, clinical success will need a clearer illustration of their multi-faced functions, as well as more advanced technologies to tune ROS level with high spatiotemporal control and species-specificity. With such progresses, the efficacy of current immunotherapies will be greatly improved by combining with ROS-targeted therapies.

• ROS
• T cell activation
• immunogenic cell death
• immunotherapy
• macrophage polarization

• Experimental autoimmune encephalomyelitis
• Immune tolerance
• Multiple sclerosis
• PD-1
• PD-L1

• Animals
• B7-H1 Antigen/metabolism
• Encephalomyelitis, Autoimmune, Experimental/metabolism
• Humans
• Mice
• Multiple Sclerosis/metabolism
• Programmed Cell Death 1 Receptor/metabolism
• Signal Transduction/physiology

• 81671177 General Program of the National Natural Science Foundation of China
• 20190201043JC Natural Science Foundation of Jilin Province Science and Technology Development Plan Project
• 20200403109SF Key Research and Development Project of Social Development Division of Jilin Science and Technology Department
• JLSWSRCZX2020-0056 Special Project for Health Professionals of Jilin Provincial Finance Department
• No. 2015-03005 Swedish Research Council
• General Program of the National Natural Science Foundation of China
• Natural Science Foundation of Jilin Province Science and Technology Development Plan Project

• Diabetes
• Drug delivery
• HuR
• IL-24
• Lung cancer
• Nanomedicine

• AKT
• DNA damage response
• DNA repair
• Mechanistic target of rapamycin (mTOR)
• drug resistance
• immunotherapy
• programmed death ligand 1 (PD-L1)
• radioimmunotherapy

• R01 CA246553 NCI NIH HHS

• Cancer heterogeneity
• Cancer stem cells
• Genetic variants
• Hepatocellular carcinoma
• Programmed death ligand 1
• Programmed death-1

• HIF-1α
• HIF-2α
• hepatocellular carcinoma
• meta-analysis
• prognosis

• Aged
• B7-H1 Antigen/blood
• B7-H1 Antigen/metabolism
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/mortality
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Non-Small-Cell Lung/radiotherapy
• Case-Control Studies
• Female
• Humans
• Lung/chemistry
• Lung/pathology
• Lung Neoplasms/metabolism
• Lung Neoplasms/mortality
• Lung Neoplasms/pathology
• Lung Neoplasms/radiotherapy
• Male
• Middle Aged
• Programmed Cell Death 1 Receptor/blood
• Programmed Cell Death 1 Receptor/metabolism

• COP9 signalosome subunit 5
• Immune evasion
• Nuclear factor-κB
• Pancreatic cancer
• Programmed death 1 ligand 1
• Signal transducer and activator of transcription 3

• Amperometry
• Cell lysates
• Dual immunosensor
• HIF-1α
• PD-L1
• Tumor hypoxia

• Antitumor
• Britannin
• HIF-1α
• Myc
• PD-L1

• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• Antineoplastic Agents, Phytogenic/pharmacology
• Cell Cycle Proteins/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Female
• HCT116 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Lactones/chemistry
• Lactones/pharmacology
• MAP Kinase Signaling System/drug effects
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Docking Simulation
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/metabolism
• Programmed Cell Death 1 Ligand 2 Protein/chemistry
• Programmed Cell Death 1 Ligand 2 Protein/genetics
• Programmed Cell Death 1 Ligand 2 Protein/metabolism
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• Sesquiterpenes/chemistry
• Sesquiterpenes/pharmacology
• T-Lymphocytes/drug effects
• T-Lymphocytes/metabolism
• TOR Serine-Threonine Kinases/metabolism
• Xenograft Model Antitumor Assays
• Mice

