Cysteine-rich intestinal protein 1 suppresses apoptosis and chemosensitivity to 5-fluorouracil in colorectal cancer through ubiquitin-mediated Fas degradation
Cysteine-rich intestinal protein 1 suppresses apoptosis and chemosensitivity to 5-fluorouracil in colorectal cancer through ubiquitin-mediated Fas degradation
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DOI：
10.1186/s13046-019-1117-z
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
Lanzhi Zhang;R. Zhou;Weibin Zhang;Xue-qing Yao;Weidong Li;Lijun Xu;Xuegang Sun;Liang Zhao
中科院分区：
文献类型：
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作者：
Lanzhi Zhang;R. Zhou;Weibin Zhang;Xue-qing Yao;Weidong Li;Lijun Xu;Xuegang Sun;Liang Zhao
富含半胱氨酸的肠道蛋白1 （CRIP1）在人类肠道中高表达，并在几种肿瘤中异常表达。然而，关于CRIP1的研究有限，其在肿瘤发生发展中的作用仍然存在争议和难以捉摸。方法采用免疫组化方法检测配对正常、结直肠肿瘤标本及结直肠细胞系中CRIP1的表达。通过CCK8、TUNEL、体内肿瘤生长等功能检测检测CRIP1的增殖、凋亡及对5-FU的应答。Western blot分析CRIP1诱导fas介导的通路。我们通过救援实验来评估CRIP1在fas介导的细胞凋亡中的重要作用。结果我们发现，与邻近的正常粘膜相比，CRIP1在结直肠癌组织中过表达。在体外，CRIP1可以显著恢复5-氟尿嘧啶（5-FU）抑制CRC细胞的增殖，在体内可能通过抑制CRC细胞凋亡来刺激CRC的肿瘤形成。此外，在体外，CRIP1还能显著恢复5-氟尿嘧啶（5-FU）诱导的肿瘤细胞凋亡。进一步研究表明，CRIP1下调Fas蛋白及Fas介导的凋亡相关蛋白的表达。CRIP1可以与Fas蛋白相互作用，刺激其泛素化和降解。此外，在大多数临床人类CRC样本中，检测到CRIP1与Fas蛋白的表达呈负相关。结论目前的研究揭示了CRIP1在结直肠癌进展中的重要作用，为结直肠癌的临床耐药提供了新的靶点，为结直肠癌的治疗策略提供了新的思路。
BackgroundCysteine-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.MethodsImmunohistochemistry 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.ResultsWe 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.ConclusionThe 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.