全球miRNA分析揭示了对亚洲和西方人群不同慢性淋巴细胞白血病发病率贡献关键分子。
Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations.
发表日期：2023 Aug 31
作者：
Panpan Liu, Kefeng Wang, Jianan Li, Marcia A Ogasawara, Zhongjun Xia, William G Wierda, Michael J Keating, Yiqing Li, Peng Huang
来源：
HAEMATOLOGICA
摘要：
几十年来众所周知，慢性淋巴细胞白血病（CLL）在亚洲地区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重要的知识空白。通过使用GeneChip® miRNA Array对亚洲和西方CLL患者以及健康个体的B淋巴细胞进行全球microRNA表达分析，我们已经鉴定出在亚洲和西方人群中差异表达的具有促进或抑制CLL功能的microRNAs。特别地，miR-4485在两个种族群体的CLL患者中上调表达，并且在亚洲健康个体中其表达明显较低。通过对CLL细胞中miR-4485进行遗传沉默，可以抑制白血病细胞的生长，而过量表达miR-4485则促进细胞增殖。在机制上，miR-4485通过抑制TGR5（G蛋白偶联胆酸受体，GPBAR1）的表达并激活ERK1/2（细胞外信号调节蛋白激酶1和2）信号通路发挥其促进CLL活性。与此相反，miR-138、miR-181a、miR-181c、miR-181d和miR-363具有抑制肿瘤功能，在亚洲健康个体中表达较高。我们的研究表明，在亚洲和西方B淋巴细胞中，数种重要的具有促进或抗CLL功能的microRNAs的差异表达可能是两个种族群体CLL发病率差异的原因之一，并且miR-4485及其下游分子TGR5可能成为潜在的治疗靶点。
It is known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in the Western countries, but the reason responsible for this difference still remains as 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 microRNAs 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 (G-protein-coupled bile acid receptor, GPBAR1) and activating the ERK1/2 (extracellular signal-regulated protein kinases 1 and 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 microRNAs 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.