AREG Upregulation in Cancer Cells via Direct Interaction with Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression Through EGFR-Erk/p38 MAPK Signaling.

IF 5.1 2区 生物学 Q2 CELL BIOLOGY Cells Pub Date : 2024-10-19 DOI:10.3390/cells13201733
Takashi Nakanishi, Yu-Ichiro Koma, Shoji Miyako, Rikuya Torigoe, Hiroki Yokoo, Masaki Omori, Keitaro Yamanaka, Nobuaki Ishihara, Shuichi Tsukamoto, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki, Yoshihiro Kakeji
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Abstract

Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and significantly contribute to the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Our previous study established a direct co-culture system of human bone marrow-derived mesenchymal stem cells (progenitors of CAFs) and ESCC cell lines, which facilitates the generation of CAF-like cells and enhances malignancy in ESCC cells. In this study, we further elucidated the mechanism by which CAFs promote ESCC progression using cDNA microarray analysis of monocultured ESCC cells and those co-cultured with CAFs. We observed an increase in the expression and secretion of amphiregulin (AREG) and the expression and phosphorylation of its receptor EGFR in co-cultured ESCC cells. Moreover, AREG treatment of ESCC cells enhanced their survival and migration via the EGFR-Erk/p38 MAPK signaling pathway. Immunohistochemical analysis of human ESCC tissues showed a positive correlation between the intensity of AREG expression at the tumor-invasive front and the expression level of the CAF marker FAP. Bioinformatics analysis confirmed significant upregulation of AREG in ESCC compared with normal tissues. These findings suggest that AREG plays a crucial role in CAF-mediated ESCC progression and could be a novel therapeutic target for ESCC.

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通过与癌症相关成纤维细胞的直接相互作用,AREG 在癌细胞中上调,并通过表皮生长因子受体-Erk/p38 MAPK 信号转导促进食管鳞状细胞癌的进展。
癌症相关成纤维细胞(CAFs)是肿瘤微环境的关键组成部分,对包括食管鳞状细胞癌(ESCC)在内的多种癌症的进展有重要作用。我们之前的研究建立了人骨髓间充质干细胞(CAFs 的祖细胞)和 ESCC 细胞系的直接共培养系统,这促进了 CAF 样细胞的生成,并增强了 ESCC 细胞的恶性程度。在本研究中,我们使用cDNA芯片分析了单培养ESCC细胞和与CAFs共培养的ESCC细胞,进一步阐明了CAFs促进ESCC进展的机制。我们观察到,在共培养的 ESCC 细胞中,安非拉酮(AREG)的表达和分泌以及其受体表皮生长因子受体(EGFR)的表达和磷酸化均有所增加。此外,通过表皮生长因子受体-Erk/p38 MAPK 信号通路,AREG 处理 ESCC 细胞可提高其存活率和迁移率。对人类 ESCC 组织的免疫组化分析表明,AREG 在肿瘤侵袭前沿的表达强度与 CAF 标记 FAP 的表达水平呈正相关。生物信息学分析证实,与正常组织相比,AREG在ESCC中明显上调。这些研究结果表明,AREG在CAF介导的ESCC进展中起着至关重要的作用,可能成为ESCC的一个新的治疗靶点。
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来源期刊
Cells
Cells Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
9.90
自引率
5.00%
发文量
3472
审稿时长
16 days
期刊介绍: Cells (ISSN 2073-4409) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided.
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