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Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells
Soyoung Park1, Cen Li1, Hong Zhao1,2
1Department of Pathology, School of Medicine, New York Medical College, Valhalla, NY, USA.
Abstract:
Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2B lung epithelial cells. The inhibition also occurs in A549 lung bronchial carcinoma cells. Cr(VI) suppresses Gene 33 expression mainly through post-transcriptional mechanisms, although the mRNA level of gene 33 also tends to be lower upon Cr(VI) treatments. Cr(VI)-induced DNA damage appears primarily in the S phases of the cell cycle despite the high basal DNA damage signals at the G2M phase. Knockdown of Gene 33 with siRNA significantly elevates Cr(VI)-induced DNA damage in both BEAS-2B and A549 cells. Depletion of Gene 33 also promotes Cr(VI)-induced micronucleus (MN) formation and cell transformation in BEAS-2B cells. Our results reveal a novel function of Gene 33 in Cr(VI)-induced DNA damage and lung epithelial cell transformation. We propose that in addition to its role in the canonical EGFR signaling pathway and other signaling pathways, Gene 33 may also inhibit Cr(VI)-induced lung carcinogenesis by reducing DNA damage triggered by Cr(VI).
Insights
Hexavalent chromium (Cr(VI)) suppresses Gene 33 protein, a key player in lung cancer. Lowering Gene 33 levels increases Cr(VI)-induced DNA damage and cell transformation, revealing its protective role.
Area of Science:
- Environmental Health
- Molecular Carcinogenesis
- Cell Biology
Background:
- Hexavalent chromium (Cr(VI)) is a known human lung carcinogen.
- The molecular mechanisms underlying Cr(VI) carcinogenesis are not fully understood.
- Gene 33 (ERRFI1, Mig6) is a multifunctional adaptor protein with potential roles in cancer signaling.
Purpose of the Study:
- To investigate the role of Gene 33 in Cr(VI)-mediated lung carcinogenesis.
- To determine how Cr(VI) affects Gene 33 expression and function.
- To explore Gene 33's impact on Cr(VI)-induced DNA damage and cell transformation.
Main Methods:
- Treatment of lung epithelial (BEAS-2B) and carcinoma (A549) cells with Cr(VI).
- Assessment of Gene 33 protein and mRNA levels.
- Analysis of cell cycle progression and DNA damage (e.g., micronucleus formation).
- Gene 33 knockdown using siRNA.
Main Results:
- Cr(VI) treatment suppressed Gene 33 protein levels in a dose- and time-dependent manner, primarily via post-transcriptional mechanisms.
- Cr(VI)-induced DNA damage was observed, particularly in S-phase cells.
- Gene 33 knockdown significantly enhanced Cr(VI)-induced DNA damage, micronucleus formation, and cell transformation.
Conclusions:
- Gene 33 plays a novel role in mitigating Cr(VI)-induced DNA damage and lung epithelial cell transformation.
- Gene 33 may act as a tumor suppressor against Cr(VI) carcinogenicity by reducing DNA damage.
- These findings highlight Gene 33 as a potential target for preventing or treating Cr(VI)-related lung cancer.
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