CDH1 作为癌基因的潜在作用及其相关 miRNAs 及其在乳腺癌中的诊断价值。
The Potential Role of CDH1 as an Oncogene Combined With Related miRNAs and Their Diagnostic Value in Breast Cancer.
机构信息
Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, China.
出版信息
Front Endocrinol (Lausanne). 2022 Jun 16;13:916469. doi: 10.3389/fendo.2022.916469. eCollection 2022.
BACKGROUND
Breast cancer (BC) is the leading cause of cancer-related mortality in females and the most common malignancy with high morbidity worldwide. It is imperative to develop new biomarkers and therapeutic targets for early diagnosis and effective treatment in BC.
METHODS
We revealed the oncogene function of cadherin 1 (CDH1) bioinformatic analysis in BC. Moreover, miRNA database was utilized to predict miRNAs upstream of CDH1. Expression of CDH1-related miRNAs in BC and their values in BC stemness and prognosis were analyzed through TCGA-BRCA datasets. In addition, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) were performed to explore the potential functions and signaling pathways of CDH1 in combination with CDH1-related miRNAs in BC progression. Finally, the differential expressions of soluble E-cadherin (sE-cad), which is formed by the secretion of CDH1-encoded E-cadherin into serum, analyzed by enzyme-linked immunosorbent assay (ELISA). Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expression level of CDH1-related miRNAs in serum samples.
RESULTS
The mRNA and protein expressions of CDH1 were elevated in BC tissues compared with normal counterparts. Moreover, CDH1 overexpression was positively correlated with BC stage, metastatic, stemness characteristics, and poor prognosis among patients. In predictive analysis, miR-340, miR-185, and miR-20a target CDH1 and are highly expressed in BC. miR-20a overexpression alone was strongly associated with high stemness characteristics and poor prognosis of BC. Additionally, GO, KEGG, and hallmark effect gene set analysis demonstrated that CDH1 in combination with overexpression of miR-340, miR-185, or miR-20a participated in multiple biological processes and underly signaling pathways involving in tumorigenesis and development of BC. Finally, we provide experimental evidence that the combined determination of serum sE-cad and miR-20a in BC has highly diagnostic efficiency.
CONCLUSIONS
This study provides evidence for CDH1 as an oncogene in BC and suggests that miR-20a may regulate the stemness characteristics of BC to exert a pro-oncogenic effect by regulating CDH1. Moreover, sE-cad and miR-20a in serum can both be used as valid noninvasive markers for BC diagnosis.
背景
乳腺癌（BC）是女性癌症相关死亡的主要原因，也是全球发病率较高的最常见恶性肿瘤。迫切需要开发新的生物标志物和治疗靶点，以实现 BC 的早期诊断和有效治疗。
方法
我们通过生物信息学分析揭示了钙粘蛋白 1（CDH1）在 BC 中的癌基因功能。此外，还利用 miRNA 数据库预测了 CDH1 上游的 miRNA。通过 TCGA-BRCA 数据集分析了 BC 中 CDH1 相关 miRNA 的表达及其在 BC 干性和预后中的价值。此外，还进行了基因本体论（GO）和基因集富集分析（GSEA），以探讨 CDH1 与 BC 进展过程中 CDH1 相关 miRNA 结合的潜在功能和信号通路。最后，通过酶联免疫吸附测定（ELISA）分析了由 CDH1 编码的 E-钙粘蛋白分泌到血清中形成的可溶性 E-钙粘蛋白（sE-cad）的差异表达。通过逆转录定量实时聚合酶链反应（RT-qPCR）检测血清样本中 CDH1 相关 miRNA 的表达水平。
结果
与正常对照相比，BC 组织中 CDH1 的 mRNA 和蛋白表达升高。此外，CDH1 过表达与患者的 BC 分期、转移性、干性特征和不良预后呈正相关。在预测分析中，miR-340、miR-185 和 miR-20a 靶向 CDH1，在 BC 中高表达。miR-20a 过表达本身与 BC 的高干性特征和不良预后密切相关。此外，GO、KEGG 和标志性效应基因集分析表明，CDH1 与 miR-340、miR-185 或 miR-20a 的过表达相结合，参与了多个生物学过程，并涉及到肿瘤发生和发展的信号通路。最后，我们提供了实验证据，表明联合测定 BC 患者血清中的 sE-cad 和 miR-20a 具有很高的诊断效率。
结论
本研究为 CDH1 作为 BC 中的癌基因提供了证据，并表明 miR-20a 可能通过调节 CDH1 来调节 BC 的干性特征，发挥致癌作用。此外，血清中的 sE-cad 和 miR-20a 均可作为有效的 BC 诊断无创标志物。
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