Interview – Dr Camille Buffet
An update on oxidative stress in thyroid carcinomas
A group of French researchers, led by Corinne Dupuy at the Gustave Roussy and Paris Sud University, has written a new review on the biological and clinical significance of oxidative stress in thyroid carcinomas.
In this interview with Endocrine-Related Cancer, author Camille Buffet answers some questions about her team’s work and the findings of the review:
ERC: Can you elaborate on what’s new in this field, and what you feel are the key take home messages of your review?
Dr Buffet: This review highlights the role of oxidative stress in thyroid tumourigenesis and recent advances in this field. Both ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis. They upregulate the expression of enzymes specialized in oxygen metabolites production (the so-called ROS or ‘reactive oxygen species’): the NADPH oxidases DUOX1 in the case of ionizing radiation and NOX4 in the case of BRAF or RAS mutated-cancers. DUOX1- and NOX4-derived ROS production will result in oxidative DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation of thyroid cancers.
ERC: Why have you chosen to specifically focus on the role of ROS in the thyroid?
Dr Buffet: ROS production, especially hydrogen peroxide, is of considerable importance for the endocrine function of the thyroid gland. Thyroid cells have the challenge to tightly control intracellular oxidative stress levels i.e. the equilibrium between ROS production and anti-oxidant defense systems. Previous evidence highlighting that oxidative stress through ROS production can cause the formation of oxidative DNA damage, which is in turn an initial step of tumorigenesis, led our team to focus on the role of ROS in thyroid specifically. Moreover, ROS through DNA damage may alter the expression of different genes important for thyroid function and differentiation, in particular the expression of the sodium iodide symporter (NIS). As the NIS controls the input of iodine into thyroid cells, which represents the rational for radioiodine treatment of patients with thyroid cancer, it is of considerable importance to understand the role of ROS in thyroid tumorigenesis and dedifferentiation.
ERC: Briefly, what role does oxidative stress have in thyroid carcinomas?
Dr Buffet: First, from a clinical point of view, it is well known that the thyroid gland is one of the most sensitive organs to the carcinogenic effects of ionizing radiation. More than 90% of thyroid cancers are papillary tumours, which present with a RET/PTC chromosomal rearrangement.
In vitro, ionizing radiation of thyroid cells leads to a first wave of temporary oxidative stress followed by a second persistent oxidative stress mediated by DUOX1 upregulation. The overexpression of DUOX1, and the ROS subsequently produced, may contribute to chronic oxidative stress, thereby promoting genomic instability, which may result in oncogenic translocation such as RET/PTC and thus tumourigenesis.
Second, the ROS-producing specialized enzyme NOX4 is overexpressed in thyroid cancers, particularly in BRAFV600E-mutated papillary thyroid cancers which are the most frequent thyroid malignant tumors. Our team has demonstrated that NOX4 is upregulated by BRAFV600E via the activation of the TGF-β-Smad3 pathway in thyroid cancer cells. Interestingly, NOX4 overexpression correlates with dedifferentiation of human thyroid cancers and decrease in the NIS expression. The reversible repression of the NIS suggests that an epigenetic mechanism, which may be redox-sensitive, could be involved.
ERC: Did you identify any potential novel avenues for research following this review of the literature?
Dr Buffet: There are many potential novel avenues in the field, including:
- Is there a role for chronic oxidative stress in the occurrence of BRAFV600E mutations?
- Is the increase of NOX4 expression in papillary thyroid cancers a cause or a consequence of dedifferentiation?
- Beyond NIS expression, is there a role for ROS in NIS cellular trafficking, knowing that NIS must be properly addressed to the plasma membrane to mediate effective iodine uptake?
ERC: How does your current research fit with the content of this review?
Dr Buffet: Our focus is currently bidirectional. On the one hand we are looking into the specific epigenetic mechanisms controlling NIS expression under the control of NOX4, following ROS-mediated oxidative DNA damage. On the other hand, we study how DUOX1 is involved in thyroid radiocarcinogenesis and, in particular, what is its potential role in DNA break formation at chromosomal fragile sites, which are hotspots for chromosomal translocations such as RET/PTC.
Read the article in full:
Oxidative stress in thyroid carcinomas: biological and clinical significance. Rabii Ameziane El Hassani, Camille Buffet, Sophie Leboulleux and Corinne Dupuy.