Knockdown of LncRNA CRNDE suppresses proliferation and P-glycoprotein-mediated multidrug resistance in acute myelocytic leukemia through the Wnt/β-catenin pathway.

Yiqing Kang,Dingming Wan,Suping Zhang,Ling Sun,Weijie Cao

doi:10.1042/bsr20193450

Abstract

Mechanisms involved in non-coding RNAs have been implicated in multidrug resistance (MDR) of acute myeloid leukemia (AML). Long non-coding RNA (lncRNAs) colorectal neoplasia differentially expressed (CRNDE) is reported to be involved in the malignant progression in AML. The purpose of the present study is to explore the roles and potential molecular mechanism of CRNDE in the MDR in AML. In our study, we confirmed that the expression of CRNDE was significantly up-regulated in patients with AML, especially in AML patients after adriamycin (ADR)-based chemotherapy. Spearman correlation analysis showed a positive correlation between the levels of CRNDE and MDR1 in AML patients after ADR-based chemotherapy. Moreover, CRNDE was up-regulated in AML cells, especially in ADR-resistant AML cells. Multidrug resistance protein 1 (MDR1)/p-glycoprotein (P-gp) levels were significantly increased in ADR-resistant AML cells, compared with parental AML cells. CRNDE down-regulation inhibited cell proliferation, promoted apoptosis, reduced Ki67 expression and enhanced cleaved caspase-3 expression in AML and ADR-resistant AML cells. In addition, CRNDE knockdown led to down-regulation of P-gp/MDR1, β-catenin, c-Myc and cyclinD1 expression, and enhanced the drug sensitivity to ADR in ADR-resistant AML cells. In conclusion, knockdown of CRNDE suppresses proliferation and P-gp-mediated MDR in ADR-resistant AML cells via inhibiting the Wnt/β-catenin pathway, suggesting that repression of CRNDE might be a therapeutic target to reverse MDR of ADR-resistant AML cells.

Highlights

Acute myeloid leukemia (AML) is an aggressive hematopoietic system malignant disease, characterized by the clonal proliferation of myeloid precursors
To determine whether expression of colorectal neoplasia differentially expressed (CRNDE) is associated with AML drug resistance, the CRNDE and Multidrug resistance protein 1 (MDR1) expression was further detected by quantitative real-time polymerase chain reaction in AML patients before and after ADR-based chemotherapy. qRT-PCR analyses showed that CRNDE level in AML patients after ADR-based chemotherapy was significantly up-regulated (Figure 1C)
The results indicated that CRNDE might affect drug resistance of AML patients

Summary

Introduction

Acute myeloid leukemia (AML) is an aggressive hematopoietic system malignant disease, characterized by the clonal proliferation of myeloid precursors. AML still remains challenging to treat owing to patient factors (age and coexisting diseases) and intrinsic biologic factors [1]. Advancement in survival rates by employing some targeted agents such as midostaurin and enasidenib, relapse rates remain high and most patients still die from AML [1,2]. Drug resistance is a chief handicap to AML chemotherapy. In majority of AML patients who respond to the initial chemotherapy later still undergo multidrug resistance (MDR) and relapse have an adverse impact on patient survival [3]. There is a high medical need to formulate the possible molecular mechanism involved in MDR, improving the outcome of AML patients

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