Department of Surgery, Kyushu University Beppu Hospital, Oita 874‑0838, Japan.
Department of Cancer Biology, Institute of Biomedical Science, Kansai Medical University, Osaka 573‑1010, Japan.
Int J Oncol. 2024 Dec;65(6). doi: 10.3892/ijo.2024.5701. Epub 2024 Oct 25.
Colorectal cancer (CRC) is widely prevalent and represents a significant contributor to global cancer‑related mortality. There remains a pressing demand for advancements in CRC treatment modalities. The E3 ubiquitin ligase is a critical enzyme involved in modulating protein expression levels via posttranslational ubiquitin‑mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In the present study, using comprehensive expression analysis involving spatial transcriptomic analysis with single‑cell RNA sequencing in clinical CRC datasets, the ubiquitin‑associated protein Shank‑associated RH domain interactor () was identified, located on amplified chromosome 8q, which could promote CRC progression. was found to be upregulated in tumor cells, with elevated expression observed in tumor tissues. This heightened expression of was positively associated with lymphatic invasion and served as an independent predictor of a poor prognosis in patients with CRC. and analyses using SHARPIN‑overexpressing or ‑knockout CRC cells revealed that SHARPIN overexpression upregulated MDM2, resulting in the downregulation of p53, while SHARPIN silencing or knockout downregulated MDM2, leading to p53 upregulation, which affects cell cycle progression, tumor cell apoptosis and tumor growth in CRC. Furthermore, was found to be overexpressed in several cancer types, exerting significant effects on survival outcomes. In conclusion, SHARPIN represents a newly identified novel gene with the potential to promote tumor growth following apoptosis inhibition and cell cycle progression in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.
结直肠癌(CRC)广泛流行,是全球癌症相关死亡率的主要原因之一。目前仍然迫切需要在 CRC 治疗方法上取得进展。E3 泛素连接酶是一种关键的酶,通过翻译后泛素介导的蛋白水解来调节蛋白表达水平,据报道它参与了多种癌症的进展,使其成为最近癌症治疗中关注的靶点。在本研究中,通过对临床 CRC 数据集进行空间转录组分析和单细胞 RNA 测序的综合表达分析,发现了位于扩增的 8q 染色体上的泛素相关蛋白 Shank 相关 RH 结构域相互作用蛋白(),它可以促进 CRC 的进展。研究发现,在肿瘤细胞中上调,在肿瘤组织中观察到表达升高。这种 的高表达与淋巴侵袭呈正相关,并且是 CRC 患者预后不良的独立预测因子。使用 SHARPIN 过表达或敲除 CRC 细胞进行的和分析表明,SHARPIN 过表达上调了 MDM2,导致 p53 下调,而 SHARPIN 沉默或敲除下调了 MDM2,导致 p53 上调,这影响了 CRC 中的细胞周期进程、肿瘤细胞凋亡和肿瘤生长。此外,发现在多种癌症类型中过表达,对生存结果有显著影响。总之,SHARPIN 是一种新发现的基因,通过上调 MDM2 抑制 p53 表达,在部分抑制细胞凋亡和细胞周期进程后促进肿瘤生长,因此,SHARPIN 可能是 CRC 的一个潜在治疗靶点。