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ADAMTS8 is frequently down-regulated in colorectal cancer and functions as a tumor suppressor
Lin Li1, Shiyun Yuan1, Xunping Zhao1
1Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
Abstract:
Colorectal cancer (CRC) is known for being a great threat to human health due to its high incidence and mortality. ADAMTS8 that belongs to the zinc metalloproteinases family acts as a tumor suppressor and is silenced by CpG methylation in several carcinomas through previous studies, but its functions in CRC remain unknown. In this report, we analyzed its expression in CRC cell lines and primary CRC tumor tissues. The results showed that ADAMTS8 was significantly down-regulated in CRC cell lines and primary tumor tissues and its expression was restored in Lovo cell lines with treatment DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine and TSA. Over-expression of ADAMTS8 in HCT116 and HT-29 resulted in inhibited cell proliferation and induced apoptosis. We also observed that ADAMTS8 suppressed cell invasion and migration. In addition, ADAMTS8 induced cell cycle arrest in G2/M phase. Furthermore, we found that ADAMTS8 led to the decrease of BCL-XL, phospho-GSK3β, β-catenin and c-myc as well as increase of cleaved caspase-9, Bax and PARP. Our findings suggest that ADAMTS8 may be considered as a functional tumor suppressor gene in CRC and has the potential to be developed as a valuable biomarker.
Insights
ADAMTS8 functions as a tumor suppressor in colorectal cancer (CRC). Silenced by methylation, its restoration inhibits CRC cell proliferation, invasion, and migration, offering potential as a biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancer (CRC) presents a significant global health challenge due to high incidence and mortality.
- ADAMTS8, a zinc metalloproteinase, is a known tumor suppressor silenced by CpG methylation in various cancers, but its role in CRC is uncharacterized.
Purpose of the Study:
- To investigate the expression and function of ADAMTS8 in colorectal cancer.
- To determine if ADAMTS8 acts as a tumor suppressor in CRC and explore its potential as a biomarker.
Main Methods:
- Analysis of ADAMTS8 expression in CRC cell lines and primary tumor tissues.
- Assessment of ADAMTS8 restoration via DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine) and TSA treatment.
- Evaluation of ADAMTS8's effects on cell proliferation, apoptosis, invasion, migration, and cell cycle progression.
- Western blot analysis to examine key protein expression changes (BCL-XL, GSK3β, β-catenin, c-myc, caspase-9, Bax, PARP).
Main Results:
- ADAMTS8 expression was significantly down-regulated in CRC cell lines and primary tumor tissues.
- Restoration of ADAMTS8 expression was achieved using 5-aza-2'-deoxycytidine and TSA.
- Over-expression of ADAMTS8 inhibited cell proliferation, induced apoptosis, suppressed invasion and migration, and caused G2/M cell cycle arrest.
- ADAMTS8 modulated the expression of proteins involved in apoptosis and cell cycle regulation, including decreased BCL-XL, phospho-GSK3β, β-catenin, c-myc, and increased cleaved caspase-9, Bax, and PARP.
Conclusions:
- ADAMTS8 functions as a tumor suppressor gene in colorectal cancer.
- The findings suggest ADAMTS8's potential as a valuable biomarker for CRC diagnosis and therapy.
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