肥大细胞通过分泌胱抑素C诱导内质网应激来抑制结直肠癌的发展。

Mast cells inhibit colorectal cancer development by inducing ER stress through secreting Cystatin C.

作者信息

Song Feifei, Zhang Youhua, Chen Qi, Bi Dexi, Yang Muqing, Lu Ling, Li Man, Zhu Huiyuan, Liu Ying, Wei Qing, Qin Huanlong, Li Jiyu

机构信息

Department of Pathology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, 200072, China.

Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200031, China.

出版信息

Oncogene. 2023 Jan;42(3):209-223. doi: 10.1038/s41388-022-02543-z. Epub 2022 Nov 19.

DOI:10.1038/s41388-022-02543-z

PMID:36402931

Abstract

Mast cells (MCs) are abundantly distributed in the human intestinal mucosa and submucosa. However, their roles and mechanisms in the development of colorectal cancer (CRC) are still unclear. In the present research, we found that the infiltration density of MCs in CRC tissues was positively correlated with improved patients' prognoses. Moreover, MCs suppressed the growth and induced the apoptosis of CRC cells in vitro and in vivo but had no effect on normal colonic epithelial cells. The present study revealed that MCs specifically induced endoplasmic reticulum stress (ERS) and activated the unfolded protein response (UPR) in CRC cells but not in normal cells, which led to the suppression of CRC development in vivo. Furthermore, we found that the secreted Cystatin C protein was the key factor for the MC-induced ERS in CRC cells. This work is of significance for uncovering the antitumor function of MCs in CRC progression and identifying the potential of CRC to respond to MC-targeted immunotherapy.

摘要

肥大细胞（MCs）大量分布于人体肠道黏膜和黏膜下层。然而，它们在结直肠癌（CRC）发生发展中的作用及机制仍不清楚。在本研究中，我们发现CRC组织中MCs的浸润密度与患者预后改善呈正相关。此外，MCs在体外和体内均抑制CRC细胞的生长并诱导其凋亡，但对正常结肠上皮细胞无影响。本研究表明，MCs特异性诱导CRC细胞内质网应激（ERS）并激活未折叠蛋白反应（UPR），而在正常细胞中则无此作用，这导致体内CRC发展受到抑制。此外，我们发现分泌的胱抑素C蛋白是MC诱导CRC细胞发生ERS的关键因素。这项工作对于揭示MCs在CRC进展中的抗肿瘤功能以及确定CRC对MC靶向免疫治疗反应的潜力具有重要意义。