Hepatic prohibitin 1 and methionine adenosyltransferase α1 defend against primary and secondary liver cancer metastasis

阻抑素 生物 转移 胰腺癌 癌症研究 癌症 分子生物学 生物化学 遗传学 线粒体
作者
Wei Fan,Duo-Yao Cao,Bing Yang,Jiaohong Wang,Xiaomo Li,Diána Kitka,Tony W.H. Li,Sungyong You,Stephen L. Shiao,Michal G. Rose,Edwin M. Posadas,Dolores Di Vizio,Maria Lauda Tomasi,Ekihiro Seki,José M. Mato,Heping Yang,Shelly C. Lu
出处
期刊:Journal of Hepatology [Elsevier]
卷期号:80 (3): 443-453 被引量:4
标识
DOI:10.1016/j.jhep.2023.11.022
摘要

Background & Aims

The liver is a common site of cancer metastasis, most commonly from colorectal cancer, and primary liver cancers that have metastasized are associated with poor outcomes. The underlying mechanisms by which the liver defends against these processes are largely unknown. Prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) are highly expressed in the liver. They positively regulate each other and their deletion results in primary liver cancer. Here we investigated their roles in primary and secondary liver cancer metastasis.

Methods

We identified common target genes of PHB1 and MAT1A using a metastasis array, and measured promoter activity and transcription factor binding using luciferase reporter assays and chromatin immunoprecipitation, respectively. We examined how PHB1 or MAT1A loss promotes liver cancer metastasis and whether their loss sensitizes to colorectal liver metastasis (CRLM).

Results

Matrix metalloproteinase-7 (MMP-7) is a common target of MAT1A and PHB1 and its induction is responsible for increased migration and invasion when MAT1A or PHB1 is silenced. Mechanistically, PHB1 and MAT1A negatively regulate MMP7 promoter activity via an AP-1 site by repressing the MAFG-FOSB complex. Loss of MAT1A or PHB1 also increased MMP-7 in extracellular vesicles, which were internalized by colon and pancreatic cancer cells to enhance their oncogenicity. Low hepatic MAT1A or PHB1 expression sensitized to CRLM, but not if endogenous hepatic MMP-7 was knocked down first, which lowered CD4+ T cells while increasing CD8+ T cells in the tumor microenvironment. Hepatocytes co-cultured with colorectal cancer cells express less MAT1A/PHB1 but more MMP-7. Consistently, CRLM raised distant hepatocytes' MMP-7 expression in mice and humans.

Conclusion

We have identified a PHB1/MAT1A-MAFG/FOSB-MMP-7 axis that controls primary liver cancer metastasis and sensitization to CRLM.

Impact and implications

Primary and secondary liver cancer metastasis is associated with poor outcomes but whether the liver has underlying defense mechanism(s) against metastasis is unknown. Here we examined the hypothesis that hepatic prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) cooperate to defend the liver against metastasis. Our studies found PHB1 and MAT1A form a complex that suppresses matrix metalloproteinase-7 (MMP-7) at the transcriptional level and loss of either PHB1 or MAT1A sensitizes the liver to metastasis via MMP-7 induction. Strategies that target the PHB1/MAT1A-MMP-7 axis may be a promising approach for the treatment of primary and secondary liver cancer metastasis.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
dicy1232003发布了新的文献求助10
刚刚
刚刚
y杨扬发布了新的文献求助10
刚刚
刚刚
沙耶酱完成签到,获得积分10
1秒前
1秒前
许多年以后完成签到,获得积分10
1秒前
木子完成签到,获得积分10
2秒前
2秒前
3秒前
3秒前
z2发布了新的文献求助10
3秒前
4秒前
包包完成签到 ,获得积分10
4秒前
lizh187发布了新的文献求助10
4秒前
4秒前
Agoni完成签到,获得积分10
4秒前
木子发布了新的文献求助10
5秒前
hzl完成签到,获得积分10
5秒前
秋秋完成签到,获得积分10
5秒前
5秒前
lala发布了新的文献求助10
5秒前
美丽的飞飞完成签到,获得积分20
5秒前
蒋时晏完成签到 ,获得积分0
6秒前
orixero应助憧憬采纳,获得10
6秒前
7秒前
7秒前
冰勾板勾完成签到,获得积分10
7秒前
7秒前
8秒前
8秒前
8秒前
玉衡完成签到,获得积分10
8秒前
等等NANO完成签到,获得积分10
8秒前
自由的凛发布了新的文献求助10
8秒前
9秒前
9秒前
ljw发布了新的文献求助10
9秒前
opticsLM完成签到,获得积分10
9秒前
Pyc完成签到,获得积分10
10秒前
高分求助中
The ACS Guide to Scholarly Communication 2500
Sustainability in Tides Chemistry 2000
Studien zur Ideengeschichte der Gesetzgebung 1000
TM 5-855-1(Fundamentals of protective design for conventional weapons) 1000
Threaded Harmony: A Sustainable Approach to Fashion 810
Pharmacogenomics: Applications to Patient Care, Third Edition 800
A Dissection Guide & Atlas to the Rabbit 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3081823
求助须知:如何正确求助?哪些是违规求助? 2734862
关于积分的说明 7534680
捐赠科研通 2384387
什么是DOI,文献DOI怎么找? 1264312
科研通“疑难数据库(出版商)”最低求助积分说明 612614
版权声明 597600