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ATP8B1基因敲低激活了肺鳞状细胞癌中的胆碱代谢途径并诱导了高水平的细胞内氧化还原稳态。

ATP8B1 Knockdown Activated the Choline Metabolism Pathway and Induced High-Level Intracellular REDOX Homeostasis in Lung Squamous Cell Carcinoma.

作者信息

Zhang Xiao, Zhang Rui, Liu Pengpeng, Zhang Runjiao, Ning Junya, Ye Yingnan, Yu Wenwen, Yu Jinpu

机构信息

Cancer Molecular Diagnostics Core, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China.

Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.

出版信息

Cancers (Basel). 2022 Feb 7;14(3):835. doi: 10.3390/cancers14030835.

DOI:10.3390/cancers14030835
PMID:35159102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8834475/
Abstract

The flippase ATPase class I type 8b member 1 (ATP8B1) is essential for maintaining the stability and polarity of the epithelial membrane and can translocate specific phospholipids from the outer membrane to the inner membrane of the cell. Although ATP8B1 plays important roles in cell functions, ATP8B1 has been poorly studied in tumors and its prognostic value in patients with lung squamous cell carcinoma (LUSC) remains unclear. By investigating the whole genomic expression profiles of LUSC samples from The Cancer Genome Atlas (TCGA) database and Tianjin Medical University Cancer Institute and Hospital (TJMUCH) cohort, we found that low expression of ATP8B1 was associated with poor prognosis of LUSC patients. The results from cellular experiments and a xenograft-bearing mice model indicated that ATP8B1 knockdown firstly induced mitochondrial dysfunction and promoted ROS production. Secondly, ATP8B1 knockdown promoted glutathione synthesis via upregulation of the CHKA-dependent choline metabolism pathway, therefore producing and maintaining high-level intracellular REDOX homeostasis to aggravate carcinogenesis and progression of LUSC. In summary, we proposed ATP8B1 as a novel predictive biomarker in LUSC and targeting ATP8B1-driven specific metabolic disorder might be a promising therapeutic strategy for LUSC.

摘要

翻转酶ATP酶I类8b成员1（ATP8B1）对于维持上皮细胞膜的稳定性和极性至关重要，并且能够将特定磷脂从细胞膜外膜转运至内膜。尽管ATP8B1在细胞功能中发挥重要作用，但其在肿瘤中的研究较少，其在肺鳞状细胞癌（LUSC）患者中的预后价值仍不清楚。通过研究来自癌症基因组图谱（TCGA）数据库和天津医科大学肿瘤研究所及医院（TJMUCH）队列的LUSC样本的全基因组表达谱，我们发现ATP8B1低表达与LUSC患者的不良预后相关。细胞实验和荷瘤小鼠模型的结果表明，ATP8B1敲低首先诱导线粒体功能障碍并促进活性氧生成。其次，ATP8B1敲低通过上调CHKA依赖性胆碱代谢途径促进谷胱甘肽合成，从而产生并维持高水平的细胞内氧化还原稳态，加重LUSC的致癌作用和进展。总之，我们提出ATP8B1作为LUSC中的一种新型预测生物标志物，靶向ATP8B1驱动的特定代谢紊乱可能是LUSC的一种有前景的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/c424fee65f81/cancers-14-00835-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/38ba74f7176c/cancers-14-00835-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/1d7dead6acf9/cancers-14-00835-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/2950a4c4ea70/cancers-14-00835-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/b179b6c0dc29/cancers-14-00835-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/c424fee65f81/cancers-14-00835-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/38ba74f7176c/cancers-14-00835-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/1d7dead6acf9/cancers-14-00835-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/2950a4c4ea70/cancers-14-00835-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/b179b6c0dc29/cancers-14-00835-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5fb2/8834475/c424fee65f81/cancers-14-00835-g005.jpg

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