Department of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150040, China.
Department of Oncology, Beidahuang Industry Group General Hospital, No. 235 Hashuang Road, Harbin, Heilongjiang Province, 150088, China.
BMC Med Genomics. 2023 Aug 25;16(1):201. doi: 10.1186/s12920-023-01594-9.
To screen the possible potential signaling pathways related to enhancer of zeste homolog 2 (EZH2) based on ceRNA mechanism, and to analyze the correlation between E2H2 and depths of various immune cell infiltration depths. The relationship between different immune checkpoints were also analyzed.
First, the expression of EZH2 in pan-cancer (18 malignancies) was analyzed with the TCGA database. Hepatocellular carcinoma (HCC) tissues of 374 cases and normal tissues of 50 cases were analyzed in terms of the differential expression, overall survival (OS) and progression-free-survival (PFS). Then, we conducted GO and KEGG enrichment analysis on target gene. We also analyzed mRNA-miRNA and MicroRNA (miRNA)- long non-coding RNA (lncRNA) correlation with starbase databse, so as to determine the potential ceRNA mechanism associated with EZH2. Finally, immunoassay and drug-sensitivity analysis of EZH2 was performed.
Seven potential EZH2-related ceRNA pathways were screened out, namely lncRNA: Small Nucleolar RNA Host Gene 1 (SNHG1), SNHG 3, and SNHG 6-miR-101-3p-EZH2; and lncRNA: Long Intergenic Non-Protein Coding RNA 1978 (LINC01978), SNHG12, Ring Finger Protein 216 Pseudogene 1 (RNF216P1), and Coiled-coil Domain Containing 18 Antisense RNA 1 (CCDC18-AS1)-let-7c-5p-EZH2. Finally, 4 potential EZH2-related ceRNA pathways were identified through qPCR.According to immune correlation analysis, EZH2 may be positively correlated with T cells follicular helper, T cells Cluster of differentiation (CD)4 memory activated, Macrophages M0, and B cells memory (P < 0.05, cof > 0.2); while be negatively correlated with T cells CD4 + memory resting (P < 0.05, cof < -0.2). And EZH2 is positively correlated with Programmed Cell Death 1 (PDCD1) (R = 0.22), CD274 (R = 0.3) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) (R = 0.23). According to drug sensitivity analysis, patients in the high expression group were more susceptible to the effects of various drugs including Sorafenib, 5-Fluorouracil, Doxorubicin, Etoposide, Paclitaxel, and Vinorelbine than those with low expression.
This study revealed seven potential pathways of Enhancer of Zeste Homolog 2 (EZH2)-related ceRNA mechanisms: lncRNA (SNHG3, 6) -Mir-101-3P-ezh2; lncRNA (SNHG12, RNF216P1)-let-7c-5p-EZH2. We also analyzed the immunity and drug sensitivity of EZH2. Our study proves that EZH2 still has great research prospects in HCC.
基于 ceRNA 机制筛选可能与增强子结合蛋白 2（EZH2）相关的潜在信号通路，并分析 EZH2 与各种免疫细胞浸润深度的相关性。还分析了不同免疫检查点之间的关系。
首先，利用 TCGA 数据库分析了 EZH2 在泛癌（18 种恶性肿瘤）中的表达情况。分析了 374 例肝癌（HCC）组织和 50 例正常组织中的差异表达、总生存期（OS）和无进展生存期（PFS）。然后，我们对靶基因进行了 GO 和 KEGG 富集分析。我们还使用 starbase 数据库分析了 mRNA-miRNA 和 miRNA-长链非编码 RNA（lncRNA）的相关性，以确定与 EZH2 相关的潜在 ceRNA 机制。最后，对 EZH2 进行了免疫检测和药物敏感性分析。
筛选出 7 个可能与 EZH2 相关的 ceRNA 通路，即 lncRNA：Small Nucleolar RNA Host Gene 1（SNHG1）、SNHG 3 和 SNHG 6-miR-101-3p-EZH2；和 lncRNA：Long Intergenic Non-Protein Coding RNA 1978（LINC01978）、SNHG12、Ring Finger Protein 216 Pseudogene 1（RNF216P1）和 Coiled-coil Domain Containing 18 Antisense RNA 1（CCDC18-AS1）-let-7c-5p-EZH2。最后，通过 qPCR 鉴定出 4 个与 EZH2 相关的 ceRNA 通路。通过免疫相关性分析，EZH2 可能与滤泡辅助性 T 细胞、CD4 记忆性 T 细胞激活、M0 巨噬细胞和记忆性 B 细胞呈正相关（P<0.05，cof>0.2）；而与 CD4+记忆静止 T 细胞呈负相关（P<0.05，cof<-0.2）。EZH2 与程序性细胞死亡蛋白 1（PDCD1）（R=0.22）、CD274（R=0.3）和细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）（R=0.23）呈正相关。根据药物敏感性分析，高表达组的患者比低表达组的患者对索拉非尼、5-氟尿嘧啶、多柔比星、依托泊苷、紫杉醇和长春瑞滨等多种药物的治疗效果更为敏感。
本研究揭示了 7 种可能与 Enhancer of Zeste Homolog 2（EZH2）相关的 ceRNA 机制途径：lncRNA（SNHG3、6）-Mir-101-3P-ezh2；lncRNA（SNHG12、RNF216P1）-let-7c-5p-EZH2。我们还分析了 EZH2 的免疫和药物敏感性。我们的研究证明，EZH2 在 HCC 中仍具有很大的研究前景。
