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Abstract：
BACKGROUND: Emerging evidence indicates the pivotal involvement of circular RNAs (circRNAs) in cancer initiation and progression. Understanding the functions and underlying mechanisms of circRNAs in tumor development holds promise for uncovering novel diagnostic indicators and therapeutic targets. In this study, our focus was to elucidate the function and regulatory mechanism of hsa-circ-0003764 in hepatocellular carcinoma (HCC).
METHODS: A newly discovered hsa-circ-0003764 (circPTPN12) was identified from the circbase database. QRT-PCR analysis was utilized to assess the expression levels of hsa-circ-0003764 in both HCC tissues and cells. We conducted in vitro and in vivo experiments to examine the impact of circPTPN12 on the proliferation and apoptosis of HCC cells. Additionally, RNA-sequencing, RNA immunoprecipitation, biotin-coupled probe pull-down assays, and FISH were employed to confirm and establish the relationship between hsa-circ-0003764, PDLIM2, OTUD6B, P65, and ESRP1.
RESULTS: In HCC, the downregulation of circPTPN12 was associated with an unfavorable prognosis. CircPTPN12 exhibited suppressive effects on the proliferation of HCC cells both in vitro and in vivo. Mechanistically, RNA sequencing assays unveiled the NF-κB signaling pathway as a targeted pathway of circPTPN12. Functionally, circPTPN12 was found to interact with the PDZ domain of PDLIM2, facilitating the ubiquitination of P65. Furthermore, circPTPN12 bolstered the assembly of the PDLIM2/OTUD6B complex by promoting the deubiquitination of PDLIM2. ESRP1 was identified to bind to pre-PTPN12, thereby fostering the generation of circPTPN12.
CONCLUSIONS: Collectively, our findings indicate the involvement of circPTPN12 in modulating PDLIM2 function, influencing HCC progression. The identified ESRP1/circPTPN12/PDLIM2/NF-κB axis shows promise as a novel therapeutic target in the context of HCC.
METHODS: A newly discovered hsa-circ-0003764 (circPTPN12) was identified from the circbase database. QRT-PCR analysis was utilized to assess the expression levels of hsa-circ-0003764 in both HCC tissues and cells. We conducted in vitro and in vivo experiments to examine the impact of circPTPN12 on the proliferation and apoptosis of HCC cells. Additionally, RNA-sequencing, RNA immunoprecipitation, biotin-coupled probe pull-down assays, and FISH were employed to confirm and establish the relationship between hsa-circ-0003764, PDLIM2, OTUD6B, P65, and ESRP1.
RESULTS: In HCC, the downregulation of circPTPN12 was associated with an unfavorable prognosis. CircPTPN12 exhibited suppressive effects on the proliferation of HCC cells both in vitro and in vivo. Mechanistically, RNA sequencing assays unveiled the NF-κB signaling pathway as a targeted pathway of circPTPN12. Functionally, circPTPN12 was found to interact with the PDZ domain of PDLIM2, facilitating the ubiquitination of P65. Furthermore, circPTPN12 bolstered the assembly of the PDLIM2/OTUD6B complex by promoting the deubiquitination of PDLIM2. ESRP1 was identified to bind to pre-PTPN12, thereby fostering the generation of circPTPN12.
CONCLUSIONS: Collectively, our findings indicate the involvement of circPTPN12 in modulating PDLIM2 function, influencing HCC progression. The identified ESRP1/circPTPN12/PDLIM2/NF-κB axis shows promise as a novel therapeutic target in the context of HCC.
摘要：
背景：新的证据表明环状RNA（circularRNAs，circRNAs）在癌症发生和进展中的关键参与。了解circRNAs在肿瘤发展中的功能和潜在机制有望发现新的诊断指标和治疗靶标。在这项研究中,我们的重点是阐明hsa-circ-0003764在肝细胞癌(HCC)中的功能和调节机制.
方法：从circbase数据库中确定了新发现的hsa-circ-0003764（circPTPN12）。QRT-PCR分析用于评估hsa-circ-0003764在HCC组织和细胞中的表达水平。我们进行了体外和体内实验，以检查circPTPN12对HCC细胞增殖和凋亡的影响。此外,RNA测序，RNA免疫沉淀，生物素偶联探针下拉测定，和FISH被用来确认和建立hsa-circ-0003764、PDLIM2、OTUD6B、P65和ESRP1。
结果：在HCC中，circPTPN12的下调与不良预后相关.CircPTPN12在体外和体内均对HCC细胞的增殖具有抑制作用。机械上,RNA测序分析揭示了NF-κB信号通路作为circPTPN12的靶向通路。功能上,发现circPTPN12与PDLIM2的PDZ结构域相互作用，促进P65的泛素化。此外，circPTPN12通过促进PDLIM2的去泛素化来支持PDLIM2/OTUD6B复合物的组装。ESRP1被鉴定为与pre-PTPN12结合,从而促进circPTPN12的产生。
结论：总的来说，我们的发现表明circPTPN12参与调节PDLIM2功能，影响HCC进展。鉴定的ESRP1/circPTPN12/PDLIM2/NF-κB轴有望作为HCC背景下的新型治疗靶标。
方法：从circbase数据库中确定了新发现的hsa-circ-0003764（circPTPN12）。QRT-PCR分析用于评估hsa-circ-0003764在HCC组织和细胞中的表达水平。我们进行了体外和体内实验，以检查circPTPN12对HCC细胞增殖和凋亡的影响。此外,RNA测序，RNA免疫沉淀，生物素偶联探针下拉测定，和FISH被用来确认和建立hsa-circ-0003764、PDLIM2、OTUD6B、P65和ESRP1。
结果：在HCC中，circPTPN12的下调与不良预后相关.CircPTPN12在体外和体内均对HCC细胞的增殖具有抑制作用。机械上,RNA测序分析揭示了NF-κB信号通路作为circPTPN12的靶向通路。功能上,发现circPTPN12与PDLIM2的PDZ结构域相互作用，促进P65的泛素化。此外，circPTPN12通过促进PDLIM2的去泛素化来支持PDLIM2/OTUD6B复合物的组装。ESRP1被鉴定为与pre-PTPN12结合,从而促进circPTPN12的产生。
结论：总的来说，我们的发现表明circPTPN12参与调节PDLIM2功能，影响HCC进展。鉴定的ESRP1/circPTPN12/PDLIM2/NF-κB轴有望作为HCC背景下的新型治疗靶标。
