CRIP1 supports the growth and migration of AML-M5 subtype cells by activating Wnt/β-catenin pathway
CRIP1 supports the growth and migration of AML-M5 subtype cells by activating Wnt/β-catenin pathway
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DOI：
10.1016/j.leukres.2023.107312
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发表时间：
2023-05-22
影响因子：
2.7
通讯作者：
Chen, Xiaoli
中科院分区：
文献类型：
--
作者：
Deng, Xiaoling;Zeng, Yanmei;Chen, Xiaoli
急性髓系白血病（AML）是一种临床和分子异质性造血疾病。为了有效根除AML，迫切需要开发新的治疗方法并确定新的分子靶点。计算机分析表明，AML 细胞中富含半胱氨酸的肠蛋白 1 (CRIP1) 的表达显着升高，并且与 AML 患者较差的总体生存率相关。然而，其在 AML 中的具体作用仍然难以捉摸。在这里，我们证明了 CRIP1 作为支持 AML 细胞存活和迁移的关键癌基因。通过功能丧失分析，我们发现慢病毒介导的 shRNA 在 U937 和 THP1 细胞中沉默 CRIP1 导致细胞生长、迁移和集落形成减少，并增加对 Ara-C 的化学敏感性。 CRIP1 沉默诱导细胞凋亡和 G1/S 转变停滞。从机械角度来说，CRIP1 沉默通过上调 axin1 蛋白导致 Wnt/β-catenin 通路失活。 Wnt/β-catenin 激动剂 SKL2001 显着挽救了 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 可能与 AML-M5 发病机制有关，并代表了 AML-M5 治疗的新靶点。
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/beta-catenin pathway through upregulating axin1 protein. The Wnt/beta-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.