The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML

Abstract

Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.

Prostaglandin E2 serves a dual role in regulating the migration of dendritic cells

“…Numerous molecules and substances that serve important roles in physiological and pathological processes have been demonstrated to exert a dual role ( 24 - 31 ). For example, as a key factor regulating cellular hypoxia, hypoxia inducible factor-1α (HIF-1α) has been reported to upregulate the expression levels of forkhead box P3 (FOXP3) to positively regulate the differentiation function of regulatory T cells ( 24 , 25 ).…”

“…On the other hand, other previous studies have indicated that HIF-1α negatively regulated the differentiation of regulatory T cells by promoting the degradation of FOXP3 ( 26 , 27 ). In cancer progression, numerous molecules have been indicated to simultaneously exhibit both tumor suppressive and oncogenic effects, such as yes-associated protein 1 and p21 (RAC1)-activated kinase 6 ( 28 - 31 ). Moreover, PGE 2 was previously identified to serve a dual role in regulating the migratory ability of macrophages ( 23 ).…”

Non-coding RNA in cancer

“…Wang et al showed that lncTCF7 was highly expressed in liver cancer stem cells (CSCs) and was important for liver CSC self-renewal [32]. [73] miR-30 promotes apoptosis [76] miR-141 promotes metastasis [74] miR-140 inhibits proliferation [77] mi-766 promotes proliferation, chemoresistance, migration and invasion [75] miR-143 inhibits proliferation [78] miR-600 inhibits stemness [79] miR-7 inhibits cell growth [80] Lung [109] miR-185 impairs survival of drug-resistant cells [110] miR-146a alleviates myeloma proliferation [111] Mechanistically, LncTCF7 recruited SWI/SNF complex to TCF7 promoter and activated Wnt signaling for sustaining liver CSC self-renewal. Epigenetically induced lncRNA1 (EPIC1) is first identified as an oncogene in luminal B breast cancer [33].…”

The Impact of lncRNAs and miRNAs in Regulation of Function of Cancer Stem Cells and Progression of Cancer

“…miR-185 has been shown to target PAK6. Suppression of PAK6 expression has interfered with activity of the RAS/MAPK pathway and mitochondria, enhancing sensitivity of resistant cells to TKIs (Lin H. et al, 2020). Table 6 shows the role of miRNAs in regulation of leukemic CSCs.…”