Yang Haijun, Zhang Ping, Li Junkuo, Gao Yang, Zhao Luyao, Li Jia, Guo Mei, Zhang Jingfang, Li Haimei, Wang Fuqiang, Yuan Yufen
Department of Pathology, Anyang Tumor Hospital, The Fourth Affiliated Hospital of Henan University of Science and Technology, Anyang 455000, People's Republic of China.
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100032, People's Republic of China.
Onco Targets Ther. 2020 Aug 25;13:8593-8600. doi: 10.2147/OTT.S247429. eCollection 2020.
Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous type of non-Hodgkin lymphoma with many molecular subtypes that can be distinguished by gene expression profiling (GEP). However, the pathogenesis of DLBCL is still unclear.
The expression levels of the prolyl isomerase PIN-1 and other related proteins were determined in 73 primary DLBCL patient samples and cell lines by Western blotting (WB) and immunohistochemical (IHC) staining. Cell cycle and apoptosis were evaluated by flow cytometry. Lymphoma cell viability was detected by CCK-8 proliferation assay.
High levels of PIN-1 expression were detected in 55% of germinal center B cell (GCB) DLBCL patient samples, whereas such abnormal expression levels were found in only 11% of non-GCB DLBCL patient samples. PIN-1 expression was positively associated with activation of the oncogenic phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in both GCB DLBCL cell lines and primary patient samples. Depletion of PIN-1 was cytotoxic to GCB DLBCL model cell lines because it led to inhibition of the PI3K/AKT signaling pathway, revealing a GCB DLBCL subgroup that is dependent on this pathway. A PI3K inhibitor was selectively toxic to GCB DLBCL lines expressing high levels of PIN-1.
Our study used PIN-1 to identify a new subgroup of GCB DLBCL associated with the PI3K/AKT signaling pathway, and our findings reveal that inhibition of PI3K is a promising therapeutic approach for GCB DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是一种高度异质性的非霍奇金淋巴瘤，有许多分子亚型，可通过基因表达谱分析（GEP）加以区分。然而，DLBCL的发病机制仍不清楚。
采用蛋白质免疫印迹法（WB）和免疫组织化学（IHC）染色，检测73例原发性DLBCL患者样本和细胞系中脯氨酰异构酶PIN-1及其他相关蛋白的表达水平。通过流式细胞术评估细胞周期和细胞凋亡情况。采用CCK-8增殖试验检测淋巴瘤细胞活力。
在55%的生发中心B细胞（GCB）DLBCL患者样本中检测到高水平的PIN-1表达，而在非GCB DLBCL患者样本中，只有11%存在这种异常表达水平。在GCB DLBCL细胞系和原发性患者样本中，PIN-1表达均与致癌性磷酸肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路的激活呈正相关。PIN-1缺失对GCB DLBCL模型细胞系具有细胞毒性，因为它会导致PI3K/AKT信号通路受到抑制，从而揭示了一个依赖该信号通路的GCB DLBCL亚组。PI3K抑制剂对高表达PIN-1的GCB DLBCL细胞系具有选择性毒性。
我们的研究利用PIN-1鉴定出一个与PI3K/AKT信号通路相关的GCB DLBCL新亚组，我们的研究结果表明，抑制PI3K是一种有前景的GCB DLBCL治疗方法。