Immune checkpoints are inhibitory receptor/ligand pairs regulating immunity that are exploited as key targets of anti-cancer therapy. Although the PD-1/PD-L1 pair is one of the most studied immune checkpoints, several aspects of its biology remain to be clarified. It has been established that PD-1 is an inhibitory receptor up-regulated by activated T, B, and NK lymphocytes and that its ligand PD-L1 mediates a negative feedback of lymphocyte activation, contributing to the restoration of the steady state condition after acute immune responses. This loop might become detrimental in the presence of either a chronic infection or a growing tumor. PD-L1 expression in tumors is currently used as a biomarker to orient therapeutic decisions; nevertheless, our knowledge about the regulation of PD-L1 expression is limited. The present review discusses how NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-κB directly induces PD-L1 gene transcription by binding to its promoter, and it can also regulate PD-L1 post-transcriptionally through indirect pathways. These processes, which under conditions of cellular stress and acute inflammation drive tissue homeostasis and promote tissue healing, are largely dysregulated in tumors. Up-regulation of PD-L1 in cancer cells is controlled via NF-κB downstream of several signals, including oncogene- and stress-induced pathways, inflammatory cytokines, and chemotherapeutic drugs. Notably, a shared signaling pathway in epithelial cancers induces both PD-L1 expression and epithelial–mesenchymal transition, suggesting that PD-L1 is part of the tissue remodeling program. Furthermore, PD-L1 expression by tumor infiltrating myeloid cells can contribute to the immune suppressive features of the tumor environment. A better understanding of the interplay between NF-κB signaling and PD-L1 expression is highly relevant to cancer biology and therapy.

• T cells
• epithelial-mesenchymal transition
• immune checkpoint inhibitors
• inflammation
• non-small-cell-lung cancer
• tissue homeostasis
• tumor associated macrophages
• tumor immunity

The liver is the largest immune organ in the body, and immunologic tolerance and escape mechanisms play an important role in hepatocellular carcinoma (HCC) development. HCC has a complex tumor microenvironment (TME), and it is necessary to study the mechanism that causes HCC cells to escape the body immune surveillance and produce therapeutic resistance in HCC clinical treatment. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that contains α subunits regulated by hypoxia. Tumor cells highly express HIF-1α in a hypoxic environment, which participates in the processes of tumor cell proliferation and metastasis, microvascular production, immune escape, and therapeutic tolerance, ultimately promoting tumorigenesis and development. In this paper, we will elaborate on the mechanisms by which HCC cells activate HIF-1α expression to promote hypoxic adaptation in cancer cells and regulate immune escape and treatment tolerance in hypoxic TME.

• Hepatocellular carcinoma
• Hypoxia inducible factor-1α
• Hypoxic microenvironment
• Immune escape
• Mechanism

Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade.

• NF-κB
• PD-L1
• immune checkpoint expression

• Animals
• B7-H1 Antigen/metabolism
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4/antagonists & inhibitors
• Cyclooxygenase 2/metabolism
• Cyclooxygenase Inhibitors/pharmacology
• Cytokines/metabolism
• ErbB Receptors/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Inflammation/metabolism
• Mice
• NF-kappa B/metabolism
• Neoplasms/metabolism
• Pentoxifylline/pharmacology
• Protein Kinase Inhibitors/pharmacology
• Protein Processing, Post-Translational
• Signal Transduction
• Toll-Like Receptors/metabolism
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/metabolism

Pemetrexed (PEM) is a useful drug that can be combined with immune checkpoint blockade therapy for treatment of patients with advanced non–small‐cell lung cancer (NSCLC). However, its effects on anti–cancer immunity, especially the sensitivity of NSCLC cells to cytotoxic immune cells, have not been fully investigated. In this study, we examined the effects of PEM on the sensitivity of human NSCLC cells to two different types of cytotoxic immune cells. Pre‐treatment with PEM increased the sensitivity of two NSCLC cell lines, PC9 and A549, to activated T cells and natural killer (NK) cells, and decreased the expression of anti–apoptotic proteins, including XIAP and Mcl‐1. In addition, PEM treatment increased the cell surface expression of programmed death‐ligand 1 (PD‐L1) on PC9 cells. PEM‐induced upregulation of PD‐L1 on PC9 cells was at least partially ascribed to activation of ERK and the NFκB pathway. In contrast, PEM treatment increased the expression of UL16‐binding proteins (ULBP), ligands for the NKG2D NK receptor, on PC9 and A549 cells, as well as the induction of senescence. Although the addition of anti–programmed cell death 1 antibody showed no effect on the sensitivity of PEM‐treated PC9 and A549 cells to activated T cells, that of anti–NKG2D antibody decreased the enhanced sensitivity of PEM‐treated A549 cells to NK cells. These results indicate that PEM can effectively sensitize human NSCLC cells to cytotoxic immune cells while modulating the expression of immune‐regulatory molecules.

