title: miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1.
abstract: Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR-181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Hongchun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Shaolei
authors.initials: S
authors.lastname: Zang
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Daoxin
authors.initials: D
authors.lastname: Ma
authors.affiliation: National Key Lab of Otolaryngology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Xiulian
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ji
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D018922:HL-60 Cells; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C579095:MCL1 protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D003561:Cytarabine; D004317:Doxorubicin