Xing Guo and Donghua He contributed equally to this work.
With 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.
Through 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.
MM 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.
Our 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.
Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R, Gertz MA, Gonsalves WI, Hayman SR, Kapoor P, Kourelis T, Kumar SK, Kyle RA, Lacy MQ, Leung N, Lin Y, Lust JA, Mikhael JR, Reeder CB, Roy V, Russell SJ, Sher T, Stewart AK, Warsame R, Zeldenrust SR, Rajkumar SV, Chanan Khan AA. Therapy for relapsed multiple myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy. Mayo Clin Proc. 2017;92(4):578–98. CrossRefPubMedPubMedCentral
Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ 3rd, Lotze MT, Tang D. HMGB1 in health and disease. Mol Asp Med. 2014;40:1–116. CrossRef
Gnanasekar M, Thirugnanam S, Ramaswamy K. Short hairpin RNA (shRNA) constructs targeting high mobility group box-1 (HMGB1) expression leads to inhibition of prostate cancer cell survival and apoptosis. Int J Oncol. 2009;34(2):425–31. PubMed
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P. Daratumumab, Lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319–31. CrossRefPubMed
Lamy L. Multiple myeloma and autophagy. Med Sci (Paris). 2013;29(8–9):685–7. CrossRef
- HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair
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