鉴定与前列腺癌骨转移、不良预后以及 M2 巨噬细胞浸润丰度增加相关的 HCG18 和 MCM3AP-AS1。
Identification of HCG18 and MCM3AP-AS1 That Associate With Bone Metastasis, Poor Prognosis and Increased Abundance of M2 Macrophage Infiltration in Prostate Cancer.
机构信息
Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
出版信息
Technol Cancer Res Treat. 2021 Jan-Dec;20:1533033821990064. doi: 10.1177/1533033821990064.
BACKGROUND
Bone metastasis is a leading cause of the high mortality rate of prostate cancer (PCa), but curative strategies remain lacking. Recent studies suggest long non-coding RNAs (lncRNAs) may be potential targets to develop drugs. However, PCa bone metastasis-specifically-related lncRNAs were rarely reported. This study aimed to identify crucial lncRNAs and reveal their function mechanisms.
METHODS
GSE32269 and GSE26964 microarray datasets, downloaded from the Gene Expression Omnibus database, were used to analyze differentially expressed genes (DEGs)/lncRNAs (DELs) and miRNAs (DEMs), respectively. Weighted gene co-expression network analysis was performed to screen PCa bone metastasis-associated modules. The co-expression and competing endogenous RNAs (ceRNAs) networks were constructed to identify hub lncRNAs. Univariate Cox regression analysis was conducted to determine their prognostic values. The correlation of lncRNAs with immune infiltrating cells was analyzed by using Tumor IMmune Estimation Resource. Therapeutic drugs were predicted by querying the Connectivity Map (CMap) and the Comparative Toxicogenomics Database (CTD).
RESULTS
A total of 18 DELs, 2,614 DEGs and 86 DEMs were screened between bone metastatic and primary PCa samples. Four modules enriched by DEGs were shown to be bone metastasis-associated. LncRNA HCG18 and MCM3AP-AS1 were identified to be important because they existed in both of the co-expression and ceRNA networks (forming the relationship pairs: HCG18/MCM3AP-AS1-KNTC1, MCM3AP-AS1-hsa-miR-508-3p-DTL and HCG18/MCM3AP-AS1-hsa-miR-127-3p-CDKN3). All the genes in these interaction pairs were significantly associated with overall survival of PCa patients. Also, HCG18, MCM3AP-AS1 and their target mRNAs were positively correlated with various tumor-infiltrated immune cells, especially increased M2 macrophages. Valproic acid and trichostatin A may be effective to treat PCa bone metastasis by targeting HCG18 and MCM3AP-AS1.
CONCLUSION
HCG18 and MCM3AP-AS1 that regulate M2 macrophage infiltration may be important targets to treat PCa bone metastasis and improve prognosis.
背景
骨转移是前列腺癌（PCa）高死亡率的主要原因，但仍缺乏有效的治疗策略。最近的研究表明，长非编码 RNA（lncRNA）可能是开发药物的潜在靶点。然而，PCa 骨转移特异性相关的 lncRNA 很少有报道。本研究旨在鉴定关键的 lncRNA 并揭示其功能机制。
方法
从基因表达综合数据库（GEO）下载 GSE32269 和 GSE26964 微阵列数据集，分别用于分析差异表达基因（DEGs）/长非编码 RNA（DELs）和 microRNAs（DEMs）。采用加权基因共表达网络分析筛选与 PCa 骨转移相关的模块。构建共表达和竞争内源性 RNA（ceRNA）网络以鉴定关键 lncRNA。采用单因素 Cox 回归分析确定其预后价值。通过肿瘤免疫估计资源分析 lncRNA 与免疫浸润细胞的相关性。通过查询连接图谱（CMap）和比较毒理学基因组数据库（CTD）预测治疗药物。
结果
筛选出骨转移和原发性 PCa 样本之间的 18 个 DEL、2614 个 DEG 和 86 个 DEM。通过 DEGs 富集的四个模块显示与骨转移相关。lncRNA HCG18 和 MCM3AP-AS1 被确定为重要的 lncRNA，因为它们存在于共表达和 ceRNA 网络中（形成关系对：HCG18/MCM3AP-AS1-KNTC1、MCM3AP-AS1-hsa-miR-508-3p-DTL 和 HCG18/MCM3AP-AS1-hsa-miR-127-3p-CDKN3）。这些相互作用对中的所有基因都与 PCa 患者的总生存率显著相关。此外，HCG18、MCM3AP-AS1 及其靶 mRNA 与各种肿瘤浸润免疫细胞呈正相关，尤其是 M2 巨噬细胞增加。丙戊酸和曲古抑菌素 A 可能通过靶向 HCG18 和 MCM3AP-AS1 有效治疗 PCa 骨转移。
结论
调节 M2 巨噬细胞浸润的 HCG18 和 MCM3AP-AS1 可能是治疗 PCa 骨转移和改善预后的重要靶点。
Zotero 插件