Human mesenchymal stem cells derived exosomes inhibit the growth of acute myeloid leukemia cells via regulating miR-23b-5p/TRIM14 pathway

Abstract

Background Acute myeloid leukemia (AML) is a malignancy commonly seen in adults. Previous studies indicated that TRIM14 played a tumorigenic role in various types of cancer and miR-23b-5p was down-regulated in human mesenchymal stem cell-derived exosomes (HMSC-exos) of AML patients. However, their roles in AML remains unclear. Our study aims to investigate the role of TRIM14 and miR-23b-5p in the pathogenesis of AML. Materials and methods The blood specimen was collected from de novo AML patients and healthy donators. Exosomes were extracted from the culture medium of human mesenchymal stem cells under ultracentrifugation. Then exosomes were co-cultured with AML cells to determine the effect of their contents. The cell proliferation was detected by cell counting kit-8 assay, whereas the cell apoptosis was detected by flow cytometry. The expression of miR-23b-5p and TRIM14 was silenced or overexpressed to explore their biological functions in AML. Luciferase reporter assay was conducted to validate the interaction between miR-23b-5p and TRIM14. Gene expression was determined by quantitative real-time PCR and immunoblots. Results TRIM14 was significantly increased in AML patients and cell lines. The inhibition of TRIM14 significantly reduced the proliferation and induced the apoptosis of AML cells via activating PI3K/AKT pathway, whereas its overexpression exhibited reversed effects. HMSC-exos could suppress the proliferation of AML cells through the delivery of miR-23b-5p. Moreover, miR-23b-5p inhibited the transcription of TRIM14 by binding on its 3’UTR region. Overexpression of TRIM14 exhibited reversed effect against the function of miR-23b-5p mimic. Conclusion TRIM14 could promote the proliferation of AML cells via activating PI3K/AKT pathway, which was reversed by HMSC-exos through delivering miR-23b-5p. These findings indicated that miR-23b-5p and TRIM14 could be applied as potential targets for the treatment of AML.

Mesenchymal stroma/stem cells: Haematologists’ friend or foe?

“…This has been shown to affect key regulatory pathways in leukaemia including PI3K/AKT/mTOR, affecting both proliferation and resistance to chemotherapy. 151,152 Taken together, these studies strengthen our understanding that the BM niche and the cross-talk between the MSCs and the leukaemia cells play a crucial role in the leukomogenic process, and thus offer new targets for future drug development.…”

“…Finally, MSCs have been shown to modulate AML cell proliferation by the release of miRNA in small EVs. This has been shown to affect key regulatory pathways in leukaemia including PI3K/AKT/mTOR, affecting both proliferation and resistance to chemotherapy 151,152 …”

“…This has been shown to affect key regulatory pathways in leukaemia including PI3K/AKT/mTOR, affecting both proliferation and resistance to chemotherapy. 151 , 152 …”

Analysis of the miRNA expression from the adipose tissue surrounding the adrenal neoplasia

“…Thus, a potential role of miRNAs was found in experimental studies on COVID-19 RNA-based drugs ( 40 ) and COVID-19 cerebrovascular events ( 41 ). Moreover, some miRNAs may represent potential targets for the treatment of acute myeloid leukemia ( 42 ) or in atherosclerosis for drug discovery ( 43 ). An interesting role in impaired insulin secretion in T2D pathogenesis was also found ( 44 ).…”

TRIM family contribute to tumorigenesis, cancer development, and drug resistance

“…TRIM14 knockdown increases the protein levels of PTEN, which subsequently inactivates AKT pathways in melanoma [ 195 ] and colorectal cancer [ 196 ]. TRIM14 overexpression resultes in lower proliferation rates and reduced apoptosis in AML [ 197 ]. In addition, similar effects were observed in osteosarcoma [ 198 ] and gastric cancer [ 199 ].…”