Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
J Exp Clin Cancer Res. 2019 Mar 8;38(1):120. doi: 10.1186/s13046-019-1117-z.
Cysteine-rich intestinal protein 1 (CRIP1) is highly expressed in human intestine and aberrantly expressed in several types of tumor. However, studies on CRIP1 are limited and its role on tumor development and progression remains controversial and elusive.
Immunohistochemistry was performed to evaluate the expression of CRIP1 in paired normal and colorectal tumor specimens, as well as colorectal cell lines. Functional assays, such as CCK8, TUNEL assay and in vivo tumor growth assay, were used to detect the proliferation, apoptosis and response to 5-FU of CRIP1. Western blot was used to analyze Fas-mediated pathway induced by CRIP1. Rescue experiments were performed to evaluate the essential role of CRIP1 for Fas-mediated apoptosis.
We demonstrated that CRIP1 is overexpressed in CRC tissues compared with adjacent normal mucosa. CRIP1 could dramatically recover the 5-Fluorouracil (5-FU) inhibited CRC cell proliferation in vitro and stimulate the tumor formation of CRC in vivo, probably through inhibiting CRC cell apoptosis. Moreover, CRIP1 also dramatically recovered the 5-Fluorouracil (5-FU) induced tumor cell apoptosis in vitro. Further study demonstrated that CRIP1 down-regulated the expression of Fas protein and proteins related to Fas-mediated apoptosis. CRIP1 could interact with Fas protein and stimulate its ubiquitination and degradation. In addition, a negative correlation was detected between the expression of CRIP1 and Fas protein in most of the clinical human CRC samples.
The current research reveals a vital role of CRIP1 in CRC progression, which provide a novel target for clinical drug resistance of colorectal cancer and undoubtedly contributing to the therapeutic strategies in CRC.
富含半胱氨酸的肠蛋白 1（CRIP1）在人类肠道中高度表达，在几种类型的肿瘤中异常表达。然而，CRIP1 的研究有限，其在肿瘤发生和发展中的作用仍存在争议和难以捉摸。
免疫组织化学法检测配对的正常和结直肠肿瘤标本以及结直肠细胞系中 CRIP1 的表达。使用 CCK8、TUNEL 检测和体内肿瘤生长检测等功能检测，检测 CRIP1 对细胞增殖、凋亡和对 5-FU 的反应。Western blot 用于分析 CRIP1 诱导的 Fas 介导的通路。进行挽救实验以评估 CRIP1 对 Fas 介导的凋亡的必需作用。
我们证明与相邻正常粘膜相比，CRIP1 在 CRC 组织中过表达。CRIP1 可显著恢复体外 5-氟尿嘧啶（5-FU）抑制的 CRC 细胞增殖，并刺激体内 CRC 肿瘤形成，可能通过抑制 CRC 细胞凋亡。此外，CRIP1 还可显著恢复体外 5-氟尿嘧啶（5-FU）诱导的肿瘤细胞凋亡。进一步的研究表明，CRIP1 下调 Fas 蛋白和 Fas 介导的凋亡相关蛋白的表达。CRIP1 可与 Fas 蛋白相互作用并刺激其泛素化和降解。此外，在大多数临床人 CRC 样本中检测到 CRIP1 表达与 Fas 蛋白之间存在负相关。
目前的研究揭示了 CRIP1 在 CRC 进展中的重要作用，为结直肠癌的临床耐药提供了新的靶点，无疑为 CRC 的治疗策略做出了贡献。
