SCUBE3 Exerts a Tumor-Promoting Effect in Tongue Squamous Cell Carcinoma by Promoting CEBPA Binding to the CCL2 Promoter.

IF 4.1 2区医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-05-02 DOI:10.1158/1541-7786.MCR-23-0038

Minhui Zhu, Yi Ma, Wei Wang, Meng Li, Shicai Chen, Fei Liu, Xiaoqiong Shi, Hongsen Bi, Chen Zhang, Fangfei Nie, Hongliang Zheng, Caiyun Zhang

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Abstract

Tongue squamous cell carcinoma (TSCC) is the main pathologic subtype of oral cancer, and the current therapeutic effect is far from satisfactory. The signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) has been shown to be a tumor-promoting factor in several malignancies. However, little is known about the role of SCUBE3 in TSCC. In this study, we identified that SCUBE3 was highly expressed in TSCC. Clinically, high expression of SCUBE3 was positively associated with tumor stage and T stage of TSCC. Functionally, SCUBE3 silence remarkably restrained cell proliferation, migration, and invasion, induced apoptosis as well as cell cycle arrest in G2-phase, and weakened the tumorigenicity of TSCC cells in vivo. Mechanistically, SCUBE3 promoted the direct binding of CCAAT enhancer binding protein alpha (CEBPA) to C-C motif chemokine ligand 2 (CCL2) promoter in TSCC cells. Interestingly, CCL2 overexpression partially reversed the inhibitory effect of SCUBE3 deficiency on TSCC cell viability and migration. Moreover, STAT3 signaling contributed to CCL2-mediated phenotypes in TSCC cells.

Implications: Our data revealed a tumor-promoting role for SCUBE3 in TSCC via the CEBPA/CCL2/STAT3 axis, which provided new insight into novel potential therapeutic target for TSCC.

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SCUBE3 通过促进 CEBPA 与 CCL2 启动子的结合，在舌鳞癌中发挥肿瘤促进作用。

舌鳞状细胞癌（TSCC）是口腔癌的主要病理亚型，目前的治疗效果并不理想。信号肽-CUB-EGF结构域含蛋白3（SCUBE3）已被证明是多种恶性肿瘤的促癌因子。然而，人们对 SCUBE3 在 TSCC 中的作用知之甚少。在这项研究中，我们发现 SCUBE3 在 TSCC 中高度表达。在临床上，SCUBE3的高表达与TSCC的肿瘤分期和T期呈正相关。在功能上，SCUBE3沉默可显著抑制细胞增殖、迁移和侵袭，诱导细胞凋亡和细胞周期停滞于G2期，并削弱TSCC细胞在体内的致瘤性。从机制上讲，SCUBE3 促进了 CCAAT 增强子结合蛋白 alpha（CEBPA）与 TSCC 细胞中的 C-C motif 趋化因子配体 2（CCL2）启动子的直接结合。有趣的是，CCL2 的过表达部分逆转了 SCUBE3 缺乏对 TSCC 细胞活力和迁移的抑制作用。此外，信号转导子和转录激活子 3（STAT3）信号转导也对 CCL2 介导的 TSCC 细胞表型起了作用。意义：我们的数据揭示了SCUBE3通过CEBPA/ CCL2/STAT3轴在TSCC中的促瘤作用，这为TSCC的新型潜在治疗靶点提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.