Interplay of TGFβ signaling and microRNA in thyroid cell loss of differentiation and cancer progression

ABSTRACT Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogene-modulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network – thus establishing a new layer of regulation. In this context, TGFβ signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition, cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFβ. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.

摘要：近二十年来，人类群体中甲状腺癌的患病率持续快速攀升，是目前最为常见的内分泌恶性肿瘤。总体而言，甲状腺癌患者的长期生存率较为可观，但仍有小部分患者预后不良。甲状腺癌的侵袭性本质上与甲状腺滤泡细胞的分化缺失及转移密切相关。此类驱动甲状腺癌发生的癌基因（如RET、RAS与BRAF）均隶属于MAPK/ERK信号通路（MAPK/ERK pathway），这一发现为甲状腺肿瘤发生机制的研究带来了全新视角。后续对其他癌基因调控信号通路的解析，揭示了一套复杂且活跃的信号串扰网络。在此类信号串扰中，作为一类小型非编码RNA的微小RNA（microRNAs），可通过调控致癌网络中的多种组分拓展该串扰的范围，由此构建了一层全新的调控层级。在此背景下，转化生长因子β（TGFβ）信号通路在癌症发生中发挥双重作用：既可对正常甲状腺滤泡细胞产生抗有丝分裂效应，又能在癌细胞中促进上皮间质转化（epithelial-to-mesenchymal transition）、细胞迁移与侵袭。本综述旨在探讨微小RNA如何通过调控转化生长因子β的双重功能，进而影响甲状腺滤泡细胞的分化缺失以及甲状腺癌侵袭性的增强。本综述为未来相关研究指明了方向，以期推动可改善侵袭性甲状腺癌治疗效果的新型诊疗策略与分子手段的开发。