Bera Alakesh, Radhakrishnan Surya, Puthillathu Narayanan, Subramanian Madhan, Gana Nahbuma, Russ Eric, Pollard Harvey B, Srivastava Meera
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Int J Mol Sci. 2024 Dec 9;25(23):13217. doi: 10.3390/ijms252313217.
Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7/p21/BRAF/MAPK/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer.
甲状腺癌是美国最常见的内分泌恶性肿瘤，总体预后良好。然而，一些患者由于对传统疗法产生耐药性而预后不佳。基因改变，包括BRAF、Met和p53的突变，在甲状腺癌进展中起关键作用，超过60%的病例检测到BRAF V600E突变。本研究调查了膜联蛋白A7（ANXA7）在甲状腺癌中的肿瘤抑制作用，重点关注其对肿瘤行为和治疗反应的潜在影响。我们的分析包括RNA测序和蛋白质分析，结果显示甲状腺癌细胞中ANXA7表达降低，尤其是那些携带BRAF V600E突变的细胞。在用靶向BRAF和MEK的抑制剂治疗后，ANXA7表达增加，导致ERK磷酸化减少和凋亡途径激活。此外，我们确定细胞周期蛋白依赖性激酶抑制剂p21是调节对BRAF抑制剂耐药性的关键因子。旨在同时提高p21和ANXA7水平的联合疗法导致凋亡显著增强。这些发现表明存在一个以前未被描述的涉及ANXA7/p21/BRAF/MAPK/p53轴的调控网络，这可能导致甲状腺癌的耐药性。本研究为克服对BRAF和MAPK抑制剂的耐药性提供了新的见解，对治疗甲状腺癌以及潜在的其他BRAF突变肿瘤具有重要意义。未来的工作将集中在高通量筛选方法上，以探索针对甲状腺癌的ANXA7靶向治疗策略。
