Dataset Information

Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner.

ABSTRACT:

Background

Cancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear.

Methods

Here, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynamics and cellular motility, as a responsible factor and elucidated its mechanism of action using molecular and cellular biology techniques.

Results

HMHA1 expression was found to be induced at the transcription initiation level in a HIF-dependent manner under hypoxia. Boyden chamber invasion assay revealed that the induction of HMHA1 expression is required for the increase in invasion of hypoxic cancer cells. Reoxygenation treatment after ionising radiation in vitro that mimics dynamic changes of a microenvironment in hypoxic regions of tumour tissues after radiation therapy further enhanced HMHA1 expression and invasive potential of HMHA1 wildtype cancer cells in ROS- and HIF-dependent manners, but not of HMHA1 knockout cells.

Conclusion

These results together provide insights into a potential molecular mechanism of the acquisition of invasiveness by hypoxic cancer cells after radiotherapy via the activation of the ROS/HIF/HMHA1 axis.

SUBMITTER: Lee PWT

PROVIDER: S-EPMC11231347 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner.

Lee Peter W T PWT Suwa Tatsuya T Kobayashi Minoru M Yang Hui H Koseki Lina R LR Takeuchi Satoshi S Chow Christalle C T CCT Yasuhara Takaaki T Harada Hiroshi H

British journal of cancer 20240513 1

<h4>Background</h4>Cancer cells in severely hypoxic regions have been reported to invade towards tumour blood vessels after surviving radiotherapy in a postirradiation reoxygenation- and hypoxia-inducible factor (HIF)-dependent manner and cause recurrence. However, how HIF induces invasiveness of irradiated and reoxygenated cancer cells remains unclear.<h4>Methods</h4>Here, we identified human minor histocompatibility antigen 1 (HMHA1), which has been suggested to function in cytoskeleton dynami ...[more]

PMID: 38740970

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Project description:BackgroundHypoxic microenvironments play a significant role in the progression of colorectal cancer (CRC). Silencing information regulator 1 (SIRT1), a class III histone deacetylase, modulates the multiple biological behaviors of cancer. However, its role in CRC remains unclear. This study aims to explore the role of SIRT1 in CRC migration and invasion under hypoxia.MethodsSIRT1 protein and mRNA levels were detected by Western blotting and real-time PCR in CRC cells exposed to hypoxia (1% O2). The migration and invasion abilities of SW480 and HCT116 cells with SIRT1 overexpression or knockdown were studied with transwell assays, and the results were confirmed by those of treatment with specific SIRT1 activator (SRT1720) and inhibitor (EX527). The dual-luciferase reporter systems with a series of SIRT1 promoter truncations were used to analyze their transcriptional activities, respectively. After a bioinformatic analysis of potential transcription factors, the direct interaction between the transcription factor and SIRT1 promoter was determined by chromatin immunoprecipitation (ChIP) assays. Western blot and real-time PCR assays were used to detect the activation and acetylation levels of the NF-κB pathway.ResultsThe protein and mRNA levels of SIRT1 were significantly decreased under hypoxia, and these effects were replicated by cobalt chloride treatment. Hypoxia promoted cell migration and invasion, which were impeded by the overexpression or activation of SIRT1 and promoted by the knockdown or inhibition of SIRT1. The dual-luciferase reporter gene and ChIP analyses revealed that the core regulatory elements located 100 bp upstream of the SIRT1 promoter and early growth response factor 1 (EGR1) could interact with this DNA sequence. Subsequent rescue experiments suggested that EGR1 was essential for hypoxia-mediated SIRT1 transcriptional suppression. Western blot analyses demonstrated that SIRT1 overexpression eliminated the p65 acetylation induced by hypoxia along with the decreased MMP-2/-9, suggesting that NF-κB was a direct downstream target of SIRT1 and might regulate cell migration and invasion through MMP-2/-9.ConclusionsOur results establish for the first time that EGR1 plays an important role in regulating SIRT1 expression under hypoxia. Hypoxia promotes CRC cell migration and invasion in a SIRT1-dependent manner. And a potential SIRT1/NF-κB/MMP-2/-9 axis modulates this process.

Dataset Information

Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner.

Background

Methods

Results

Conclusion

Publications

Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner.

Similar Datasets

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