Abstract
BackgroundLaryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck. Autophagy and circular RNAs (circRNAs) play critical roles in cancer progression and chemoresistance. However, the function and mechanism of circRNA in autophagy regulation of LSCC remain unclear.MethodsThe autophagy-suppressive circRNA circPARD3 was identified via RNA sequencing of 107 LSCC tissues and paired adjacent normal mucosal (ANM) tissues and high-content screening. RT-PCR, Sanger sequencing, qPCR and fluorescence in situ hybridization were performed to detect circPARD3 expression and subcellular localization. Biological functions of circPARD3 were assessed by proliferation, migration, invasion, autophagic flux, and chemoresistance assays using in vitro and in vivo models. The mechanism of circPARD3 was investigated by RNA immunoprecipitation, RNA pulldown, luciferase reporter assays, western blotting and immunohistochemical staining.ResultsAutophagy was inhibited in LSCC, and circPARD3 was upregulated in the LSCC tissues (n = 100, p < 0.001). High circPARD3 level was associated with advanced T stages (p < 0.05), N stages (p = 0.001), clinical stages (p < 0.001), poor differentiation degree (p = 0.025), and poor prognosis (p = 0.002) of LSCC patients (n = 100). Functionally, circPARD3 inhibited autophagy and promoted LSCC cell proliferation, migration, invasion and chemoresistance. We further revealed that activation of the PRKCI-Akt-mTOR pathway through sponging miR-145-5p was the main mechanism of circPARD3 inhibited autophagy, promoting LSCC progression and chemoresistance.ConclusionOur study reveals that the novel autophagy-suppressive circPARD3 promotes LSCC progression and chemoresistance through the PRKCI-Akt-mTOR pathway, providing new insights into circRNA-mediated autophagy regulation and potential biomarker and target for LSCC treatment.Graphical abstract
Highlights
Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck
Our study reveals that the novel autophagy-suppressive circPARD3 promotes LSCC progression and chemoresistance through the PRKCI-Akt-Mammalian target of rapamycin (mTOR) pathway, providing new insights into Circular RNA (circRNA)-mediated autophagy regulation and potential biomarker and target for LSCC treatment
Enrichment of circPARD3 in RNA samples after RNA immunoprecipitation (RIP) assays was determined by quantitative real time PCR (qPCR) analysis. b Venn diagram shows the intersection of predicted circPARD3 binding miRNAs and miRNAs downregulated in 107 LSCC tissues from the RNA sequencing data. c RNA pulldown assay was performed using Biotin-labeled circPARD3 probes in FD-LSC-1 cells, the enrichment of the indicated miRNAs was detected by qPCR analysis. d Expression of miR-145-5p in LSCC cells overexpressing or silencing of circPARD3 was determined by qPCR analysis. e Luciferase reporter assay of FD-LSC-1 cells cotransfected with miR-145-5p mimics and luciferase reporter plasmid containing wild-type (WT) and miR-145-5p binding site mutated (Mut) circPARD3
Summary
Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck. Autophagy and circular RNAs (circRNAs) play critical roles in cancer progression and chemoresistance. The function and mechanism of circRNA in autophagy regulation of LSCC remain unclear. Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck, with increasing incidence and mortality [1]. LSCC is prone to local invasion, cervical lymph node metastasis and chemoresistance, which are the main factors leading to poor prognosis in patients [2, 3]. Autophagy is the biological process of eukaryotic cells using lysosomes to degrade their damaged organelles and macromolecular substances. Recent studies suggested that autophagy plays pivotal role in tumorigenesis, recurrence, metastasis, and chemoresistance [5]. The autophagy status and regulatory mechanisms in LSCC remain unclear
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