hnRNPK regulates Wnt/β-catenin signaling pathway to inhibit ferroptosis in breast cancer

您当前的位置：

首页 >

文章列表页 >

hnRNPK regulates Wnt/β-catenin signaling pathway to inhibit ferroptosis in breast cancer

Article | 更新时间：2025-12-31

- hnRNPK regulates Wnt/β-catenin signaling pathway to inhibit ferroptosis in breast cancer
- China Oncology Vol. 34, Issue 10, Pages: 931-943(2024)
- 作者机构：
  
  1. 宁夏医科大学总医院医学科学研究院，宁夏银川 750004
  2. 宁夏医科大学总医院肿瘤外二科，宁夏银川 750004
  3. 银川市妇幼保健院病理科，宁夏银川 750004
  4. 宁夏医科大学总医院急诊科，宁夏银川 750004
  5. 宁夏医科大学总医院肿瘤内二科，宁夏银川 750004
  6. 灵武市人民医院心血管内科，宁夏灵武 751400
- 作者简介：
  
  CAO Jia
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2024.10.003
  CLC： R735.3
- Received：11 June 2024，
  
  Revised：2024-09-11，
  
  Published：30 October 2024
- 稿件说明：
移动端阅览
Xiaolan MA, Juan WANG, Bin SHI, et al. hnRNPK regulates Wnt/β-catenin signaling pathway to inhibit ferroptosis in breast cancer[J]. China Oncology, 2024, 34(10): 931-943.
DOI：

Xiaolan MA, Juan WANG, Bin SHI, et al. hnRNPK regulates Wnt/β-catenin signaling pathway to inhibit ferroptosis in breast cancer[J]. China Oncology, 2024, 34(10): 931-943. DOI： 10.19401/j.cnki.1007-3639.2024.10.003.

摘要

背景与目的：

核内不均一核糖核蛋白K（heterogeneous nuclear ribonucleoprotein K，hnRNPK）是一种调控基因表达和蛋白翻译的RNA结合蛋白，已被发现与多种肿瘤恶性进展密切相关，但其在乳腺癌中的作用尚未明确。本研究旨在探讨hnRNPK对乳腺癌细胞铁死亡的影响及其作用机制。

方法：

基于癌症基因组图谱（The Cancer Genome Atlas，TCGA）和基因表达综合（Gene Expression Omnibus，GEO）数据库，联合生信分析hnRNPK在乳

腺癌组织及正常组织中的表达及与临床预后的关系；采用实时定量逆转录聚合酶链反应（real-time quantitative reverse transcription polymerase chain reaction，qRT-PCR）、蛋白质印迹法（Western blot）、免疫组织化学法检测hnRNPK在乳腺癌细胞及组织中的表达；将乳腺癌MDA-MB-231和MCF-7细胞进行siRNA转染，设置分组为对照组（control）、空载体组（NC）、干扰载体组（si-hnRNPK），采用细胞计数试剂盒（cell counting kit-8，CCK-8）和平板克隆实验检测细胞增殖能力；高通量RNA测序（RNA-sequencing，RNA-seq）分析hnRNPK富集的生物学功能及信号转导通路，Western blot及活性氧（reactive oxygen species，ROS）、丙二醛（malondialdehyde，MDA）、谷胱甘肽（glutathione，GSH）、Fe

2＋

试剂盒检测hnRNPK对铁死亡表型的影响，并利用铁死亡抑制剂（ferrostatin-1，Fer-1）检测敲低hnRNPK对铁死亡的回复作用；通过Western blot检测hnRNPK对Wnt/β-catenin通路蛋白表达的影响。

结果：

数据库结合生物信息学分析结果显示，hnRNPK在乳腺癌组织中表达上调（

P

<

0.01），hnRNPK高表达组患者总生存期OS低于hnRNPK低表达组（

P

<

0.05）；hnRNPK在乳腺癌组织及细胞中呈高表达，敲低hnRNPK后乳腺癌细胞增殖能力减弱（

P

<

0.05）；RNA-seq分析发现hnRNPK显著富集铁死亡、凋亡、Wnt/β-catenin信号转导通路；敲低hnRNPK通过促进脂质ROS和MDA产生、Fe

2＋

富集促进乳腺癌细胞铁死亡（

P

<

0.05），且联合Fer-1有效抑制敲低hnRNPK对铁死亡的促进作用（

P

<

0.05）；hnRNPK下调导致Wnt/β-catenin信号转导通路中β-catenin、c-Myc表达降低，CK1α、APC、GSK-3β复合物表达升高（

P

<

0.05）。

结论：

hnRNPK在乳腺癌中呈高表达，敲低hnRNPK通过抑制Wnt/β-catenin信号转导通路促进乳腺癌细胞铁死亡，抑制乳腺癌恶性进展。

Abstract

Background and purpose:

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an RNA special binding protein that participates in regulating the expression of related genes and protein translation. It has been linked to the malignant occurrence and development of various tumors

but its role in breast cancer remains unclear. The aim of this study was to investigate the effects of hnRNPK on ferroptosis in breast cancer cells and the underlying mechanisms.

