Two Cancer Genes Pull in Opposite Directions in Papillary Thyroid Tumors

Papillary thyroid cancer is the most common form of thyroid malignancy, and although most patients respond well to surgery and have excellent long-term survival, a meaningful minority develop tumors that behave far more aggressively, invading surrounding tissues, spreading to lymph nodes, and resisting standard therapy. The central challenge for researchers has long been to identify molecular signals that distinguish the indolent tumors from the dangerous ones before the difference becomes clinically obvious. A new study from researchers at Kahramanmaras Sutcu Imam University in Turkey, published in BMC Endocrine Disorders, adds an intriguing piece to that puzzle by examining two genes with very different reputations in cancer biology: EGFR, the epidermal growth factor receptor, and GLI1, the downstream effector of the Hedgehog signaling pathway.

The research team, led by pathologists Beyza Erbagci and Rabia Hursitoglu together with biochemist Hasan Dagli, measured the expression of both genes in formalin-fixed, paraffin-embedded tumor tissue from 125 patients with papillary thyroid cancer. In 33 of those cases, the investigators also had access to peritumoral, non-tumoral thyroid tissue from the same patients, which served as matched control samples. Using quantitative real-time reverse transcription polymerase chain reaction, a technique that amplifies and quantifies specific messenger RNA sequences, they compared gene expression levels between tumor and healthy tissue and then searched for relationships between those levels and a battery of clinicopathological parameters, including tumor size, lymph node metastasis, lymphovascular invasion, perineural invasion, extrathyroidal extension, and tumor stage.

The first headline finding concerns what happens to the two genes inside the tumor itself. Both EGFR and GLI1 were upregulated in tumor tissue relative to the adjacent non-tumoral thyroid, confirming that these pathways are active in papillary thyroid cancer. But the more striking result was the relationship between them: rather than rising and falling together, as one might expect if the two genes were part of a single coordinated program, their expression levels showed a significant inverse correlation, with a correlation coefficient of minus 0.589 and a p-value below 0.001. In plain terms, tumors that expressed high levels of EGFR tended to express low levels of GLI1, and vice versa. That statistical signature suggests the two pathways may occupy opposing or mutually exclusive positions within the biology of these tumors, a pattern that could reflect distinct tumor subtypes or competing signaling circuits.

To understand why that inverse relationship matters, it helps to recall what each gene does. EGFR sits on the cell surface and, when activated by its ligands, triggers cascades such as RAS-MAPK and PI3K-AKT that promote cell proliferation, survival, and migration. It is a famous oncogene, amplified or mutated in many cancers, and the target of approved drugs in lung cancer and colorectal cancer. GLI1, by contrast, is a transcription factor, a protein that binds DNA and switches other genes on. It is the terminal effector of the Hedgehog pathway, an embryonic developmental program that is normally silenced in adult tissue but can be reawakened in cancer. When the pathway is active, the membrane protein Smoothened relieves inhibition of GLI proteins, allowing GLI1 to enter the nucleus and drive transcription of genes involved in cell cycle progression, stemness, and epithelial-mesenchymal transition, the process by which cancer cells acquire the mobility needed to invade and metastasize. Previous work has linked Hedgehog pathway activity to poor clinical outcomes in papillary thyroid cancer, which is precisely why the Turkish team wanted to test GLI1 as a potential marker of aggressive disease.

When the researchers cross-referenced expression levels with clinical and pathological features, the results were more restrained than the correlation finding. For most of the parameters they examined, neither EGFR nor GLI1 showed a statistically significant association. EGFR, in particular, proved disappointing as a marker: receiver operating characteristic analysis, a standard method for evaluating how well a continuous measurement discriminates between two clinical groups, showed that EGFR expression had limited performance across all the parameters tested. In other words, knowing how much EGFR messenger RNA a tumor expressed did not meaningfully help predict whether that tumor had spread to lymph nodes, invaded vessels, or extended beyond the thyroid capsule.

