Identification of DPP4/CTNNB1/MET as a Theranostic Signature of Thyroid Cancer and Evaluation of the Therapeutic Potential of Sitagliptin

SIMPLE SUMMARY: In recent years, the incidence of thyroid cancer has been increasing globally, with papillary thyroid cancer (PTCa) being the most prevalent pathological type. Although PTCa has been regarded to be slow growing and has a good prognosis, in some cases, PTCa can be aggressive and progress despite surgery and radioactive iodine treatment. Therefore, searching for new targets and therapies is required. We utilized bioinformatics analyses to identify critical theranostic markers for PTCa. We found that DPP4/CTNNB1/MET is an oncogenic signature that is overexpressed in PTCa and associated with disease progression, distant metastasis, treatment resistance, immuno-evasive phenotypes, and poor clinical outcomes. Interestingly, our in silico molecular docking results revealed that sitagliptin, an antidiabetic drug, has strong affinities and potential for targeting DPP4/CTNNB1/MET signatures, even higher than standard inhibitors of these genes. Collectively, our findings suggest that sitagliptin could be repurposed for treating PTCa. ABSTRACT: In recent years, the incidence of thyroid cancer has been increasing globally, with papillary thyroid cancer (PTCa) being the most prevalent pathological type, accounting for approximately 80% of all cases. Although PTCa has been regarded to be slow growing and has a good prognosis, in some cases, PTCa can be aggressive and progress despite surgery and radioactive iodine treatment. In addition, most cancer treatment drugs have been shown to be cytotoxic and nonspecific to cancer cells, as they also affect normal cells and consequently cause harm to the body. Therefore, searching for new targets and therapies is required. Herein, we explored a bioinformatics analysis to identify important theranostic markers for THCA. Interestingly, we identified that the DPP4/CTNNB1/MET gene signature was overexpressed in PTCa, which, according to our analysis, is associated with immuno-invasive phenotypes, cancer progression, metastasis, resistance, and unfavorable clinical outcomes of thyroid cancer cohorts. Since most cancer drugs were shown to exhibit cytotoxicity and to be nonspecific, herein, we evaluated the anticancer effects of the antidiabetic drug sitagliptin, which was recently shown to possess anticancer activities, and is well tolerated and effective. Interestingly, our in silico molecular docking results exhibited putative binding affinities of sitagliptin with DPP4/CTNNB1/MET signatures, even higher than standard inhibitors of these genes. This suggests that sitagliptin is a potential THCA therapeutic, worthy of further investigation both in vitro and in vivo and in clinical settings.