circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway

Mol Cancer. 2020 Nov 24;19(1):166. doi: 10.1186/s12943-020-01279-2.


Background: 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. However, the function and mechanism of circRNA in autophagy regulation of LSCC remain unclear.

Methods: The 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.

Results: Autophagy 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.

Conclusion: Our 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.

Keywords: Autophagy; Chemoresistance; Circular RNA; Migration and invasion; PI3K-Akt-mTOR signaling pathway; PRKCI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Autophagy*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Cycle Proteins
  • Cell Proliferation
  • Cisplatin / pharmacology
  • Disease Progression
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Laryngeal Neoplasms / drug therapy
  • Laryngeal Neoplasms / genetics
  • Laryngeal Neoplasms / metabolism
  • Laryngeal Neoplasms / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • Prognosis
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Circular / genetics*
  • Survival Rate
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • Isoenzymes
  • MIRN145 microRNA, human
  • MicroRNAs
  • PARD3 protein, human
  • RNA, Circular
  • MTOR protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Protein Kinase C
  • protein kinase C lambda
  • Cisplatin