Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations
Panpan Liu,
Kefeng Wang,
Jianan Li,
Marcia A. Ogasawara,
Zhongjun Xia,
William G. Wierda,
Michael J. Keating,
Yiqing Li,
Peng Huang
Affiliations
Panpan Liu
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
Kefeng Wang
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
Jianan Li
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou
Marcia A. Ogasawara
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
Zhongjun Xia
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou
William G. Wierda
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
Michael J. Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
Yiqing Li
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 Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China
Peng Huang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou
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.