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| PLEKHA7 通过维持铜稳态并促进食管鳞状细胞癌增殖 |
| PLEKHA7 promotes the proliferation of esophageal squamous cell carcinoma by maintaining copper homeostasis. |
| 投稿时间：2025-03-11 修订日期：2025-05-06 |
| DOI： |
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| 中文关键词: 食管鳞状细胞癌，铜死亡，PLEKHA7 |
| 英文关键词:Esophageal squamous cell carcinoma, Cuproptosis, PLEKHA7 |
| 基金项目: |
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| 摘要点击次数: 30 |
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| 中文摘要: |
| 目的:
本研究旨在探讨PLEKHA7在食管鳞状细胞癌（ESCC）中的功能及其在铜死亡（cuproptosis）中的调控机制，旨在为ESCC的诊疗提供新的分子靶点。通过深入分析PLEKHA7在铜死亡过程中的作用，期望为ESCC的靶向治疗和临床管理提供新的理论依据和潜在治疗策略。
方法：
基于文献筛选铜死亡相关基因（CRGs），并通过单因素Cox回归分析和LASSO回归方法筛选出关键预后基因。采用定量逆转录聚合酶链式反应（qRT-PCR）和Western blot技术检测PLEKHA7在食管鳞状细胞癌（ESCC）细胞中的表达，并构建了PLEKHA7过表达和敲低模型。通过CCK-8、克隆形成及EdU实验评估PLEKHA7对细胞增殖的影响。利用Elesclomol-CuCl?诱导铜死亡，检测细胞内铜离子水平及相关蛋白表达的变化。
结果：
功能实验结果表明，PLEKHA7显著促进了肿瘤细胞的增殖（P < 0.01）。敲低PLEKHA7可增强食管鳞状细胞癌（ESCC）细胞对Elesclomol-CuCl?诱导的铜死亡的敏感性（P < 0.01），而过表达PLEKHA7则显著降低了细胞对铜死亡的易感性（P < 0.01）。机制研究进一步表明，PLEKHA7可能通过促进铜离子的外排（P < 0.01），维持细胞铜稳态，从而抑制铜死亡的发生。此外，铜死亡相关的关键蛋白（如FDX1、LIAS、DLAT、HSP70、SLC31A1、ATP7A、ATP7B）的表达水平在PLEKHA7的调控下发生了显著变化，进一步支持其在铜死亡中的重要作用。进一步实验还发现，使用铜离子螯合剂TTM预处理后，能够部分逆转PLEKHA7敲低引起的细胞增殖能力下降（P < 0.01）。
结论：
本研究揭示了PLEKHA7在食管鳞状细胞癌（ESCC）中通过维持细胞铜稳态、抑制铜死亡，进而促进肿瘤细胞增殖的作用。我们的结果表明，PLEKHA7可能是ESCC中铜死亡的重要调控因子，为ESCC的靶向治疗提供了新的潜在策略。这一发现不仅加深了我们对铜死亡机制的理解，也为未来开发针对PLEKHA7的治疗方法提供了理论依据。 |
| 英文摘要: |
| Objective
This study aims to investigate the function of PLEKHA7 in esophageal squamous cell carcinoma (ESCC) and its regulatory mechanism in copper-induced cell death (cuproptosis), with the goal of providing new molecular targets for the diagnosis and treatment of ESCC. By thoroughly analyzing the role of PLEKHA7 in copper death, this study seeks to offer new theoretical insights and potential therapeutic strategies for targeted treatment and clinical management of ESCC.
Methods
Based on literature review, copper death-related genes (CRGs) were screened, and key prognostic genes were identified through univariate Cox regression and LASSO regression analysis. The expression of PLEKHA7 in esophageal squamous cell carcinoma (ESCC) cells was detected by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) and Western blot, and overexpression and knockdown models were constructed. The effect of PLEKHA7 on cell proliferation was assessed using CCK-8, colony formation, and EdU assays. Copper death was induced by Elesclomol-CuCl2, and changes in intracellular copper levels and related protein expression were detected.
Results
Functional experiments revealed that PLEKHA7 significantly promotes tumor cell proliferation (P < 0.01). Knockdown of PLEKHA7 enhances the sensitivity of esophageal squamous cell carcinoma (ESCC) cells to copper death induced by Elesclomol-CuCl2 (P < 0.01), while overexpression of PLEKHA7 significantly reduces the cells' susceptibility to copper death (P < 0.01). Mechanistic studies further suggest that PLEKHA7 may inhibit the occurrence of copper death by promoting copper ion efflux (P < 0.01), thus maintaining cellular copper homeostasis. Additionally, the expression levels of key proteins associated with copper death (such as FDX1, LIAS, DLAT, HSP70, SLC31A1, ATP7A, and ATP7B) significantly change under the regulation of PLEKHA7, further supporting its critical role in copper death. Further experiments also showed that pre-treatment with the copper chelator TTM partially reversed the decrease in cell proliferation caused by PLEKHA7 knockdown (P < 0.01).
Conclusion
This study reveals that PLEKHA7 promotes tumor cell proliferation in esophageal squamous cell carcinoma (ESCC) by maintaining intracellular copper homeostasis and inhibiting copper-induced cell death. Our results suggest that PLEKHA7 may be a key regulator of copper death in ESCC, providing a novel potential strategy for targeted therapy in ESCC. This finding not only enhances our understanding of the mechanisms of copper death but also provides a theoretical basis for the development of PLEKHA7-targeted therapeutic approaches. |
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