Methods:

Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases

hnRNPK expression in breast cancer tissues and normal tissues and its relationship with clinical prognosis were analyzed by bioinformatics. We detected hnRNPK expression in breast cancer cells and tissues using real-time qu

antitative reverse transcription polymerase chain reaction (qRT-PCR)

Western blot

and immunohistochemistry staining diagnosis methods. MCF-7 and MDA-MB-231 breast cancer cells were transfected with siRNA

and divided into control group (control)

empty body group (NC)

and interference vector group (si-hnRNPK). Cell proliferation was detected by cell counting kit-8 (CCK-8) and plate clone formation assays. RNA-seq analysis was applied to explore potential targeted biological functions and signaling pathways affected by hnRNPK. Additionally

we investigated the impact of hnRNPK on ferroptosis phenotype using Western blot and commercial kits for reactive oxygen species (ROS)

malondialdehyde (MDA)

glutathione (GSH)

and Fe

2+

ferroptosis inhibitor (ferrostatin-1

Fer-1) was used to detect the rescue effect of hnRNPK knockdown on ferroptosis. The impact of hnRNPK on the expressions of Wnt/β-catenin pathway-related proteins were determined by Western blot.

Results:

The bioinformatics analyses indicated hnRNPK was upregulated in breast cancer tissues (

P

<

0.01)

and the overall survival of patients in the high expression group was poorer compared with those in the low expression group (

P

<

0.05). hnRNPK was highly expressed in breast cancer tissues and cells

and knocking down hnRNPK weakened the proliferation ability of breast cancer cells (

P

<

0.05). The RNA-seq analysis showed that hnRNPK was significantly enriched in ferroptosis

apoptosis

and the Wnt/β-catenin signaling pathway. Knocking down hnRNPK promoted ferroptosis in breast cancer cells by inducing lipid ROS and MDA

as well as Fe

2+

accumulation (

P

<

0.05). Interestingly

the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed the promotive effect of hnRNPK knockdown on ferroptosis (

P

<

0.05). Downregulation of hnRNPK led to a decrease in the expressions of β-catenin and c-Myc in the Wnt/β-catenin signaling pathway

while express

ions of CK1α

APC and the GSK-3β complex were elevated (

P

<

0.05).

Conclusion:

hnRNPK is highly expressed in breast cancer

and knocking down hnRNPK promotes ferroptosis in breast cancer cells by inhibiting the Wnt/β-catenin signaling pathway

thereby suppressing the malignant progression of breast cancer.

关键词

Keywords

references

BRAY F , LAVERSANNE M , SUNG H , et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J ] . CA Cancer J Clin , 2024 , 74 ( 3 ): 229 - 263 .

WANG Z L , LI S Q , XU F , et al. ncRNAs-mediated high expression of TIMM8A correlates with poor prognosis and act as an oncogene in breast cancer [J ] . Cancer Cell Int , 2022 , 22 ( 1 ): 177.

GADALETA E , THORN G J , ROSS-ADAMS H , et al. Field cancerization in breast cancer [J ] . J Pathol , 2022 , 257 ( 4 ): 561 - 574 .

SUI S Y , XU S P , PANG D . Emerging role of ferroptosis in breast cancer: new dawn for overcoming tumor progression [J ] . Pharmacol Ther , 2022 , 232 : 107992 .

LEI G , ZHUANG L , GAN B Y . Targeting ferroptosis as a vulnerability in cancer [J ] . Nat Rev Cancer , 2022 , 22 ( 7 ): 381 - 396 . DOI: 10.1038/s41568-022-00459-0 http://doi.org/10.1038/s41568-022-00459-0

WANG Z Y , QIU H , HE J B , et al. The emerging roles of hnRNPK [J ] . J Cell Physiol , 2020 , 235 ( 3 ): 1995 - 2008 . DOI: 10.1002/jcp.29186 http://doi.org/10.1002/jcp.29186

ZHOU W W , JIE Q L , PAN T , et al. Single-cell RNA binding protein regulatory network analyses reveal oncogenic HNRNPK-MYC signalling pathway in cancer [J ] . Commun Biol , 2023 , 6 ( 1 ): 82.

LEE W J , SHIN C H , JI H , et al. hnRNPK-regulated LINC00263 promotes malignant phenotypes through miR-147a/CAPN2 [J ] . Cell Death Dis , 2021 , 12 ( 4 ): 290.