• PD-L1
• T cells
• natural killer cells
• non-small-cell lung cancer
• pemetrexed

• NSCLC
• RSF1
• SNHG6
• miR-490-3p
• progression

• STAT3/NF-κB
• hypoxia
• immune escape
• liver cancer
• programmed cell death 1 ligand 1

• Cancer immunity
• PTM
• Phosphorylation
• Tyrosine kinase

近年来，有关程序性死亡受体1（programmed death-1, PD-1）及其配体（programmed death-1 ligand, PD-L1）抑制剂的研究取得突破性进展，迅速改变着非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗模式。但表皮生长因子受体（epidermal growth factor receptor, EGFR）突变患者应用PD-1/PD-L1抑制剂的治疗效果并不理想。既往研究显示，肿瘤细胞PD-L1表达率与免疫抑制剂治疗效果存在相关性。但目前EGFR突变对PD-L1表达的影响并不能达成一致。我们将对相关研究进行总结，以期对基础研究或临床治疗有所帮助。

• EGFR mutation
• Lung neoplasms
• PD-1/PD-L1 inhibitors
• PD-L1

• Non-small cell lung cancer
• Prognosis
• Programmed cell death ligand 1
• c-Myc

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/secondary
• B7-H1 Antigen/genetics
• B7-H1 Antigen/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/secondary
• Female
• Follow-Up Studies
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Prognosis
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• Survival Rate

• 81872308 National Natural Science Foundation of China
• 81500030 National Natural Science Foundation of China
• 2017A030313573 National Science Foundation of Guangdong Province
• 2016A030313272 National Science Foundation of Guangdong Province
• 2016A030313277 National Science Foundation of Guangdong Province
• SYSD2016062 project of the Suzhou industrial technology innovation (applied basic research of the people's Livelihood technology and applied health care)
• 2017Q005 Youth Project of Health and Family Planning Bureau of Suzhou High-tech Zone

Autophagy, as an important non-selective degradation mechanism, could promote tumor initiation and progression by maintaining cellular homeostasis and the cell metabolism as well as cell viability. CircCDR1as has been shown to function as an oncogene in cancer progression, however, it remains largely unknown as to how autophagy is regulated by circCDR1as in oral squamous cell carcinoma (OSCC). In this study, we validated the functional roles of circCDR1as in regulation of autophagy in OSCC cells and further investigated how circCDR1as contributed to cell survival via up-regulating autophagy under a hypoxic microenvironment by using combination of human tissue model, in vitro cell experiments and in vivo mice model. We found that hypoxia promoted the expression level of circCDR1as in OSCC cells and elevated autophagy. In addition, circCDR1as further increased hypoxia-mediated autophagy by targeting multiple key regulators of autophagy. We revealed that circCDR1as enhanced autophagy in OSCC cells via inhibition of rapamycin (mTOR) activity and upregulation of AKT and ERK_½ pathways. Overexpression of circCDR1as enhanced OSCC cells viability, endoplasmic reticulum (ER) stress, and inhibited cell apoptosis under a hypoxic microenvironment. Moreover, circCDR1as promoted autophagy in OSCC cells by sponging miR-671-5p. Collectively, these results revealed that high expression of circCDR1as enhanced the viability of OSCC cells under a hypoxic microenvironment by promoting autophagy, suggesting a novel treatment strategy involving circCDR1as and the inhibition of autophagy in OSCC cells.