Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma.
Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma.
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衣霉素通过上调甲状腺癌内质网应激诱导的 GRP78 表达促进转移
DOI：
10.1186/s13578-020-00478-0
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发表时间：
2020
影响因子：
7.5
通讯作者：
Gao B
中科院分区：
文献类型：
--
作者：
Zhao G;Kang J;Xu G;Wei J;Wang X;Jing X;Zhang L;Yang A;Wang K;Wang J;Wang L;Hou J;Liu Q;Jiao K;Gao B
甲状腺癌（Thyroid cancer，TC）是最常见的内分泌恶性肿瘤，其发病率近年来呈上升趋势。低分化甲状腺癌（PDTC）和间变性甲状腺癌（ATC）是甲状腺癌中恶性程度最高的两种类型，由于其侵袭性和转移性，传统的手术、放疗和化疗难以提高其疗效。葡萄糖调节蛋白（GRP 78）是肿瘤生长、凋亡和转移的关键分子。然而，GRP 78在TC中的潜在机制仍然需要讨论。本研究旨在探讨GRP 78在TC中的作用及其可能机制。此外，在体外研究中，GRP 78的下调显著抑制ATC细胞的转移和增殖能力。此外，衣霉素诱导的内质网应激可上调GRP 78、PERK和XBP 1的表达，并逆转GRP 78在ATC细胞中的转移能力。针对si-GRP 78和si-对照的RNA测序数据的基因本体（GO）富集和京都基因和基因组百科全书（KEGG）途径的生物信息学和统计分析显示，GRP 78可能通过ATC细胞中的细胞外基质（ECM）重塑以及ECM组分如COL 1A 1和MMP 13的表达来调节转移能力，与ATC细胞高度相关。GEPIA数据库分析证实MMP 13和COL 1A 1基因组扩增与肿瘤TNM分期相关。进一步的Western blotting分析表明，MMP 13可能是GRP 78在ATC细胞中的作用靶点，ER应激可激活MMP 13的表达，而GRP 78的缺失可抑制MMP 13的表达。此外，GRP 78的功能可能是通过ATC细胞ECM重塑介导的，暗示其是TC的治疗靶点。
BackgroundThyroid cancer (TC) is the most common type of endocrine malignancy and its incidence is increasing over years. Conventional surgery, radiotherapy and chemotherapy are difficult to improve the significant effects of it due to aggression and metastasis of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), and these are regarded as the most malignant types of TC. Glucose-regulated protein (GRP78) is the key molecule of tumor growth, apoptosis and metastasis. However, the underlying mechanisms of GRP78 in TC still require discussion. This study aimed to explore the role of GRP78 and its potential mechanism in TC.ResultsGRP78 expression was increased in TC tissues when compared with adjacent normal tissues. Besides, down-regulation of GRP78 significantly inhibited the metastatic and proliferative ability of ATC cells in in vitro studies. In addition, tunicamycin-induced ER stress up-regulated the expression of GRP78, PERK and XBP1 as well as reversed the metastatic ability of GRP78 in ATC cells. Bioinformatics and statistical analysis of gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for RNA-sequencing data with regard to si-GRP78 and si-control showed that GRP78 might regulate the ability of metastasis through extracellular matrix (ECM) remodeling in ATC cells, as well as the expression of ECM components such as COL1A1 and MMP13, which were highly relevant to ATC cells. The analysis of GEPIA database confirmed that high genomic amplification of MMP13 and COL1A1 in TC tissues showed correlation with TNM stage. Further western blotting analysis showed that MMP13 might be the target of GRP78 in ATC cells and ER stress could activate the expression of MMP13 that is suppressed by GRP78 depletion.ConclusionsGRP78 acts as an important regulator of metastasis under ER stress. In addition, the function of GRP78 might be mediated by ECM remodeling in ATC cells, implicating it as a therapeutic target in TC.
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