MUCHA B , QIE S , BAJPAI S , et al. Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation [J ] . Nat Commun , 2022 , 13 ( 1 ): 6614.

LI Y X , YANG Y , MA Q , et al. HNRNPK/CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction [J ] . Int J Biol Sci , 2022 , 18 ( 16 ): 6084 - 6101 . DOI: 10.7150/ijbs.76083 http://doi.org/10.7150/ijbs.76083

IWABUCHI E , MIKI Y , SUZUKI T , et al. Heterogeneous nuclear ribonucleoprotein K is involved in the estrogen-signaling pathway in breast cancer [J ] . Int J Mol Sci , 2021 , 22 ( 5 ): 2581.

GALLARDO M , LEE H J , ZHANG X R , et al. hnRNP K is a haploinsufficient tumor suppressor that regulates proliferation and differentiation programs in hematologic malignancies [J ] . Cancer Cell , 2015 , 28 ( 4 ): 486 - 499 . DOI: S1535-6108(15)00305-0 http://doi.org/S1535-6108(15)00305-0

XU Y J , WU W , HAN Q , et al. Post-translational modification control of RNA-binding protein hnRNPK function [J ] . Open Biol , 2019 , 9 ( 3 ): 180239.

XI Z H , HUANG H H , HU J , et al. LINC00571 drives tricarboxylic acid cycle metabolism in triple-negative breast cancer through HNRNPK/ILF2/IDH2 axis [J ] . J Exp Clin Cancer Res , 2024 , 43 ( 1 ): 22.

ZHOU X M , ZOU L B , LIAO H Y , et al. Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer [J ] . Acta Pharm Sin B , 2022 , 12 ( 2 ): 692 - 707 .

LV Y , TANG W T , ZHANG Z Y , et al. Cullin-9/p53 mediates HNRNPC degradation to inhibit erastin-induced ferroptosis and is blocked by MDM2 inhibition in colorectal cancer [J ] . Oncogene , 2022 , 41 ( 23 ): 3210 - 3221 . DOI: 10.1038/s41388-022-02284-z http://doi.org/10.1038/s41388-022-02284-z

ZHANG C , LIU X Y , JIN S D , et al. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance [J ] . Mol Cancer , 2022 , 21 ( 1 ): 47.

CHEN X , KANG R , KROEMER G , et al. Broadening horizons: the role of ferroptosis in cancer [J ] . Nat Rev Clin Oncol , 2021 , 18 ( 5 ): 280 - 296 . DOI: 10.1038/s41571-020-00462-0 http://doi.org/10.1038/s41571-020-00462-0

ZHU L Z , TIAN Q , GAO H , et al. PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK [J ] . Int J Biol Sci , 2022 , 18 ( 5 ): 2032 - 2046 . DOI: 10.7150/ijbs.68960 http://doi.org/10.7150/ijbs.68960

LIU H F , CHEN X H , YANG X J , et al. Involvement of the Wnt/β-catenin signaling pathway in the heterogenous nuclear ribonucleoprotein K-driven inhibition of proliferation and migration in head and neck squamous cell carcinoma [J ] . Oncol Lett , 2020 , 20 ( 6 ): 394.

YU F Y , YU C H , LI F F , et al. Wnt/β-catenin signaling in cancers and targeted therapies [J ] . Signal Transduct Target Ther , 2021 , 6 ( 1 ): 307.

LIU J Q , XIAO Q , XIAO J N , et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities [J ] . Signal Transduct Target Ther , 2022 , 7 ( 1 ): 3.

XU X F , ZHANG M F , XU F Y , et al. Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities [J ] . Mol Cancer , 2020 , 19 ( 1 ): 165.

0

Views

2583

下载量

0

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Related Articles

Guidelines for breast cancer diagnosis and treatment by China Anti-Cancer Association (2026 edition)

Progress and prospects of CENPA-driven chromosomal instability in breast cancer: mechanisms, prognostic implications, and therapeutic perspectives

A study of 30-year trends in incidence and mortality risks of breast cancer among young women in China

Impact of miR-193a-3p on migration and invasion of breast cancer stem cells through targeting TRIM14

Axillary management after neoadjuvant therapy for breast cancer and optimization of sentinel lymph node diagnosis and treatment

Related Author

The Society of Breast Cancer China Anti-Cancer Association

Breast Oncology Group of the Oncology Branch of the Chinese Medical Association

LU Ye

ZHANG Wenxiang

KONG Xiangyi

FANG Yi

WANG Jing

GAO Jidong

Related Institution

Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital& Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University

Shanghai Engineering Research Center of Artificial Intelligence Technology for Tumor Diseases

Department of Laboratory Medicine, Xingtai People’s Hospital

AI问答

⁰