Role of Annexin 7 (ANXA7) as a tumor suppressor and a regulator of drug resistance in thyroid cancer

Abstract

Thyroid cancer ranks as the predominant endocrine malignancy in the United States, boasting a generally favorable prognosis. However, a subset of patients faces a grim outlook due to the emergence of drug resistance. The progression and aggressiveness of thyroid cancer have been linked to the differential expression and mutation of key genes such as BRAF, Met, and p53, with the V600E mutation in BRAF present in over 60% of cases. ANXA7, a versatile protein with tumor-suppressive properties observed across various cancers, warrants attention concerning its role in thyroid cancer. Our investigation delved into the interplay between ANXA7 expression, BRAF mutation, and their impact on disease progression, aggressiveness, and drug response. High-throughput RNA-seq and protein array analyses revealed diminished ANXA7 expression in thyroid cancer, particularly in cell lines harboring the BRAF mutation. Treatment of thyroid cancer cells with BRAF and MEK inhibitors led to upregulated ANXA7 expression, decreased Ph-ERK levels, and increased apoptotic markers. Notably, our findings unveiled the cyclin-dependent kinase inhibitor p21 as a novel regulator of BRAF-mediated chemoresistance. Combining drugs to elevate both p21 and ANXA7 levels synergistically enhanced apoptotic signaling. These discoveries shed light on a novel pathway implicated in thyroid malignancy and drug resistance, involving the ANXA7/p21/BRAF/MAPK axis. Our study marks the first elucidation of this pathway, offering promising insights into overcoming resistance to BRAF or MAPK-targeting drugs into treatment of thyroid cancer or even BRAF mutation mediated melanoma. Future translational endeavors, leveraging high-throughput functional screenings, are imperative for developing innovative ANXA7-based therapeutic strategies tailored to thyroid cancer.