FUS/COL11A1/ZEB1轴在口腔鳞状细胞癌的发生发展中起作用。
The FUS/COL11A1/ZEB1 Axis Contributes to the Development of Oral Squamous Cell Carcinoma.
作者信息
Zhou Tianyuan, Liu Shuang, Shi Lixin, Zhang Lei
机构信息
Department of Stomatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Department of Stomatology, Kunshan Dental Doctor, Kunshan, China.
出版信息
J Oral Pathol Med. 2025 Mar;54(3):182-191. doi: 10.1111/jop.13610. Epub 2025 Feb 6.
OBJECTIVE
Oral squamous cell carcinoma (OSCC) is a common type of head and neck cancer with high metastasis rate and poor prognosis. This study aimed to explore the role of collagen type XI alpha 1 (COL11A1) and its detailed mechanisms in OSCC progression.
METHODS
Quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis was used to measure the level of COL11A1, fused in sarcoma/translocated in liposarcoma (FUS) and zinc finger E-box binding homeobox 1 (ZEB1). The protein expression of COL11A1, E-cadherin, N-cadherin, FUS, and ZEB1 were detected using Western blot. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5-Ethynyl-2'-deoxyuridine (EdU) staining assays were conducted to measure cell proliferation. Cell migration and invasion were evaluated via wound-healing assay and transwell migration and invasion assays, respectively. Moreover, epithelial mesenchymal transition (EMT) was determined via detecting the expression of EMT-related proteins, including E-cadherin and N-cadherin. RNA immunoprecipitation assay was conducted to evaluate the relationship between ZEB1 and COL11A1. In vivo animal experiments were carried out to explore the role of COL11A1 in OSCC mice, and immunohistochemistry assay was performed to detect the level of ZEB1 and EMT-related proteins in tumor tissues from mice.
RESULTS
COL11A1 was augmented in OSCC tissues and cells. COL11A1 knockdown significantly inhibited cell proliferation, migration, invasion, and EMT in OSCC cells. FUS was increased in OSCC tissues. FUS stabilized the mRNA level of COL11A1 and positively regulated the protein expression of COL11A1. ZEB1 was highly expressed in OSCC tissues, and COL11A1directly targeted ZEB1. The inhibition effects of COL11A1 knockdown on cell proliferation, invasion, migration, and EMT were reversed by ZEB1 overexpression in OSCC cells. Additionally, COL11A1 depletion markedly repressed tumor growth through decreasing ZEB1 expression in vivo.
CONCLUSION
FUS stabilized COL11A1 to promote the malignant progression of OSCC via regulating ZEB1 expression.
目的
口腔鳞状细胞癌（OSCC）是头颈部常见的癌症类型，转移率高且预后较差。本研究旨在探讨Ⅺ型胶原α1（COL11A1）在OSCC进展中的作用及其详细机制。
方法
采用定量逆转录聚合酶链反应（RT-qPCR）分析检测COL11A1、肉瘤融合基因/脂肪肉瘤易位基因（FUS）和锌指E盒结合同源框1（ZEB1）的水平。使用蛋白质印迹法检测COL11A1、E-钙黏蛋白、N-钙黏蛋白、FUS和ZEB1的蛋白表达。采用3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-四氮唑溴盐（MTT）和5-乙炔基-2'-脱氧尿苷（EdU）染色试验检测细胞增殖。分别通过伤口愈合试验和Transwell迁移及侵袭试验评估细胞迁移和侵袭能力。此外，通过检测E-钙黏蛋白和N-钙黏蛋白等上皮间质转化（EMT）相关蛋白的表达来确定EMT情况。进行RNA免疫沉淀试验以评估ZEB1与COL11A1之间的关系。开展体内动物实验以探究COL11A1在OSCC小鼠中的作用，并进行免疫组织化学试验检测小鼠肿瘤组织中ZEB1和EMT相关蛋白的水平。
结果
COL11A1在OSCC组织和细胞中表达上调。敲低COL11A1可显著抑制OSCC细胞的增殖、迁移、侵袭及EMT。FUS在OSCC组织中表达增加。FUS稳定COL11A1的mRNA水平并正向调节COL11A1的蛋白表达。ZEB1在OSCC组织中高表达，且COL11A1直接靶向ZEB1。在OSCC细胞中，ZEB1过表达可逆转敲低COL11A1对细胞增殖、侵袭、迁移及EMT的抑制作用。此外，在体内，COL11A1缺失通过降低ZEB1表达显著抑制肿瘤生长。
结论
FUS通过调节ZEB1表达稳定COL-11A1，促进OSCC的恶性进展。
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