miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding

Abstract

Leukemia stem cells (LSCs) are responsible for acute myeloid leukemia (AML) chemotherapy resistance and relapse. Here, we discovered that miR-34c-5p, a microRNA central to the senescence regulation network, was significantly down-regulated in AML (non-acute promyelocytic leukemia, non-APL) stem cells compared to that in normal hematopoietic stem cells (HSCs). The lower expression of miR-34c-5p in LSCs was closely correlated to the adverse prognosis and poor responses to therapy of AML patients. Increased miR-34c-5p expression induced LSCs senescence ex vivo, prevented leukemia development and promoted the eradication of LSCs in immune deficient mice. Mechanistically, forced expression of miR-34-5p induced senescence in LSCs through p53-p21-Cyclin-dependent kinase (CDK)/Cyclin or p53-independent CDK/Cyclin pathways. Exosome-mediated transfer of miR-34c-5p was one of the reasons for miR-34c-5p deficiency in LSCs. Furthermore, miR-34c-5p could increase its intracellular level by inhibiting exosome-mediated transfer via a positive feedback loop through RAB27B, a molecule that promotes exosome shedding. Overall, this study establishes a new strategy for treatment of AML patients by targeting LSCs to reinitiate senescence via increased miR-34c-5p expression. This miRNA-mediated tumor stem cell senescence could also have important therapeutic value in other malignancies.

The study of mechanism of miR-34c-5p targeting FLOT2 to regulate proliferation, migration and invasion of osteosarcoma cells

“…Interestingly, miR-34c-5p functions as a carcinogen in various cancers, such as colon cancer [22] and bladder cancer [23]. However, increasing evidence indicates that miR-34c-5p acts as a tumor suppressor in various tumors, such as acute myeloid leukemia [24]. miRNAs have different roles in different cancers, which are related to the tumor microenvironment.…”

Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia

“…In return, miR-34c-5p could suppress exosome-mediated transfer via a positive feedback loop through RAB27B, a molecule that promotes exosome shedding. By targeting RAB27B, miR-34c-5p could enrich its intracellular level and induce LSC senescence [62].…”

Aberrant expression profiles and bioinformatic analysis of CAF-derived exosomal miRNAs from three moderately differentiated supraglottic LSCC patients

“…MiR-16-5p was reportedly downregulated in breast cancer [76], hepatocellular carcinoma [77] and glioma [78], in agreement with our ndings. Overall, miR-29a-3p has been reported to function as a tumour suppressor and is downregulated in many types of cancers, such as thyroid carcinoma [32], colorectal carcinoma [79] and hepatocellular carcinoma [80].The downregulation of miR-34c-5p has been reported in several types of cancer, such as leukaemia [57] and osteosarcoma [58], and it has been closely associated with poor prognosis. Similarly, miR-490-5p is markedly downregulated in hepatocellular carcinoma tissues [81], in renal cell carcinoma tissues and cells [82] and in childhood neuroblastomas and cell lines [83].…”

“…MiR-34c-5p was downregulated in leukaemia stem cells [57], osteosarcoma tissues and cells [58] and aryngeal squamous cell carcinoma [59]. Let-7i-3p was upregulated in the serum-derived exosomes from osteosarcoma patients [60], but downregulated in the sera of lung cancer patients [61] and in hepatoblastoma tumours [62].…”