Why Does Cancer Progress? Study Provides Insight

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Academic Journal
Main Category: Cancer / Oncology
Article Date: 24 Feb 2012 - 10:00 PST


According to the University of Kentucky, a study funded by a National Cancer Institute research grant and conducted by Dr. Daret St. Clair, the James Graham Brown Endowed Chair and professor of toxicology, provides new understanding into the association between two types of suppressors in cancerous tumors. Results from the study will help researchers to better understand transcriptional mechanisms in carcinogenesis.

The study was recently published in Cancer Research.

The researchers produced transgenic mice expressing a luciferase reporter gene controlled by human manganese superoxide dismutase (MnSOD) promoter-enhancer elements. The team then used the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model, in order to examine the changes of MnSOD transcription.

MnSOD is vital for aerobic life to survive, and its abnormal expression has been involved in tumor resistance to treatment as well as carcinogenesis. Even though studies have thoroughly investigated MnSOD regulation and the role it plays in cancer, researchers are unsure how and when the change of MsSOD expression takes place during the process of tumor development in vivo.

MnSOD expression was suppressed at an extremely early stage, according to results from the study, however the expression increased at late stages of skin carcinogenesis. The researchers found that two transcription factors, Sp1 and p53 mediated the suppression and subsequent restoration of MnSOD expression.

p53 was activated and decreased McSOD expression via p52-mediated suppression of Sp1 binding to the MnSOD promoter in normal looking skin and benign papillomas when exposed to DMBA and TPA. As a result of loss of functional p53, Sp1 binding increased in squamous cell carcinomas.

In order to confirm the roles of Sp1 and p53 in the expression of MnSOD at each stage of cancer development, the researchers used chromatin immunoprecipitation, electrophoretic mobility shift assay, as well as knockdown and overexpression of Sp1 and p53.

According to results from the study, MnSOD is a p53-controlled gene that alternates between early and late stages of cancer. In addition, these results could help to develop a way to reactivate p53 for the prevention of tumor progression.

St. Clair, who is also an associate director for basic research at the UK Markey Cancer Center, explained:

"This study reports a novel genetic model of skin cancer that reveals the importance of a linkage between an antioxidant enzyme, MnSOD, which plays an important role in survival, and the progression of cancer. In the future, developing a means to inhibit the enzyme MnSOD in advanced cancer may prevent resistance to cancer therapy."

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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