State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510000, China; Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital,Sun Yat-sen University, Guangzhou.
Haematologica. 2024 Feb 1;109(2):479-492. doi: 10.3324/haematol.2023.283181.
It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.
几十年来，人们已经知道亚洲慢性淋巴细胞白血病（CLL）的发病率明显低于西方国家，但导致这种差异的原因仍然是一个主要的知识空白。本研究使用 GeneChip® miRNA 阵列分析亚洲和西方 CLL 患者和健康个体的 B 淋巴细胞的全球 microRNA 表达，我们已经确定了具有促进或抑制 CLL 功能的 microRNA，这些 microRNA在亚洲人和西方人中表达不同。特别是，miR-4485 在两个种族的 CLL 患者中均上调，而亚洲健康个体中的表达显著降低。CLL 细胞中 miR-4485 的遗传沉默抑制白血病细胞生长，而 miR-4485 的异位表达促进细胞增殖。在机制上，miR-4485 通过抑制 TGR5 的表达并激活 ERK1/2 途径发挥其促进 CLL 的活性。相比之下，在亚洲健康个体中高度表达具有抑瘤功能的几个重要 microRNA，如 miR-138、miR-181a、miR-181c、miR-181d 和 miR-363。我们的研究表明，亚洲和西方 B 淋巴细胞中几种具有促或抗 CLL 功能的重要 microRNA 的差异表达可能导致两个种族之间 CLL 发病率的差异，miR-4485 和其下游分子 TGR5 可能是潜在的治疗靶点。
