Department of Laboratory Medicine, Affiliated hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
Cell Death Dis. 2019 Feb 6;10(2):106. doi: 10.1038/s41419-018-1219-0.
Radiotherapy, chemotherapy, autologous/allogeneic stem cell transplantation, and targeted drug therapy are currently available therapeutic options for multiple myeloma (MM), but the clinical outcome remains unsatisfactory owing to frequent occurrence of drug resistance. Anti apoptosis is one of the main mechanisms to mediate drug resistance. Studies have shown that MCL-1 plays a key role in the growth of cancer cells "escaping" drug attacks, but the underlying mechanism remains unclear. Our previous study demonstrated that lncRNA H19 was highly expressed in the serum of MM patients. Bioinformatics predicts that miR-29b-3p is the downstream target gene, and MCL-1 is the downstream target protein of miR-29b-3p. Therefore, we speculated that MCL-1 may be involved in the occurrence of drug resistance through epigenetics. On the basis of these previous findings, the present study was intended to explore the biological function of H19, interactions between the downstream target genes, and the effect of H19 on BTZ resistance of myeloma cells. In addition, in vivo experiments we have also confirmed that H19 promoted tumor growth and may develop resistance to bortezomib partly. It was found that H19 reduced cell sensitivity to the chemotherapeutic drug BTZ by working as a miRNA sponge to inhibit the expression of miR-29b-3p, enhance MCL-1 transcriptional translation and inhibit apoptosis. These findings may help gain insights into the molecular mechanism of acquired BTZ resistance and develop new drug targets for the clinical treatment of MM.
放療、化療、自體/異體幹細胞移植和靶向藥物治療是目前多發性骨髓瘤（MM）的治療選擇，但由於頻繁發生耐藥性，臨床療效仍不滿意。抗凋亡是介導耐藥性的主要機制之一。研究表明，MCL-1 在癌細胞“逃避”藥物攻擊的生長中起關鍵作用，但潛在機制尚不清楚。我們之前的研究表明，lncRNA H19 在 MM 患者血清中表達水平升高。生物信息學預測 miR-29b-3p 是下游靶基因，而 MCL-1 是 miR-29b-3p 的下游靶蛋白。因此，我們推測 MCL-1 可能通過表觀遺傳學參與耐藥性的發生。基於這些先前的發現，本研究旨在探討 H19 的生物功能、下游靶基因之間的相互作用以及 H19 對骨髓瘤細胞 BTZ 耐藥性的影響。此外，在體內實驗中，我們也證實了 H19 通過作為 miRNA 海綿來抑制 miR-29b-3p 的表達，從而增強 MCL-1 的轉錄翻譯，抑制細胞凋亡，從而降低化療藥物 BTZ 對細胞的敏感性，從而促進腫瘤生長，並可能部分發展對硼替佐米的耐藥性。這些發現可能有助於深入了解獲得性 BTZ 耐藥的分子機制，並為 MM 的臨床治療開發新的藥物靶點。
