Jiangxi Health Commission Key Laboratory of Leukemia, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China; Ganzhou Key Laboratory of Molecular Medicine, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China.
Jiangxi Health Commission Key Laboratory of Leukemia, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi 341000, China.
Leuk Res. 2023 Jul;130:107312. doi: 10.1016/j.leukres.2023.107312. Epub 2023 May 12.
Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous hematopoietic disorder. To effectively eradicate AML, it is urgent to develop new therapeutic approaches and identify novel molecular targets. In silico analysis indicated that the expression of cysteine-rich intestinal protein 1 (CRIP1) was significantly elevated in AML cells and correlated with worse overall survival of the AML patients. However, its specific roles in AML remain elusive. Here we demonstrated that CRIP1 acted as a key oncogene to support AML cell survival and migration. Using a loss-of-function analysis, we found that CRIP1 silencing in U937 and THP1 cells by lentivirus-mediated shRNAs resulted in a decrease in cell growth, migration and colony formation, and an increase in chemosensitivity to Ara-C. CRIP1 silencing induced cell apoptosis and G1/S transition arrest. Mechanically, CRIP1 silencing caused inactivation of Wnt/β-catenin pathway through upregulating axin1 protein. The Wnt/β-catenin agonist SKL2001 markedly rescued the cell growth and migration defect induced by CRIP1 silencing. Our findings reveals that CRIP1 may contribute to AML-M5 pathogenesis and represent a novel target for AML-M5 treatment.
急性髓系白血病（AML）是一种临床和分子上具有异质性的造血系统疾病。为了有效地根除 AML，迫切需要开发新的治疗方法并确定新的分子靶标。计算机分析表明，半胱氨酸丰富的肠蛋白 1（CRIP1）在 AML 细胞中的表达显著升高，并且与 AML 患者的总体生存率较差相关。然而，其在 AML 中的具体作用仍不清楚。在这里，我们证明 CRIP1 作为一种关键的癌基因，可支持 AML 细胞的存活和迁移。通过使用失活功能分析，我们发现通过慢病毒介导的 shRNAs 在 U937 和 THP1 细胞中沉默 CRIP1 会导致细胞生长、迁移和集落形成减少，并且对阿糖胞苷的化疗敏感性增加。CRIP1 沉默诱导细胞凋亡和 G1/S 期阻滞。从机制上讲，CRIP1 沉默通过上调轴蛋白 1（axin1 蛋白）使 Wnt/β-连环蛋白通路失活。Wnt/β-连环蛋白激动剂 SKL2001 明显挽救了由 CRIP1 沉默引起的细胞生长和迁移缺陷。我们的研究结果表明，CRIP1 可能有助于 AML-M5 的发病机制，并代表 AML-M5 治疗的新靶标。
