Mg2+ Transporters in Digestive Cancers

Despite magnesium (Mg²⁺) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg²⁺ homeostasis is regulated by Mg²⁺ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg²⁺ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg²⁺ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg²⁺ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg²⁺ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.     

结肠癌免疫相关 lncRNA 风险预测模型的建立

目的 分析影响结肠癌预后的免疫相关 lncRNA, 并构建预测结肠癌患者预后的相关预测模型。 方法 下载 TCGA 数据库中的结肠癌 lncRNA 表达谱, 数据经 TPM 标准化后分析所有 lncRNA 的差异性表 达, 其中缺失值的补充采用 KNN 法, 通过共表达方法提取并鉴定免疫相关 lncRNA, 然后对差异性表达的 lncRNA 进行 LASSO 回归分析, 再进行单因素和多因素 COX 回归分析。 最后使用 R 4. 0. 2 统计学软件的 ggplot2 包基于 lncRNA 风险评分与基因表达关系, 构建风险因子关联图、 KM 曲线及评价模型预测价值的 ROC 曲线。 结果 经过表达差异性分析发现, 共有 2 258 个 lncRNA 在癌和癌旁组织中差异性表达, 其中上 调的有 1 648 个, 下调的有 610 个。 选取差异表达前 100 位的免疫相关 lncRNA 进行 LASSO 回归分析, 共筛 选出 12 个 lncRNA, 再进行单因素和多因素 COX 回归分析后显示 AC092723. 1、 AC007182. 1 和 AC004947. 1 与预后明显相关, 使用 R 4. 0. 2 统计学软件构建预后风险因子关联图, ROC 曲线显示其预测 1 年、 3 年和 5 年的预测价值均较高, 其 AUC 分别为 0. 79 (95 % CI: 0. 67 ~ 0. 91), 0. 78 (95 % CI: 0. 66 ~ 0. 9), 0. 7 (95 % CI: 0. 51 ~ 0. 9)。 结论 研究使用 TCGA 公共数据库进行生物信息学分析并构建的预后模型显示有 较高的预测价值, 除具有一定的临床意义外, 对未来 lncRNA 相关结肠癌的研究也提供了一定的方向。     

Upregulation of matrix metalloproteinase 14 (MMP14) is associated with poor prognosis in renal clear cell carcinoma—a bioinformatics analysis

BackgroundMatrix metalloproteinase 14 (MMP14) has been reported to be upregulated in some types of cancer and to promote cancer cell invasion and metastasis. However, the expression profile and functional role of MMP14 in kidney renal clear cell carcinoma (KIRC) remains unknown. This study investigated the association between MMP14 expression level and prognosis in KIRC.MethodsThe messenger RNA (mRNA) expression profile and clinical data (including T stage, N stage, M stage, pathologic stage, gender, race, age, histologic grade, serum calcium, hemoglobin) were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Protein expression was evaluated by immunohistochemistry in the Human Protein Atlas (HPA) database. Correlation analyses between MMP14 and all mRNAs in KIRC were batch calculated, and gene set enrichment analyses (GSEA) were then conducted of Disease Ontology (DO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using R packages. Multivariate logistic regression analysis was used to explore the prognostic factors of KIRC patients.ResultsThe gene expression of MMP14 was significantly upregulated in KIRC tissues when compared with the normal tissue (P<0.001). The predictive ability of MMP14 as a variable for predicting tumor and normal outcomes had certain accuracy based on the receiver operating characteristic (ROC) model [area under the curve (AUC) =0.881, confidence interval (CI): 0.844-0.917]. When compared with the normal kidney tissue, the protein expression of MMP14 in KIRC got an increased trend, but due to the limited sample size, the difference is not statistically significant (P>0.05). Survival analysis revealed that MMP14 was significantly associated with overall survival in KIRC (P=0.013). GSEA of DO terms indicated high expression of MMP14 was related to KIRC, and GSEA of KEGG pathways showed that MMP14 and its coexpressed genes were significantly positively correlated with pathways in cancer. Signaling pathway GSEA indicated the upregulation of MMP14 in KIRC may activate cancer pathways.ConclusionsMMP14 may be associated with poor prognosis in KIRC and may be a potential prognostic marker for KIRC.     

The prognostic value of an immune-related gene signature and infiltrating tumor immune cells based on bioinformatics analysis in primary esophageal cancer

BackgroundImmunotherapy is a promising novel treatment for esophageal cancer (ESCA). However, previous studies provide limited direct information about the prognostic significance of immune-related genes (IRGs) in primary ESCA development. This study explored the prognostic value of IRGs and infiltrating tumor immune cells in primary ESCA.MethodsThe ribonucleic acid (RNA)-sequencing data and clinical information of primary ESCA were downloaded from The Cancer Genome Atlas (TCGA) database. Which included the clinical factors and prognosis outcomes of the ESCA patients. The IRGs were downloaded from the ImmPORT database.ResultsWe established the robust IRG prognostic signature of 4 IRGs (i.e., heat shock protein family A member 6, Oncostatin M, androgen receptor, and nuclear receptor subfamily 2 group F member 2) in primary ESCA, and divided the ESCA patients into high- and low-risk groups based on overall survival (OS). The Kaplan-Meier curves showed the high predictive ability of the prognostic signature in the training, testing, and full data sets (P=2.407e-03, P=1.044e-02, and P=2.535e-04, respectively). Multivariate Cox regression analyses were performed with age, grade, tumor stage, tumor type and the risk score as covariables. The risk score supports the use of a prognostic signature as an independent prognostic factor [training data set: hazard ratio (HR) =1.185, 95% confidence interval (95% CI): 1.013–1.388, P=0.034; testing data set: HR =2.056, 95% CI: 1.015–4.166, P=0.045; full data set: HR =1.197, 95% CI: 1.059–1.354, P=0.004]. The area under the curve (AUC) of the receiver operating characteristic curve validated the high predictive accuracy of the IRG signature in the training, testing, and full data set (AUCs =0.808, 0.657, and 0.751, respectively). The infiltration level of the activated mast cells was significantly higher in the high-risk group than the low-risk group; thus, infiltrating mast cells are associated with worse OS in ESCA patients.ConclusionsOur IRG prognostic signature provides a new direction to predict the survival of primary ESCA patients and has the potential ability to establish, promote, and improve personalized treatment procedures based on each patient’s risk.     

