Downregulation of microRNA let‐7f mediated the Adriamycin resistance in leukemia cell line

Abstract

Multidrug resistance (MDR) has become the major cause of failure chemotherapy for leukemia and high mortality of leukemia. The study aimed to investigate whether the let‐7f mediate the Adriamycin (ADR) resistance of leukemia, and to explore the potential molecular mechanism. Cell proliferation was examined by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and the soft agar clone formation assay. Flow cytometry was performed to detected cell cycle and apoptosis. The targeted regulationship was analyzed by dual‐luciferase assay. Real‐time polymerase chain reaction and Western blot were used to measure the expressions of let‐7f, ABCC5, ABCC10, cell cycle‐related proteins, and apoptosis‐related proteins. The xenograft mouse model was used to conduct the tumor formation assay in vivo. The results demonstrated that the expression of let‐7f was lower in multidrug‐resistant K562/A02 cell lines compared to that in K562, while ABCC5 and ABCC10 were upregulated. Overexpression of let‐7f in K562/A02 cell lines downregulated the ABCC5 and ABCC10 expression, enhanced cell sensitivity to ADR, promoted cell apoptosis, and inhibited cell proliferation. let‐7f was proved to negatively regulate ABCC5 and ABCC10. Tumor formation assay further determined that let‐7f overexpression increased sensitivity to ADR. Taken together, the let‐7f downregulation induced the ADR resistance of leukemia by upregulating ABCC5 and ABCC10 expression. Our study provided a novel perspective to study the mechanism of MDR and a new target for the reversal of MDR.

MicroRNA let-7b downregulates AML1-ETO oncogene expression in t(8;21) AML by targeting its 3′UTR

“…The let-7 family of miRNAs are well described tumor suppressors in a variety of cancers, including leukemias [40][41][42]. Members of the let-7 miRNA family have demonstrated roles in sensitizing leukemic cells to chemotherapy [43][44][45][46][47]. Furthermore, the overexpression of let-7 miRNAs have also been shown to inhibit proliferation and promote differentiation in certain leukemic contexts [40,48].…”

A Novel miR-98 Negatively Regulates the Resistance of Endometrial Cancer Cells to Paclitaxel by Suppressing ABCC10/MRP-7

“…Despite the link between MRP-7 expression and chemoresistance, earlier investigations have also suggested that MRP-7 may play other biological roles during carcinogenesis and cancer progression (9)(10)(11)(12)36). MRP-7 expression has been found to be high in lung cancer tissues, while it was rarely detected in normal lung tissues (36).…”

“…Studies have shown that high MRP-7 expression is associated with a worse prognosis in patients with gastric cancer and lung cancer ( 9 , 10 ). Other research has recently revealed that MRP-7 stimulates cell proliferation and attenuates apoptosis in human leukemia cells ( 11 ). In ovarian cancer cells, MRP-7 has also been shown to trigger EMT-related signaling and promote cell migration ( 12 ).…”

“…In the current research, we predicted possible miRNAs that might influence the expression of MRP-7, and reported for the first time that restoring miR-98 re-sensitized EC cells to paclitaxel, and inhibited EC cell proliferation and invasion by directly binding to the 3′-UTR region of MRP-7 mRNA. Additionally, the expression of MRP-7 in tumor cells was mediated by some other miRNAs (including let-7a, let-7e, let-7g, let-7i, and let-7f) ( 11 , 37 – 39 ). Taken together, it is possible that chemoresistance and aggressiveness associated with MRP-7 may be induced by the downregulation of miR-98 and other miRNAs.…”

“…In patients with gastric cancer and lung cancer, increased MRP-7 expression levels have been linked to a worse prognosis in several studies ( 9 , 10 ). Overexpression of MRP-7 inhibits apoptosis and promotes cell proliferation in human leukemia cells ( 11 ). Interestingly, MRP-7 has been shown to promote ovarian cancer cell motility and cause epithelial-mesenchymal transition (EMT) ( 12 ).…”