Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma

Shuangshuang DUAN; Abudusaimaiti GULINAIZAIER; Lijun ZHANG; Miao SUN; Huibin LIU

doi:10.19401/j.cnki.1007-3639.2025.08.004

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Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma

Article | 更新时间：2025-12-31

- Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma
- China Oncology Vol. 35, Issue 8, Pages: 761-768(2025)
- 作者机构：
  
  1. 新疆医科大学药学院，新疆乌鲁木齐 830000
  2. 新疆医科大学附属肿瘤医院药物临床试验机构，新疆乌鲁木齐 830000
- 作者简介：
- 基金信息：
  
  National Natural Science Foundation of China(2022D01C518)
- DOI：10.19401/j.cnki.1007-3639.2025.08.004
  CLC： R737.11
- Received：07 March 2025，
  
  Revised：2025-06-04，
  
  Published：30 August 2025
- 稿件说明：
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Shuangshuang DUAN, Abudusaimaiti GULINAIZAIER, Lijun ZHANG, et al. Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma[J]. China Oncology, 2025, 35(8): 761-768.
DOI：

Shuangshuang DUAN, Abudusaimaiti GULINAIZAIER, Lijun ZHANG, et al. Mechanisms of PTEN-regulated PDK1 in modulating malignant phenotypes of clear cell renal cell carcinoma[J]. China Oncology, 2025, 35(8): 761-768. DOI： 10.19401/j.cnki.1007-3639.2025.08.004.

摘要

背景与目的：

通常情况下，丙酮酸脱氢酶激酶1（pyruvate dehydrogenase kinase 1，PDK1）异常活化通过介导有氧糖酵解效应驱动肿瘤微环境重塑与转移。10号染色体上缺失的磷酸酶及张力蛋白同源物基因（phosphatase and tensin homolog deleted on chromoseme ten，PTEN）作为关键抑癌磷酸酶，其表达缺失可激活PDK1诱导有氧糖酵解，加速肿瘤进展。但二者在肾透明细胞癌（kidney renal clear cell carcinoma，KIRC）中的分子调控机制亟待阐明。本研究旨在探究PTEN通过靶向调控PDK1抑制KIRC恶性生物学表型的作用机制。

方法：

采用生物信息学分析癌症基因组图谱计划（The Cancer Genome Atlas，TCGA）-KIRC数据库中PTEN与PDK1的表达差异及其与患者预后的相关性。构建PDK1敲降/过表达的肾癌细胞模型，通过细胞计数试剂盒（cell counting kit-8，CCK-8）增殖检测、克隆形成实验、划痕实验及transwell侵袭实验评估细胞恶性表型。采用PTEN特异性抑制剂处理PDK1过表达的肾癌细胞系，验证二者之间的调控关系。

结果：

TCGA-KIRC转录组数据显示，KIRC组织中PTEN与PDK1 mRNA表达显著高于配对癌旁组织（

0.05）。生存分析揭示高表达患者总生存期显著延长（

0.01），且二者在基因水平的表达呈强正相关（

=0.52，

0.001）。功能实验证实，抑制PDK1表达可显著增强肾癌细胞的增殖、迁移及侵袭能力（

0.05），过表达PDK1则呈现相反表型。机制研究发现，PTEN抑制剂处理后可促进肾癌细胞恶性行为，而过表达PDK1能有效逆转该效应。

结论：

本研究揭示了PTEN-PDK1生物学轴在肾癌中的双重抑癌作用，这一发现有望为确立基于新靶点的肾癌精准治疗策略提供理论依据。

Abstract

Background and purpose:

The aberrant activation of pyruvate dehydrogenase kinase 1 (PDK1) drives tumor microenvironment remodeling and metastasis through mediating the Warburg effect. As a critical tumor-suppressive phosphatase

phosphatase and tensin homolog deleted on chromoseme ten (PTEN) activates PDK1 via loss of expression to induce aerobic glycolysis and accelerate tumor progression. The molecular interplay between PDK1 and PTEN in kidney renal clear cell carcinoma (KIRC) urgently requires systematic elucidation. This study aimed to clarify how PTEN regulates PDK1 to inhibit malignant phenotypes in KIRC.

Methods:

Bioinformatics analysis was conducted to compare PTEN and PDK1 expression levels as well as their prognostic corre

lations in the Cancer Genome Atlas (TCGA)-KIRC datasets. KIRC cell models was established by either silencing PDK1 or enhancing its expression

subsequently evaluating their malignancy characteristics through cell counting kit-8 (CCK-8) proliferation

colony formation

cell migration

and invasion assays. To validate the regulatory interactions

we used PDK1-overexpressing cells treated with a PTEN-specific inhibitor. Western blot was used to dectect the protein expression.

Results:

The TCGA-KIRC analysis found significantly higher mRNA levels of PTEN and PDK1 in tumor tissues compared to normal controls (

0.05)

yet this high expression was associated with improved overall survival (

0.01). Besides

a strong positive correlation was observed between PTEN and PDK1 expressions (

=0.52

0.001). Functional assays demonstrated that PDK1 knockdown markedly promoted cell proliferation

migration

and invasion

whereas PDK1 overexpression exhibited opposing effects. Mechanistically

inhibiting PTEN worsened malignant behaviors (

0.01)

however

these effects were reversed by overexpressing PDK1.

Conclusion:

This study presents the first evidence of the dual tumor-suppressive function of the PTEN-PDK1 biological axis in renal cancer

which supports the development of precision treatment strategies based on novel targets.

关键词

Keywords

references

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