基于网络药理学和生物信息学探讨小柴胡汤治疗肝细胞癌的作用机制

目的 采用TCGA数据挖掘和网络药理学方法分析小柴胡汤治疗肝细胞癌(HCC)的药效物质基础及药理机制.方法 通过TCGA数据库挖掘HCC差异表达基因、通过TCMID、TCMSP数据库和文献检索得到小柴胡汤的活性成分及其作用靶点;绘制韦恩图获得小柴胡汤-HCC共有靶点.通过Cytoscape软件构建疾病-药物-有效成分-...     

基于TCGA数据库挖掘甲状腺乳头状癌淋巴结转移相关的突变基因及其机制探讨

目的:挖掘并筛选与甲状腺乳头状癌(papillary thyroid carcinoma, PTC)淋巴结转移相关的突变基因及其潜在的机制。方法:从TCGA数据库获得377例PTC患者的测序数据及完整的临床资料,并分为淋巴结转移组（LM,n=212）与无淋巴结转移组（NLM,n=165）。利用R语言（v3.6.2）对转移组特有的突变基因进行富集分析。采用String在线软件绘制蛋白互作网络,Cytoscape软件筛选网络中的核心基因。在UALCAN网站上验证基因表达量与淋巴结转移之间的关系。利用荧光实时定量PCR测定候选基因在细胞系中mRNA的表达量。结果：一共筛选出1 197个仅在LM组发生突变的基因,它们主要富集在黏着连接、细胞黏附分子（cell adhesion molecules,CAMs）通路。CAMs通路的核心基因ITGB1与VCAN的表达量与淋巴结转移相关。与正常甲状腺细胞系相比,VCAN基因在PTC细胞系TPC-1和B-CPAP中mRNA的表达量较高,尤其是B-CPAP细胞系。结论：CAMs通路可能是PTC淋巴结转移相关机制之一,其中VCAN基因可能是潜在的分子标志物。     

Tumor Mutation Burden,Immune Cell Infiltration,and Construction of Immune-Related Genes Prognostic Model in Head and Neck Cancer

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and the prognosis of HNSCC remains bleak. Numerous studies revealed that the tumor mutation burden (TMB) could predict the survival outcomes of a variety of tumors.Objectives: This study aimed to investigate the TMB and immune cell infiltration in these patients and construct an immune-related genes (IRGs) prognostic model.Methods: The expression data of 546 HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) database. All patients were divided into high- and low- TMB groups, and the relationship between TMB and clinical relevance was further analyzed. The differentially expressed genes (DEGs) were identified using the R software package, limma. Functional enrichment analyses were conducted to identify the significantly enriched pathways between two groups. CIBERSORT algorithm was adopted to calculate the abundance of 22 leukocyte subtypes. The IRGs prognostic model was constructed via the multivariate Cox regression analysis.Results: Missense mutation and single nucleotide variants (SNV) were the most predominant mutation types in HNSCC. TP53, TTN, and FAT1 were the most frequently mutated genes. Patients with high TMB were observed with worse survival outcomes. The functional analysis of TMB associated DEGs showed that the identified DEGs mainly involved in spliceosome, RNA degradation, proteasome, and RNA polymerase pathways. We observed that macrophages, T cells CD8, and T cells CD4 memory were the most commonly infiltrated subtypes of immune cells in HNSCC. Finally, an IRGs prognostic model was constructed, and the AUC of the ROC curve was 0.635.Conclusions: Our results suggest that high TMB is associated with poor prognosis in HNSCC patients. The constructed model has potential prognostic value for the prognosis of these individuals, and it needs to be further validated in large-scale and prospective studies.     

基于TCGA数据库挖掘恶性脑胶质瘤乏氧与免疫微环境相关预后价值基因

目的 挖掘恶性脑胶质瘤中与乏氧诱导因子-1α（hypoxia inducible factor-1α,HIF-1α）表达存在相关性的免疫通路或基因,并进一步分析其对脑胶质瘤预后的影响。方法 从肿瘤基因组图谱（the cancer genome atlas,TCGA）数据库提取脑胶质瘤HIF-1α基因表达谱数据,采用R语言分析HIF-1α基因与其他基因之间的相关性,通过GO和KEGG数据库对差异表达基因进行功能注释,包括细胞组分、生物学过程、分子功能及相关信号通路。并采集了74例人脑胶质瘤组织进一步验证分析。结果 TCGA数据库中共收集到169例脑胶质瘤患者的数据,其中与HIF-1α基因有相关性的基因有455个。对455个满足条件的相关性基因进行GO和Pathway富集分析,共得到66个KEGG Pathway;最终发现基因TNFRSF1α的P值具有统计差异。进一步对比分析TCGA数据库169例脑胶质瘤患者与529例非肿瘤患者数据中TNFRSF1α表达的情况。结果 提示TNFRSF1α与HIF-1α在脑胶质瘤组织中显著高于癌旁组织。且人脑胶质瘤组织TNFRSF1α表达水平与胶质瘤的病理分级正相关。结论 KEGG通路发现TNFRSF1α基因与乏氧有关,提示TNFRSF1α基因可能与乏氧共同影响脑胶质瘤患者的预后。