Significance and Possible Biological Mechanism for CLDN8 Downregulation in Kidney Renal Clear Cell Carcinoma Tissues.

IF 2.1 Q3 ONCOLOGY

World Journal of Oncology Pub Date : 2024-08-01 Epub Date: 2024-07-05 DOI:10.14740/wjon1869

Han Chu Ji, Jian Di Li, Guan Lan Zhang, Zhi Guang Huang, Ji Wen Cheng, Sheng Hua Li, Chun Yan Zhao, Yu Xing Tang, Kai Qin, You Liang Ma, Yu Long, Gang Chen, Bin Qin

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引用次数: 0

Abstract

Background: The clinical role of claudin 8 (CLDN8) in kidney renal clear cell carcinoma (KIRC) remains unclarified. Herein, the expression level and potential molecular mechanisms of CLDN8 underlying KIRC were determined.

Methods: High-throughput datasets of KIRC were collected from GEO, ArrayExpress, SRA, and TCGA databases to determine the mRNA expression level of the CLDN8. In-house tissue microarrays and immunochemistry were performed to examine CLDN8 protein expression. A summary receiver operating characteristic curve (SROC) and standardized mean difference (SMD) forest plot were generated using Stata v16.0. Single-cell analysis was conducted to further prove the expression level of CLDN8. A clustered regularly interspaced short palindromic repeats knockout screen analysis was executed to assess the growth impact of CLDN8. Functional enrichment analysis was conducted using the Metascape database. Additionally, single-sample gene set enrichment analysis was implied to explore immune cell infiltration in KIRC.

Results: A total of 17 mRNA datasets comprising 1,060 KIRC samples and 452 non-cancerous control samples were included in this study. Additionally, 105 KIRC and 16 non-KIRC tissues were analyzed using in-house immunohistochemistry. The combined SMD was -5.25 (95% confidence interval (CI): -6.13 to -4.37), and CLDN8 downregulation yielded an SROC area under the curve (AUC) close to 1.00 (95% CI: 0.99 - 1.00). CLDN8 downregulation was also confirmed at the single-cell level. Knocking out CLDN8 stimulated KIRC cell proliferation. Lower CLDN8 expression was correlated with worse overall survival of KIRC patients (hazard ratio of CLDN8 downregulation = 1.69, 95% CI: 1.2 - 2.4). Functional pathways associated with CLDN8 co-expressed genes were centered on carbon metabolism obstruction, with key hub genes ACADM, ACO2, NDUFS1, PDHB, SDHD, SUCLA2, SUCLG1, and SUCLG2.

Conclusions: CLDN8 is downregulated in KIRC and is considered a potential tumor suppressor. CLDN8 deficiency may promote the initiation and progression of KIRC, potentially in conjunction with metabolic dysfunction.

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肾脏透明细胞癌组织中 CLDN8 下调的意义和可能的生物学机制

背景：Claudin 8（CLDN8）在肾透明细胞癌（KIRC）中的临床作用仍未明确。方法：从 GEO、ArrayExpress、SRA 和 TCGA 数据库中收集 KIRC 的高通量数据集，以确定 CLDN8 的 mRNA 表达水平。为了检测CLDN8蛋白的表达，还进行了内部组织微阵列和免疫化学研究。使用Stata v16.0生成了接收者操作特征曲线（SROC）和标准化平均差（SMD）森林图。为进一步证明CLDN8的表达水平，还进行了单细胞分析。为评估 CLDN8 对生长的影响，进行了聚类规律性间隔短回文重复敲除筛选分析。利用 Metascape 数据库进行了功能富集分析。此外，还进行了单样本基因组富集分析，以探讨免疫细胞在KIRC中的浸润情况：本研究共纳入了 17 个 mRNA 数据集，包括 1,060 个 KIRC 样本和 452 个非癌症对照样本。此外，还使用内部免疫组化方法分析了 105 例 KIRC 和 16 例非 KIRC 组织。综合SMD为-5.25（95%置信区间（CI）：-6.13至-4.37），CLDN8下调产生的SROC曲线下面积（AUC）接近1.00（95% CI：0.99 - 1.00）。CLDN8 下调也在单细胞水平上得到了证实。敲除 CLDN8 会刺激 KIRC 细胞增殖。较低的CLDN8表达与KIRC患者较差的总生存率相关（CLDN8下调的危险比=1.69，95% CI：1.2 - 2.4）。与CLDN8共表达基因相关的功能通路以碳代谢障碍为中心，关键枢纽基因为ACADM、ACO2、NDUFS1、PDHB、SDHD、SUCLA2、SUCLG1和SUCLG2：CLDN8在KIRC中下调，被认为是潜在的肿瘤抑制因子。CLDN8缺乏可能与代谢功能障碍一起促进KIRC的发生和发展。

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来源期刊

World Journal of Oncology ONCOLOGY-

CiteScore

6.10

自引率

15.40%

发文量

期刊介绍： World Journal of Oncology, bimonthly, publishes original contributions describing basic research and clinical investigation of cancer, on the cellular, molecular, prevention, diagnosis, therapy and prognosis aspects. The submissions can be basic research or clinical investigation oriented. This journal welcomes those submissions focused on the clinical trials of new treatment modalities for cancer, and those submissions focused on molecular or cellular research of the oncology pathogenesis. Case reports submitted for consideration of publication should explore either a novel genomic event/description or a new safety signal from an oncolytic agent. The areas of interested manuscripts are these disciplines: tumor immunology and immunotherapy; cancer molecular pharmacology and chemotherapy; drug sensitivity and resistance; cancer epidemiology; clinical trials; cancer pathology; radiobiology and radiation oncology; solid tumor oncology; hematological malignancies; surgical oncology; pediatric oncology; molecular oncology and cancer genes; gene therapy; cancer endocrinology; cancer metastasis; prevention and diagnosis of cancer; other cancer related subjects. The types of manuscripts accepted are original article, review, editorial, short communication, case report, letter to the editor, book review.