Xia Shujun, Ji Ri, Xu Yongmin, Ni Xiaofeng, Dong Yijie, Zhan Weiwei
Ultrasound Department, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Huang Pu District, Shanghai, 200025, P. R. of China.
Department of Spine Surgery, Yijishan Hospital, the First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, P. R. of China.
J Cancer. 2017 Aug 23;8(14):2816-2827. doi: 10.7150/jca.18482. eCollection 2017.
Bone morphogenetic proteins (BMPs) are growth factors that have important functions in cell proliferation, migration and differentiation. To date, BMP pathway activation has been found in multiple human tumors and is associated with enhanced malignant tumor growth and metastasis. BMP activity is tightly regulated by a family of soluble extracellular secreted BMP modulators. Twisted gastrulation BMP signaling modulator 1 (TWSG1) is a direct BMP regulator that is required for the full signaling activity of BMPs. However, the functions and mechanisms of TWSG1 in papillary thyroid cancer (PTC) metastasis have not been reported. TWSG1 expression was detected in 44 PTC tissues with lymph node metastasis (LNM) and 56 PTC tissues without LNM using quantitative real-time polymerase chain reaction (qRT-PCR). Gain- and loss-of-function approaches were used to assess the biological function of TWSG1 in PTC cells. Matrigel assays demonstrated the effect of tumor cell-derived TWSG1 on endothelial cell function. Our results showed that TWSG1 expression was significantly enhanced in PTC with LNM compared to that in PTC without LNM. TWSG1 knockdown inhibited migration, invasion and proliferation of PTC cells. Additionally, TWSG1 suppression impaired the tumor cell-induced endothelial cell sprout formation. We found that TWSG1 signaling may be transduced by the BMP target transcription factor inhibitor of DNA binding 1 (Id1) and matrix metalloproteinases (MMPs) 2 and 9. In conclusion, TWSG1 was highly expressed in metastasized PTC; tumor growth, migration and invasion were dependent on TWSG1, and it may be a new diagnostic and therapeutic target for PTC.
骨形态发生蛋白（BMPs）是在细胞增殖、迁移和分化中具有重要功能的生长因子。迄今为止，已在多种人类肿瘤中发现BMP信号通路激活，且其与恶性肿瘤生长和转移增强有关。BMP活性受到一族可溶性细胞外分泌BMP调节剂的严格调控。扭曲原肠胚形成BMP信号调节剂1（TWSG1）是一种直接的BMP调节剂，是BMPs充分信号活性所必需的。然而，TWSG1在甲状腺乳头状癌（PTC）转移中的功能和机制尚未见报道。采用定量实时聚合酶链反应（qRT-PCR）检测了44例伴有淋巴结转移（LNM）的PTC组织和56例无LNM的PTC组织中TWSG1的表达。采用功能获得和功能缺失方法评估TWSG1在PTC细胞中的生物学功能。基质胶实验证明了肿瘤细胞来源的TWSG1对内皮细胞功能的影响。我们的结果显示，与无LNM的PTC相比，伴有LNM的PTC中TWSG1表达显著增强。敲低TWSG1可抑制PTC细胞的迁移、侵袭和增殖。此外，抑制TWSG1会损害肿瘤细胞诱导的内皮细胞芽形成。我们发现TWSG1信号可能通过BMP靶标转录因子DNA结合抑制因子1（Id1）以及基质金属蛋白酶（MMPs）2和9进行转导。总之，TWSG1在转移性PTC中高表达；肿瘤生长、迁移和侵袭依赖于TWSG1，它可能是PTC新的诊断和治疗靶点。
