PMID- 33234130 OWN - NLM STAT- MEDLINE DCOM- 20210803 LR - 20211204 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 19 IP - 1 DP - 2020 Nov 24 TI - circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway. PG - 166 LID - 10.1186/s12943-020-01279-2 [doi] LID - 166 AB - 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. FAU - Gao, Wei AU - Gao W AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China. AD - Department of Cell Biology and Genetics, Basic Medical School of Shanxi Medical University, Taiyuan, 030001, China. FAU - Guo, Huina AU - Guo H AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Niu, Min AU - Niu M AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Zheng, Xiwang AU - Zheng X AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Zhang, Yuliang AU - Zhang Y AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Xue, Xuting AU - Xue X AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Bo, Yunfeng AU - Bo Y AD - Department of Pathology, Shanxi Cancer Hospital, Shanxi Medical University, Taiyuan, 030013, China. FAU - Guan, Xiaoya AU - Guan X AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Li, Zhongxun AU - Li Z AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Guo, Yujia AU - Guo Y AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - He, Long AU - He L AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. FAU - Zhang, Yu AU - Zhang Y AD - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China. AD - Department of Physiology, Shanxi Medical University, Taiyuan, 030001, China. FAU - Li, Li AU - Li L AD - Department of Cell Biology and Genetics, Basic Medical School of Shanxi Medical University, Taiyuan, 030001, China. FAU - Cao, Jimin AU - Cao J AD - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China. AD - Department of Physiology, Shanxi Medical University, Taiyuan, 030001, China. FAU - Wu, Yongyan AU - Wu Y AUID- ORCID: 0000-0003-1669-3860 AD - Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. wuyongyan@sxent.org. AD - Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. wuyongyan@sxent.org. AD - Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan, 030001, China. wuyongyan@sxent.org. AD - Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China. wuyongyan@sxent.org. AD - Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, 030001, China. wuyongyan@sxent.org. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201124 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (Cell Cycle Proteins) RN - 0 (Isoenzymes) RN - 0 (MIRN145 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (PARD3 protein, human) RN - 0 (RNA, Circular) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 2.7.11.13 (protein kinase C lambda) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Animals MH - Antineoplastic Agents/pharmacology MH - Apoptosis MH - *Autophagy MH - Biomarkers, Tumor/genetics/*metabolism MH - Carcinoma, Squamous Cell/drug therapy/genetics/metabolism/*pathology MH - Cell Cycle Proteins MH - Cell Proliferation MH - Cisplatin/pharmacology MH - Disease Progression MH - *Drug Resistance, Neoplasm MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Isoenzymes/genetics/metabolism MH - Laryngeal Neoplasms/drug therapy/genetics/metabolism/*pathology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - MicroRNAs/genetics MH - Prognosis MH - Protein Kinase C/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - RNA, Circular/*genetics MH - Survival Rate MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays PMC - PMC7686732 OTO - NOTNLM OT - Autophagy OT - Chemoresistance OT - Circular RNA OT - Migration and invasion OT - PI3K-Akt-mTOR signaling pathway OT - PRKCI COIS- The authors declare that they have no competing interests. EDAT- 2020/11/26 06:00 MHDA- 2021/08/04 06:00 PMCR- 2020/11/24 CRDT- 2020/11/25 05:31 PHST- 2020/08/17 00:00 [received] PHST- 2020/11/03 00:00 [accepted] PHST- 2020/11/25 05:31 [entrez] PHST- 2020/11/26 06:00 [pubmed] PHST- 2021/08/04 06:00 [medline] PHST- 2020/11/24 00:00 [pmc-release] AID - 10.1186/s12943-020-01279-2 [pii] AID - 1279 [pii] AID - 10.1186/s12943-020-01279-2 [doi] PST - epublish SO - Mol Cancer. 2020 Nov 24;19(1):166. doi: 10.1186/s12943-020-01279-2.