circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway.
circPARD3 drives malignant progression and chemoresistance of laryngeal squamous cell carcinoma by inhibiting autophagy through the PRKCI-Akt-mTOR pathway.
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DOI：
10.1186/s12943-020-01279-2
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发表时间：
2020-11-24
期刊：
影响因子：
37.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Gao W;Guo H;Niu M;Zheng X;Zhang Y;Xue X;Bo Y;Guan X;Li Z;Guo Y;He L;Zhang Y;Li L;Cao J;Wu Y
喉鳞状细胞癌是头颈部第二常见的恶性肿瘤。自噬和环状RNA(CircRNAs)在癌症进展和化疗耐药中发挥关键作用。然而，CircRNA在喉鳞状细胞癌自噬调控中的作用和机制尚不清楚。通过对107例喉鳞状细胞癌组织和配对的癌旁正常粘膜(ANM)组织进行RNA测序和高含量筛选，鉴定出具有自噬抑制作用的CircRNA CircRNACircPARD3。采用逆转录聚合酶链式反应、Sanger测序、定量聚合酶链式反应和荧光原位杂交等方法检测CircPARD3的表达和亚细胞定位。利用体外和体内模型，通过增殖、迁移、侵袭、自噬通量和耐药实验评价了CircPARD3的生物学功能。通过RNA免疫沉淀、RNA下拉、荧光素酶报告、免疫印迹和免疫组织化学染色等方法研究了CircPARD3的作用机制。喉鳞状细胞癌组织中自噬受到抑制， 基因表达上调(n=100，p<；0.001)。喉鳞癌患者(n= 0.001)的T分期(p<；0.0 5)、N分期(p= 0.001)、临床分期(p<；0.001)、分化程度差(p= 0.025)、预后不良(p= 0.002)与CircPARD3的高表达有关。在功能上，CircPARD3抑制自噬，促进LSCC细胞的增殖、迁移、侵袭和化疗耐药。我们进一步揭示了通过海绵miR-145-5P激活PRKCI-Akt-mTOR通路是CircPARD3抑制自噬、促进LSCC进展和化疗耐药的主要机制。我们的研究揭示了新的自噬抑制的CircPARD3通过PRKCI-Akt-mTor途径促进喉癌的进展和化疗耐药，为CircRNA介导的自噬调控和潜在的生物标志物和治疗LSCC的靶点提供了新的见解。网上版载有补充材料，可在10.1186/s12943-020-01279-2查阅。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s12943-020-01279-2.
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