假性激酶TRIB3促进非霍奇金氏淋巴瘤发生发展的作用和机制

Patients with relapsed/refractory Non-Hodgkin's lymphoma (NHL) have a dismal prognosis, which makes NHL become one of the most serious types of malignant tumors. Currently there is an urgent need for novel agents and new treatment options for NHL therapy. Targeting lymphoma stem cells inhibits tumorigenesis, drug resistance and recurrence through the reduction of key oncoprotein expressions, which is considered as a new strategy of NHL treatment. Pseudokinase TRIB3 acts as a metabolic stress protein, which is closely related to the tumour occurrence and development. We recently found that TRIB3 was highly expressed in non-Hodgkin's lymphoma tissues, and TRIB3 depletion inhibited lymphoma growth and stem-like traits, and reduced the expressions of multiple tumor-promoting factors including C-Myc and Ras. Based on our previous findings, we intend to use in vitro cell models, transgenic animal models, PDX models and clinical specimens to investigate the molecular mechanism of TRIB3 in the lymphoma development and progression by interacting with the key tumor-promoting factors. This study may not only provide new insights into the specific mechanism of TRIB3 in the pathogenesis of NHL, but also provide clues and opportunity for the development of anti-lymphoma drugs.

非霍奇金氏淋巴瘤已成为威胁人类健康的恶性肿瘤之一，需要寻找新的治疗药物及方法有效地治疗复发难治性患者并延长其生存期。靶向具有起始、维持肿瘤能力的干细胞已经成为淋巴瘤治疗的首要目标，而降低关键原癌蛋白的表达是抑制淋巴瘤干细胞的新策略。假性激酶TRIB3是一种压力和代谢应激蛋白，与肿瘤发生发展密切相关。我们最近发现，非霍奇金氏淋巴瘤组织高表达TRIB3，敲除TRIB3抑制淋巴瘤生长和肿瘤干性，并显著降低C-Myc等多个促肿瘤因子表达。但TRIB3如何调节促肿瘤因子表达、促进淋巴瘤发生发展的机制尚不明确。为此，我们将采用体内外模型，从临床-动物-细胞-分子四个层次，确定TRIB3是否通过与C-Myc等促肿瘤因子发生相互作用参与淋巴瘤干性维持，进而发挥促淋巴瘤效应；阐明TRIB3调节C-Myc等促肿瘤因子表达的分子机制。本研究不但揭示TRIB3促淋巴瘤的生物学机制，也为抗淋巴瘤药物研发提供新思路。

淋巴瘤是起源于淋巴系统的恶性克隆性和增生性疾病。我国淋巴瘤患者大部分为非霍奇金氏淋巴瘤（NHL）。NHL的复发是临床治疗的难点，而肿瘤干细胞的存在是导致淋巴瘤复发的重要原因之一。靶向肿瘤起始细胞或肿瘤干细胞已经成为淋巴瘤治疗的首要目标，降低关键原癌蛋白的表达被认为是清除淋巴瘤干细胞的新型策略本团队前期研究工作提示，假性激酶TRIB3通过调节急性早幼粒白血病(APL)起始因子PML-RARa的稳定性参与APL疾病进程，其作用机制为TRIB3与PML-RARa蛋白相互作用抑制PML-RARa的苏木化、泛素化及降解。提示抑制TRIB3是靶向治疗白血病的新选择。然而TRIB3在其它血液系统肿瘤中的作用尚不明确。本项目研究发现tribbles homologue 3 (TRIB3)的高表达与淋巴瘤标本中MYC表达升高呈正相关;TRIB3缺失通过降低MYC表达来减弱MYC驱动淋巴瘤的发生和发展。在机制上，TRIB3与MYC相互作用抑制E3泛素连接酶ube3b介导的MYC泛素化和降解，从而增强MYC的转录活性，导致淋巴瘤细胞的高增殖和自我更新。使用肽干扰TRIB3-MYC相互作用与阿霉素一起降低MycEμ小鼠和患者来源的异种移植的肿瘤负担。UBE3B、TRIB3和MYC的病理生理相关性在人类淋巴瘤中得到进一步证实。我们的研究强调了控制MYC表达的关键机制，以及治疗TRIB3-MYC高表达淋巴瘤的潜在治疗方案。该研究为血液肿瘤的治疗提供新策略和新靶点，亦为抗肿瘤多肽药物研发奠定理论基础。该研究目前已发表于Theranostics （IF=11.556）和Molecules杂志（IF=4.927）。基于该多肽我们申请了一项专利。培养博士研究生2名，参加国外学术会议一次。