Abstract
BackgroundWith the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear.MethodsThrough gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance.ResultsMM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice.ConclusionsOur research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.
Highlights
With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved
Affymetrix HTA 2.0 array MM cells before and after high-mobility group box 1 (HMGB1) knockdown were sent in TRIzol reagent to Biotechnology Corporation (Shanghai, China), and changes in gene expression were assessed according to the manufacturer’s protocol
Four-week-old male NOD–SCID mice were purchased from Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China); 7 × 106 RPMI8226 cells were subcutaneously injected into the right flank of the mice
Summary
With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear. Studies have found that HMGB1 is involved in inflammation and angiogenesis as well as in the invasion, progression, metastasis, and drug resistance of cancers. Some researchers have found that HMGB1 is overexpressed in many hematological malignancies, such as leukemia and lymphoma, and that it mediates drug resistance through autophagy [12, 13]. The aim of this study was to explore the role of HMGB1 in MM cell proliferation and drug resistance
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