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Published on: July 28, 2010
Breast cancer susceptibility gene 1 regulates oxidative damage via nuclear factor erythroid 2-related factor 2 in
Xiaofei Yu1, Yao Liu2, Keqing Pan3
1Beijing Stomatological Hospital, Capital Medical University, Tiantanxili No 4#, Dongcheng District, Beijing 100050, China; Department of Stomatology, The Affiliated Hospital of Qingdao University, No.1677 Wutaishan Road, Huangdao District, Qingdao, Shandong 266000, China.
Objective:
To determine whether the breast cancer susceptibility gene 1 (BRCA1) regulates oxidative damage in oral cancer cells by interacting with nuclear factor erythroid 2-like 2 (NRF2).
Design:
The BRCA1 gene was silenced in CAL-27 and DOK cells using specific shRNA, and NRF2 was activated with sulforaphane. The expression levels of BRCA1, NRF2 and its target genes were assessed by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8 assay was used to detect cell proliferation, apoptosis was detected by flow cytometry, and 8-OXo-2'-deoxyguanosine level was measured by enzyme-linked immunosorbent assay. The expression of BRCA1 and NRF2 in patients with oral leukoplakia and oral squamous cell carcinoma were evaluated by immunohistochemistry.
Results:
BRCA1 knockdown downregulated NRF2 and its target genes, increased proliferation rates, reduced apoptosis, and increased 8-OXo-2'-deoxyguanosine levels compared to the control. Activation of NRF2 by sulforaphane significantly upregulated NRF2 levels in the BRCA1-depleted cells, and restored proliferation, apoptosis and 8-OXo-2'-deoxyguanosine level in a dose-dependent manner. Compared with patients with leukoplakia, BRCA1 and NRF2 expression were increased in patients with oral squamous cell carcinoma.
Conclusions:
BRCA1 depletion increases oxidative damage and promotes the malignant phenotype, which may eventually promote oral carcinogenesis. The NRF2-activator sulforaphane is a potential chemo-preventive agent for oral cancer.
Insights
Breast cancer susceptibility gene 1 (BRCA1) depletion in oral cancer cells increases oxidative damage and promotes malignancy. Nuclear factor erythroid 2-like 2 (NRF2) activation with sulforaphane may offer chemo-prevention for oral cancer.
Area of Science:
- Oncology
- Molecular Biology
- Oxidative Stress Research
Background:
- Oxidative damage plays a critical role in oral carcinogenesis.
- The interplay between BRCA1 and NRF2 in oral cancer pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the regulatory role of BRCA1 in oxidative damage within oral cancer cells.
- To explore the interaction between BRCA1 and NRF2 in the context of oral cancer.
Main Methods:
- BRCA1 gene silencing and NRF2 activation using sulforaphane in oral cancer cell lines (CAL-27, DOK).
- Quantitative real-time PCR and western blotting to assess gene expression.
- Cell counting kit-8 assay, flow cytometry, and ELISA to evaluate cell proliferation, apoptosis, and oxidative damage (8-OXo-2'-deoxyguanosine).
- Immunohistochemistry to analyze BRCA1 and NRF2 expression in patient samples.
Main Results:
- BRCA1 knockdown led to decreased NRF2 expression, increased cell proliferation, reduced apoptosis, and elevated oxidative damage.
- Sulforaphane treatment upregulated NRF2 and restored normal levels of proliferation, apoptosis, and oxidative damage in BRCA1-depleted cells.
- Elevated BRCA1 and NRF2 expression was observed in oral squamous cell carcinoma patients compared to those with leukoplakia.
Conclusions:
- BRCA1 depletion exacerbates oxidative damage and promotes a malignant phenotype, potentially driving oral carcinogenesis.
- NRF2 activation via sulforaphane presents a promising strategy for oral cancer chemoprevention.
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