Li Lin, Li Qi, Zou Zhengrong, Huang Zoufang, Chen Yijian
Suzhou Medical College of Soochow University, Suzhou 215123, China.
Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China.
Cancers (Basel). 2023 Jan 8;15(2):417. doi: 10.3390/cancers15020417.
Accumulating evidence suggests that members of the tripartite motif (TRIMs) family play a crucial role in the development and progression of hematological malignancy. Here, we explored the expression and potential role of TRIM10 in acute myeloid leukemia (AML).
The expression levels of TRIM10 were investigated in AML patients and cell lines by RNA-seq, qRT-PCR and Western blotting analysis. Lentiviral infection was used to regulate the level of TRIM10 in AML cells. The effects of TRIM10 on apoptosis, drug sensitivity and proliferation of AML cells were evaluated by flow cytometry and cell-counting kit-8 (CCK-8) assay, as well as being assessed in a murine model.
TRIM10 mRNA and protein expression was reduced in primary AML samples and AML cell lines in comparison to the normal controls and a human normal hematopoietic cell line, respectively. Moreover, overexpression of TRIM10 in HL60 and K562 cells inhibited AML cell proliferation and induced cell apoptosis. The nude mice study further confirmed that overexpression of TRIM10 blocked tumor growth and inhibited cell proliferation. In contrast, knockdown of TRIM10 in AML cells showed contrary results. Subsequent mechanistic studies demonstrated that knockdown of TRIM10 enhanced the expression of nuclear protein P65, which implied the activation of the NF-κB signal pathway. Consistently, overexpression of TRIM10 in AML cells showed a contrary result. These data indicated that inactivation of the NF-κB pathway is involved in TRIM10-mediated regulation in AML. TRIM10 expression can be de-repressed by a combination that targets both DNA methyltransferase and histone deacetylase.
Our results strongly suggested that TRIM10 plays a tumor suppressive role in AML development associated with the NF-κB signal pathway and may be a potential target of epigenetic therapy against leukemia.
越来越多的证据表明，三方基序（TRIMs）家族成员在血液系统恶性肿瘤的发生和发展中起关键作用。在此，我们探讨了TRIM10在急性髓系白血病（AML）中的表达及潜在作用。
通过RNA测序、qRT-PCR和蛋白质印迹分析，研究AML患者和细胞系中TRIM10的表达水平。采用慢病毒感染调节AML细胞中TRIM10的水平。通过流式细胞术和细胞计数试剂盒-8（CCK-8）检测，以及在小鼠模型中评估，来评价TRIM10对AML细胞凋亡、药物敏感性和增殖的影响。
与正常对照和人正常造血细胞系相比，原发性AML样本和AML细胞系中TRIM10 mRNA和蛋白表达分别降低。此外，在HL60和K562细胞中过表达TRIM10可抑制AML细胞增殖并诱导细胞凋亡。裸鼠研究进一步证实，TRIM10过表达可阻断肿瘤生长并抑制细胞增殖。相反，AML细胞中敲低TRIM10则显示相反结果。随后的机制研究表明，敲低TRIM10可增强核蛋白P65的表达，这意味着NF-κB信号通路被激活。同样，AML细胞中TRIM10过表达显示相反结果。这些数据表明，NF-κB通路失活参与了TRIM10介导的AML调节。TRIM10表达可通过靶向DNA甲基转移酶和组蛋白脱乙酰酶的组合去抑制。
我们的结果强烈表明，TRIM10在与NF-κB信号通路相关的AML发展中起肿瘤抑制作用，可能是白血病表观遗传治疗的潜在靶点。
