PAX8 is a protein that plays a role in regulating genes, acting as a master controller for the development and function of certain organs. It is part of the PAX gene family, which provides instructions for making proteins that attach to specific areas of DNA. By binding to these regions, PAX8 helps to control which genes are turned on or off, influencing various biological processes in the body.
PAX8’s Role in Healthy Organs
PAX8 contributes to the formation and function of several organs. As a transcription factor, it regulates gene expression, which is important during embryonic development and for cellular function.
The thyroid gland relies on PAX8 for its formation and thyroid hormone production. PAX8 helps differentiate thyroid follicular cells and express thyroid-specific genes like thyroglobulin, thyroperoxidase, and the sodium/iodide symporter (NIS), all crucial for hormone synthesis. Without PAX8, the thyroid gland can be unusually small or absent, impacting growth, brain development, and metabolism.
PAX8 also plays a role in kidney development. While not solely necessary, it cooperates with other PAX genes, such as PAX2, to ensure proper kidney development, including the formation of nephrons and collecting ducts.
In the female reproductive tract, specifically the Müllerian system, PAX8 contributes to the development of structures like the fallopian tubes, uterus, and upper vagina. It remains expressed in adult tissues such as the fallopian tube and uterine epithelium.
PAX8 and Thyroid Gland Disorders
PAX8 is connected to health issues affecting the thyroid gland, particularly cancer. Its expression is often used as a diagnostic tool for identifying thyroid cancers.
PAX8 expression is observed in thyroid cancers, including papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), with high positivity rates. This makes PAX8 a useful marker for distinguishing thyroid cancers from other head and neck tumors, even challenging cases like undifferentiated or anaplastic thyroid carcinoma. Immunohistochemical staining for PAX8 can help confirm their thyroid origin.
Alterations in the PAX8 gene or protein can contribute to thyroid cancer development. For instance, the PAX8-PPARγ fusion is found in 30-35% of FTCs and some follicular variant papillary thyroid carcinomas. This fusion results from a translocation between chromosomes 2 and 3, creating a new protein that promotes cell growth and reduces programmed cell death, leading to tumor development.
PAX8 mutations can also lead to congenital hypothyroidism, a condition with abnormally low thyroid hormone levels. These mutations often disrupt the PAX8 protein’s ability to bind DNA or interact with other transcription factors, impairing its role in regulating thyroid hormone production. This can result in an unusually small thyroid gland or impaired thyroid function. Some individuals with PAX8 mutations may have a normal-sized thyroid gland but still experience functional defects.
PAX8 in Other Diseases
Beyond the thyroid, PAX8 is implicated in other health conditions, extending its importance to several organ systems.
PAX8 is expressed in certain types of ovarian cancer, such as high-grade serous carcinoma, detected in 80-99% of cases. This makes PAX8 a useful diagnostic marker for distinguishing ovarian cancers, particularly those of Müllerian origin, from other malignancies like breast carcinoma or gastrointestinal tumors.
In kidney disorders, PAX8 is found in certain kidney cancers, including renal cell carcinoma (RCC). It is expressed in 80-100% of RCCs, depending on the subtype, and is a useful diagnostic marker for these tumors. PAX8 is also linked to congenital kidney anomalies, such as renal hypoplasia, where the kidney is underdeveloped.
PAX8 expression has been noted in a limited number of other cancers. For instance, it can be found in some urothelial neoplasms, with positivity rates ranging from 2% to 24%. While its role is most clearly defined in thyroid and ovarian health, its involvement in these additional conditions highlights its broader influence.