Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea.
Department of Surgery, Gil Medical Center, College of Medicine, Gachon University, Incheon 21999, Korea.
Int J Mol Sci. 2020 Dec 15;21(24):9537. doi: 10.3390/ijms21249537.
Thyroid cancer incidence has increased worldwide; however, investigations of thyroid cancer-related factors as potential prognosis markers remain insufficient. Secreted proteins from the cancer secretome are regulators of several molecular mechanisms and are, thereby, ideal candidates for potential markers. We aimed to identify a specific factor for thyroid cancer by analyzing the secretome from normal thyroid cells, papillary thyroid cancer (PTC) cells, and anaplastic thyroid cancer cells using mass spectrometry (MS). Cathepsin B (CTSB) showed highest expression in PTC cells compared to other cell lines, and CTSB levels in tumor samples were higher than that seen in normal tissue. Further, among thyroid cancer patients, increased CTSB expression was related to higher risk of lymph node metastasis (LNM) and advanced N stage. Overexpression of CTSB in thyroid cancer cell lines activated cell migration by increasing the expression of vimentin and Snail, while its siRNA-mediated silencing inhibited cell migration by decreasing vimentin and Snail expression. Mechanistically, CTSB-associated enhanced cell migration and upregulation of vimentin and Snail occurred via increased phosphorylation of p38. As our results suggest that elevated CTSB in thyroid cancer induces the expression of metastatic proteins and thereby leads to LNM, CTSB may be a good and clinically relevant prognostic marker.
甲状腺癌的发病率在全球范围内呈上升趋势；然而，对于甲状腺癌相关因素作为潜在预后标志物的研究仍然不足。癌症分泌组中的分泌蛋白是几种分子机制的调节剂，因此是潜在标志物的理想候选物。我们旨在通过使用质谱（MS）分析正常甲状腺细胞、甲状腺乳头状癌（PTC）细胞和间变性甲状腺癌细胞的分泌组，来鉴定甲状腺癌的特定因子。与其他细胞系相比，组织蛋白酶 B（CTSB）在 PTC 细胞中的表达最高，肿瘤样本中的 CTSB 水平高于正常组织。此外，在甲状腺癌患者中，CTSB 的表达增加与淋巴结转移（LNM）和晚期 N 期的风险增加有关。在甲状腺癌细胞系中过表达 CTSB 通过增加波形蛋白和 Snail 的表达来激活细胞迁移，而其 siRNA 介导的沉默通过降低波形蛋白和 Snail 的表达来抑制细胞迁移。从机制上讲，CTSB 相关的增强细胞迁移和波形蛋白和 Snail 的上调是通过 p38 的磷酸化增加而发生的。由于我们的研究结果表明，甲状腺癌中升高的 CTSB 诱导了转移性蛋白的表达，从而导致了 LNM，因此 CTSB 可能是一种良好的、具有临床相关性的预后标志物。
