| 邹冠南,曹 祥,宗 丹,等.PLEKHA7通过维持铜稳态促进食管鳞状细胞癌增殖[J].肿瘤学杂志,2025,31(6):530-540. |
| PLEKHA7通过维持铜稳态促进食管鳞状细胞癌增殖 |
| PLEKHA7 Promotes Proliferation of Esophageal Squamous Cell Carcinoma by Maintaining Copper Homeostasis |
| 投稿时间：2025-03-11 |
| DOI：10.11735/j.issn.1671-170X.2025.06.B009 |
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| 中文关键词: 食管肿瘤 鳞状细胞癌 铜死亡 PLEKHA7 |
| 英文关键词:esophageal neoplasms squamous cell carcinoma cuproptosis PLEKHA7 |
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| 中文摘要: |
| 摘 要：［目的］ 探讨PLEKHA7在食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）中的功能及其在铜死亡中的调控机制。［方法］ 从癌症基因组图谱数据库和基因表达综合数据库中获取铜死亡相关基因（copper death-related genes，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和Western blot技术检测PLEKHA7在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-CuCl2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ESCC细胞对Elesclomol-CuCl2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）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，使用铜离子螯合剂四硫钼酸盐预处理后，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］PLEKHA7在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。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。 |
| 英文摘要: |
| Abstract：［Objective］ To investigate the effect of PLEKHA7 on proliferation of esophageal squamous cell carcinoma(ESCC) and its regulatory mechanism in copper-induced cell death (cuproptosis). ［Methods］ Copper death-related genes(CRGs) were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus(GEO) databases. The key prognostic genes were identified through univariate Cox regression and LASSO regression analysis. The expression of PLEKHA7 in ESCC cells was detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot， and PLEKHA7 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 promoted tumor cell proliferation (P<0.01). Knockdown of PLEKHA7 enhanced the sensitivity of ESCC cells to cuproptosis induced by Elesclomol-CuCl2(P<0.01)， while overexpression of PLEKHA7 significantly reduced the susceptibility of ESCC cells to cuproptosis (P<0.01). Mechanistic studies further suggested that PLEKHA7 inhibited the occurrence of cuproptosis by promoting copper ion efflux (P<0.01)， thus maintaining cellular copper homeostasis. Additionally， the expression levels of key proteins associated with cuproptosis (such as FDX1， LIAS， DLAT， HSP70， SLC31A1， ATP7A， and ATP7B) significantly changed under the regulation of PLEKHA7， further supporting its critical role in cuproptosis. Further experiments also showed that pre-treatment with the copper chelator tetrathiomolybdate partially reversed the decrease in cell proliferation caused by PLEKHA7 knockdown (P<0.01). ［Conclusion］ PLEKHA7 promotes ESCC proliferation by maintaining intracellular copper homeostasis and inhibiting copper-induced cell death. PLEKHA7 may be a key regulator of cuproptosis in ESCC， which may provide a novel insight for targeted therapy in ESCC. |
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