Integrated analysis of the functions and clinical implications of exosome circRNAs in colorectal cancer.
Integrated analysis of the functions and clinical implications of exosome circRNAs in colorectal cancer.
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外泌体circRNA在结直肠癌中的功能和临床意义的综合分析
DOI：
10.3389/fimmu.2022.919014
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
外泌体环状rna （Exo-circRNAs）调节肿瘤微环境中的癌症进展和细胞间串扰。然而，它们在结直肠癌（CRC）中的生物学功能和潜在的临床重要性尚不清楚。我们使用exoRBase 2.0数据识别结直肠癌患者和健康个体中显着差异表达的Exo-circRNAs （Exo-DEcircRNAs）。采用最小绝对收缩和选择运算算法、支持向量机递归特征消去和多变量Cox回归分析筛选候选exo - circrna并构建诊断模型。定量逆转录-聚合酶链反应分析证实Exo-circRNAs在患者血清样本中的表达。此外，我们构建了CRC的外泌体circRNA-miRNA-mRNA网络。外泌体竞争内源性RNA （Exo-ceRNA）网络中上调的靶mrna用于功能和途径富集分析。我们使用CIBERSORT在结直肠癌患者中鉴定了22种免疫细胞类型。相关分析揭示了Exo-ceRNA网络与免疫浸润细胞之间的关系。并探讨了靶mrna与免疫治疗反应的关系。最后，使用Kaplan-Meier生存曲线，筛选预后上调的靶mRNA。我们构建了存活相关的Exo-ceRNA子网，并探讨了Exo-ceRNA子网与免疫浸润细胞的相关性。所构建的诊断模型在训练集和验证集均具有较高的曲线下面积（AUC）， AUC分别为0.744和0.741。qRT-PCR证实，Exo-circRNAs在结直肠癌血清样本中存在差异表达。我们基于CRC中7个上调的exo - decircrna、8个差异表达的mirna和22个差异表达的mrna之间的相互作用构建了Exo-ceRNA网络。功能富集分析显示，上调的靶mrna在细胞骨架运动活性和PI3K-Akt信号通路中显著富集。共表达分析显示Exo-ceRNA网络与免疫细胞之间存在显著相关性。靶mrna与免疫治疗反应之间存在显著相关性。此外，基于预后上调靶基因（RGS2），我们构建了生存相关的Exo-ceRNA子网络（Exosome hsa_circ_0050334-hsa_miR_182_5p-RGS2）。CIBERSORT结果显示，Exo-ceRNA子网络与M2巨噬细胞相关（P = 4.6e-07, R = 0.31）。本研究确定了exo诊断模型，建立了Exo-ceRNA网络，并探讨了Exo-ceRNA网络与CRC免疫细胞浸润的相关性。这些发现阐明了exo - circrna的生物学功能及其潜在的临床意义。
Exosome circRNAs (Exo-circRNAs) regulate cancer progression and intercellular crosstalk in the tumor microenvironment. However, their biological functions and potential clinical importance in colorectal cancer (CRC) remain unknown. We used exoRBase 2.0 data to identify significant differentially expressed Exo-circRNAs (Exo-DEcircRNAs) in CRC patients and healthy individuals. The least absolute shrinkage and selector operation algorithm, support vector machine-recursive feature elimination, and multivariate Cox regression analyses were used to select candidate Exo-circRNAs and constructed a diagnostic model. Quantitative reverse transcription-polymerase chain reaction analysis was performed to confirm the expression of Exo-circRNAs in the serum samples of patients. Furthermore, we constructed an exosome circRNA-miRNA-mRNA network for CRC. Upregulated target mRNAs in the exosome competing endogenous RNA (Exo-ceRNA) network were used for functional and pathway enrichment analyses. We identified 22 immune cell types in CRC patients using CIBERSORT. Correlation analysis revealed the relationship between Exo-ceRNA networks and immune-infiltrating cells. The relationship between target mRNAs and immunotherapeutic response was also explored. Finally, using the Kaplan–Meier survival curve, a prognostic upregulated target mRNA was screened. We constructed a survival-related Exo-ceRNA subnetwork and explored the correlation between the Exo-ceRNA subnetwork and immune-infiltrating cells. The constructed diagnostic model had a high area under the curve (AUC) value in both the training and validation sets (AUC = 0.744 and AUC = 0.741, respectively). qRT-PCR confirmed that the Exo-circRNAs were differentially expressed in CRC serum samples. We constructed Exo-ceRNA networks based on the interactions among seven upregulated Exo-DEcircRNAs, eight differentially expressed miRNAs, and twenty-two differentially expressed mRNAs in CRC. Functional enrichment analysis revealed that the upregulated target mRNAs were significantly enriched in cytoskeletal motor activity and the PI3K-Akt signaling pathway. Co-expression analysis showed a significant correlation between the Exo-ceRNA networks and immune cells. The significant correlation was observed between target mRNAs and the immunotherapeutic response. Additionally, based on the prognostic upregulated target gene (RGS2), we constructed a survival-related Exo-ceRNA subnetwork (Exosome hsa_circ_0050334-hsa_miR_182_5p-RGS2). CIBERSORT results revealed that the Exo-ceRNA subnetwork correlated with M2 macrophages (P = 4.6e-07, R = 0.31). Our study identified an Exo-diagnostic model, established Exo-ceRNA networks, and explored the correlation between Exo-ceRNA networks and immune cell infiltration in CRC. These findings elucidated the biological functions of Exo-circRNAs and their potential clinical implications.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
2.8
作者：
Linder, Anna;Larsson, Karin;Damber, Jan-Erik
通讯作者：
Damber, Jan-Erik
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
影响因子：
3.7
作者：
Jiang A;Liu N;Bai S;Wang J;Gao H;Zheng X;Fu X;Ren M;Zhang X;Tian T;Ruan Z;Yao Y;Liang X
通讯作者：
Liang X
M2巨噬细胞衍生的外泌体促进结肠癌细胞迁移和侵袭
影响因子：
11.2
作者：
Lan, Jingqin;Sun, Li;Wang, Guihua
通讯作者：
Wang, Guihua