以HMGB1为新靶向治疗弥漫性大B细胞淋巴瘤的作用机制和应用价值的研究

Diffuse large B-cell lymphoma (DLBCL) is the most common and most aggressive lymphoma worldwide and about 1/3 DLBCL patients currently remains incurable with conventional chemotherapy approaches. It is characterized by highly biological heterogeneity which is caused not only tumour cells themselves but also dependent on their microenvironment. Soluble factors, called cytokines, in the microenvironment, support DLBCL cell proliferation and prevent them from dying. Recently, we have found significantly increased levels of the cytokine HMGB1 in the blood of B-cell malignancy patients and levels are associated with a worse clinical outcome. These damage‐associated molecules are released by malignant B cells and can make tumour cells produce more cytokines which amplify and prolong tumour cell survival. The mechanisms by which HMGB1 induces DLBCL cell survival are unclear. The aim of this project is to understand exactly how the HMGB1 prolongs the lifespan of DLBCL cells and whether DLBCL cells respond differently from normal B‐cells to this inflammatory complex. This project involves experiments determining how this inflammatory cytokine contacts signals on cell surface, signal transduction inside the cell, and then cytokine production by primary DLBCL cells. This study will afford great opportunity for us to find key molecules that are involved in DLBCL cell survival that can be used as therapeutic targets to kill DLBCL cells.

弥漫性大B细胞淋巴瘤(DLBCL)是世界范围内常见的、恶性度最高的淋巴系统肿瘤。大约1/3患者常规化疗效果不佳。造成这些差异的原因除了肿瘤细胞内在某些分子表达异常外还与肿瘤生长的微环境密切相关。在DLBCL微环境中细胞因子起到保护肿瘤细胞免于死亡并促进其增殖的作用。我们发现B细胞恶性肿瘤患者血浆中细胞因子HMGB1的含量显著高于正常人，并且HMGB1含量高的患者临床预后较差；而B细胞恶性肿瘤可以释放HMGB1。细胞外的HMGB1刺激免疫细胞和基质细胞分泌多种细胞因子以此达到延长肿瘤细胞存活之目的。HMGB1引起DLBCL抑制死亡的机制目前还不清楚，本项目将研究HMGB1如何延长DLBCL生存的作用机制, 研究范围从HMGB1与细胞膜表面的受体连接方式到细胞内部信号传导通路的调控, 以及细胞产生和分泌HMGB1的机制。本研究将为发现调控DLBCL生存的关键分子和临床治疗新靶向提供良好契机。

HMGB1是近年来备受关注的炎性因子之一，在细胞内是与染色质相关的核蛋白，在肿瘤及正常细胞内均有表达。HMGB1参与调控肿瘤细胞浸润转移，与耐药机制和临床预后密切相关。在白血病细胞中，HMGB1与NF-ҡB结合并使之活性增强，因上调Bcl-2的表达而抑制细胞凋亡发生。细胞外的HMGB1与自身表面受体RAGE或TLRs结合，可引起多种肿瘤细胞生长和增殖。而HMGB1在弥漫大B细胞淋巴瘤的作用却鲜为人知。本项目的研究我们发现HMGB1可通过STAT3、AKT和ERK通路引起肿瘤细胞增殖，而这种增殖仅限于GCB型而不是ABC型DLBCL细胞。丙酮酸乙酯（Ethyl pyruvate）是HMGB 1抑制剂，体内和体外实验均证明EP可通过阻滞细胞S期抑制DLBCL细胞增殖。在非小细胞肺癌中，EP可抑制STAT3，NF-кB的活性，上调Bax和降低Bcl-2，Mcl-1表达引起细胞死亡。无论是肺腺癌还是肺鳞癌对EP均具有相同的敏感性。我们的发现为弥漫大B细胞淋巴瘤和非小细胞肺癌的治疗提供新的设想和理论基础，同时证明HMGB1作为肿瘤治疗新靶点具有潜在的临床价值。