Paired Box Gene 8 (PAX8) is part of the PAX family of transcription factors, genes that guide the formation of tissues and organs during embryonic development. Like all genes, the proper function of PAX8 is important for health, and alterations can lead to various medical conditions.
Understanding PAX8 Gene’s Role in Development
The PAX8 gene directs the creation of a protein that functions as a transcription factor. This protein binds to specific DNA regions to control other genes, turning them “on” or “off” at precise times. This regulatory function is especially important during embryonic development for the formation of tissues and organs.
PAX8’s influence is most pronounced in developing the thyroid gland, kidneys, and Müllerian system. In the thyroid, it guides the formation of follicular cells, which produce hormones that regulate metabolism, growth, and brain development. The gene also works with other transcription factors to activate genes for thyroid proteins like thyroglobulin and thyroperoxidase.
PAX8 is also active in early kidney formation, helping specify the initial renal cells. In the developing female reproductive tract, or Müllerian system, PAX8 contributes to structures that become the fallopian tubes, uterus, and endocervix. Its expression in these tissues highlights its targeted role in organ formation.
Health Implications of PAX8 Gene Alterations
Mutations in the PAX8 gene compromise its ability to regulate other genes, leading to health conditions present from birth. These alterations can change the PAX8 protein’s structure, disrupt its production, or prevent it from binding to DNA. The consequences primarily affect the thyroid gland and urinary system.
A documented outcome of PAX8 mutations is congenital hypothyroidism, a condition of insufficient thyroid hormone production from birth. The gene’s disruption impairs thyroid gland development, often resulting in an abnormally small or underdeveloped gland (thyroid dysgenesis). Without proper regulation by the PAX8 protein, the gland cannot function correctly, leading to developmental issues if untreated.
PAX8 gene alterations are also associated with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). These can manifest as structural problems like underdeveloped kidneys (renal hypoplasia) or the absence of a kidney (renal agenesis). In females, PAX8 mutations are also linked to anomalies in the reproductive tract. Genetic testing is often used to detect pathogenic PAX8 variants in individuals with these congenital anomalies.
The PAX8 Gene’s Significance in Cancer
In oncology, the PAX8 gene is a tool for cancer diagnosis. While the PAX8 protein is absent from most adult organs, its expression is retained in cells of the thyroid, kidney, and Müllerian-derived tissues. Pathologists use this specific expression as an immunohistochemical marker, detecting the protein in tumor samples with antibodies to help identify a cancer’s origin.
This application helps determine the primary site of metastatic cancers, where cells have spread from their original location. For example, if a tumor is found in the lung, staining for PAX8 can reveal if it is a metastasis from a PAX8-positive cancer. PAX8 is highly expressed in most thyroid carcinomas, renal cell carcinomas, and many ovarian and endometrial carcinomas, making it a reliable marker.
PAX8 is expressed in about 90% of thyroid and renal cell carcinomas, nearly all non-mucinous ovarian cancers, and most endometrial cancers. Because PAX8 is absent in breast, lung, colon, and stomach cancers, it is effective for distinguishing between tumor types. Research also investigates PAX8’s direct role in cancer development, such as chromosomal rearrangements that create a PAX8-PPARγ fusion protein in some follicular thyroid cancers.
Advancements in PAX8 Gene Research
Ongoing research continues to uncover the complex functions of the PAX8 gene. In cancer research, the focus is shifting from its diagnostic use to its role as a potential oncogene—a gene that can drive cancer progression—in renal and ovarian cancers. Studies show that silencing PAX8 in renal cell carcinoma cell lines decreases proliferation, suggesting these cancer cells depend on it for growth. This dependency makes PAX8 a potential therapeutic target.
A primary challenge is developing drugs to inhibit transcription factors like PAX8, which are historically difficult to target. Research is exploring innovative approaches, such as targeting other proteins required for PAX8 production. Other studies examine the interaction between PAX8 and SOX17, a transcription factor that promotes blood vessel growth in ovarian tumors. Developing small molecules to disrupt this interaction could offer a new way to halt tumor growth.