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Published on: July 20, 2019
Reduced Fhit protein expression in nickel-transformed mouse cells and in nickel-induced murine sarcomas
Renata Kowara1, Konstantin Salnikow, Bhalchandra A Diwan
1Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA.
Abstract:
Nickel compounds are carcinogenic and induce malignant transformation of cultured cells. Since nickel has low mutagenic potential, it may act predominantly through epigenetic mechanisms, including down-regulation of tumor suppressor genes. FHIT is a tumor suppressor gene whose expression is frequently reduced or lost in tumors and pre-malignant lesions. Previously, we have shown that the phosphohydrolase activity of Fhit protein, associated with its tumor suppressor action, is inhibited by nickel. In cells, such effect would assist in carcinogenesis. The latter could be further enhanced if nickel also lowered cellular levels of Fhit protein itself, e.g. by down-regulation of FHIT gene. To test this possibility, we determined Fhit protein and Fhit-mRNA levels in a nickel-transformed mouse cell line and in nickel-induced murine sarcomas. In B200 cells, derived by nickel treatment of BALB/c-3T3 cells and exhibiting a malignant phenotype, Fhit protein levels were 50% of those in the parental cells, while Fhit-mRNA expression remained unchanged. A decrease of up to > 90% in Fhit protein levels was also observed in 22 local sarcomas (mostly fibrosarcomas) induced by i.m. injection of nickel subsulfide in C57BL/6 and MT+ (C57BL/6 overexpressing metallothionein) mice, as compared with normal muscles. Moreover, Fhit was absent in 3 out of 10 sarcomas from MT+ mice and in 1 of 12 sarcomas from C57BL/6 mice. The lack of Fhit protein coincided with the absence of the Fhit-mRNA transcript in these tumors. However, in the other tumors, the decreased Fhit levels were not always accompanied by reduced expression of Fhit-mRNA. Thus, the observed lowering of Fhit protein levels is mostly associated with changes in mRNA expression and protein translation or turnover rates, and rarely with a full silencing of the gene itself. Overall, the decline of Fhit in cells or tissues malignantly transformed by nickel may indicate possible involvement of this effect in the mechanisms of nickel carcinogenesis.
Insights
Nickel exposure reduces Fhit protein levels, a key tumor suppressor, in nickel-transformed cells and tumors. This decline, often without gene silencing, may contribute to nickel-induced carcinogenesis through epigenetic mechanisms.
Area of Science:
- Oncology
- Environmental Toxicology
- Molecular Biology
Background:
- Nickel compounds are carcinogenic, potentially acting via epigenetic mechanisms like tumor suppressor gene down-regulation.
- FHIT (Fragile Histidine Triad) is a tumor suppressor gene frequently lost in cancers.
- Nickel inhibits Fhit protein's phosphohydrolase activity, a function linked to tumor suppression.
Purpose of the Study:
- To investigate if nickel exposure lowers Fhit protein levels.
- To determine if nickel down-regulates FHIT gene expression.
- To explore the role of Fhit protein decline in nickel carcinogenesis.
Main Methods:
- Assessed Fhit protein and Fhit-mRNA levels in nickel-transformed mouse cell line (B200).
- Quantified Fhit protein and Fhit-mRNA in nickel-induced murine sarcomas (fibrosarcomas).
- Compared Fhit levels in nickel-exposed cells/tissues with controls (parental cells, normal muscle).
Main Results:
- Fhit protein levels were reduced by 50% in nickel-transformed B200 cells; Fhit-mRNA was unchanged.
- Fhit protein levels decreased by over 90% in nickel-induced sarcomas compared to normal muscle.
- Fhit protein loss sometimes coincided with absent Fhit-mRNA, but often occurred independently of gene expression changes, suggesting post-transcriptional regulation.
Conclusions:
- Nickel exposure leads to decreased Fhit protein levels in transformed cells and tumors.
- The reduction in Fhit protein, primarily through post-transcriptional mechanisms, may contribute to nickel carcinogenesis.
- Targeting Fhit protein levels could be a strategy in combating nickel-induced cancers.