GLI1 told a more interesting story. While it too failed to correlate with most clinicopathological variables, it was significantly associated with one of them: microscopic extrathyroidal extension, the finding of tumor cells breaching the thyroid capsule on histological examination. This feature, reported with a p-value of 0.010, matters clinically because extrathyroidal extension is incorporated into staging systems such as the American Joint Committee on Cancer tumor-node-metastasis classification and is known to influence recurrence risk and management decisions. Beyond the single association, the ROC analysis suggested that GLI1 expression may carry discriminatory value for aggressive clinicopathological features more broadly, even though the authors characterize that ability as modest.

The authors are careful about what these results do and do not establish. Their conclusion, as stated in the paper, is that GLI1, as a key effector of the Hedgehog pathway, showed modest discriminatory ability for features associated with tumor aggressiveness in papillary thyroid cancer, and that further research is warranted to explore its therapeutic implications. That phrasing reflects a common and honest pattern in biomarker research: a gene may be biologically active and statistically interesting without being, on its own, a clinically decisive test. A single messenger RNA measurement in a heterogeneous tumor rarely captures the full complexity of pathway activation, which can depend on protein localization, ligand availability, and interactions with other signaling networks.

Nevertheless, the inverse correlation between EGFR and GLI1 is the kind of finding that can shape future hypotheses. One possibility raised by the broader literature is crosstalk between growth factor signaling and developmental pathways: in several cancer types, EGFR signaling and Hedgehog signaling have been shown to interact, sometimes cooperatively and sometimes antagonistically, depending on cellular context. If the two pathways indeed occupy alternative states in papillary thyroid cancer, tumors might be classifiable into molecular subgroups with different dependencies, and those subgroups could respond differently to targeted therapies. Hedgehog pathway inhibitors, such as smoothened antagonists already approved for basal cell carcinoma, have been explored in various malignancies, and the new data provide a rationale for asking whether a subset of thyroid tumors defined by high GLI1 expression might be candidates for such approaches.

The study also demonstrates the practical value of archival tissue. Because the investigators used formalin-fixed, paraffin-embedded samples, the standard medium of hospital pathology laboratories, their approach could be replicated in other institutions without prospective tissue collection, and the retrospective design allowed the ethics committee to waive individual informed consent given the use of anonymized archival material. The work was supported by the Scientific Research Projects Coordination Unit of Kahramanmaras Sutcu Imam University, and the authors declare no competing interests. The sample size of 125 tumors is respectable for a single-center molecular pathology study, though the 33 matched controls represent a smaller subset, and the authors’ statistical honesty about which associations reached significance and which did not is a model of careful reporting.

For patients and clinicians, the immediate takeaway is not a new test but a sharpened question. Papillary thyroid cancer is usually curable, yet the small fraction of aggressive tumors drives most of the morbidity and mortality, and the field still lacks reliable molecular tools to flag them early. This study strengthens the case that the Hedgehog pathway, acting through GLI1, participates in the biology of tumor invasion in the thyroid, while simultaneously tempering expectations about EGFR as a prognostic marker in this disease. The next steps, as the authors indicate, lie in larger and ideally prospective cohorts, in protein-level validation by immunohistochemistry, and in functional experiments that test whether manipulating GLI1 or EGFR in thyroid cancer cells changes invasive behavior. If those lines of evidence converge, the opposing expression pattern documented here could evolve from a statistical curiosity into a genuine handle on the most dangerous forms of a common cancer.

Subject of Research: EGFR and GLI1 gene expression and their association with clinicopathological features in papillary thyroid cancer

Article Title: Association of EGFR and GLI1 gene expression with clinicopathological features in papillary thyroid cancer

Article References: Erbagci, B., Hursitoglu, R., & Dagli, H. (2026). Association of EGFR and GLI1 gene expression with clinicopathological features in papillary thyroid cancer. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02556-9

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02556-9

Keywords: papillary thyroid cancer, EGFR, GLI1, Hedgehog signaling, gene expression, biomarker, extrathyroidal extension, ROC analysis, qRT-PCR, thyroid tumor aggressiveness, oncogene, transcription factor