Xiao Shuxin, Fan Chuanbo, Ma Jinlong, Xue Hongwei, Xu Liqin
Department of Lymphoma and Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Hematology, Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, China.
Acta Haematol. 2022;145(4):371-383. doi: 10.1159/000521445. Epub 2021 Dec 14.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and a candidate therapeutic option for human cancers. However, the underlying mechanism of STAT3 in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) is yet to be established. We studied here whether STAT3 contributes to C-C motif chemokine ligand (CCL4) transcription elevation in DLBCL. Our established protein-protein interactions network revealed the overexpression of STAT3 and CCL4 in DLBCL. Mechanistically, STAT3 activated CCL4 transcription to induce the Wnt/β-catenin pathway. The prognostic analysis exhibited that the overall survival of patients with high STAT3 and CCL4 were poorer than those with low STAT3 and CCL4 expression. In addition, silencing of STAT3 reverted the malignant phenotype in DLBCL cells. CCL4 overexpression partly weakened the si-STAT3-mediated antitumor effects on DLBCL cells. Tumor xenograft models showed that si-STAT3 inhibited tumor growth in vivo and decreased proliferative and mitogenic activities in tumor tissues, which was consistent with the in vitro data. Hence, this study provides new evidence that STAT3 and CCL4 may be new prognostic biomarkers and therapeutic targets for treating DLBCL.
信号转导与转录激活因子3（STAT3）是一种转录因子，也是人类癌症的一种潜在治疗选择。然而，STAT3在弥漫性大B细胞淋巴瘤（DLBCL）发病机制中的潜在机制尚未明确。我们在此研究了STAT3是否导致DLBCL中C-C基序趋化因子配体（CCL4）转录升高。我们建立的蛋白质-蛋白质相互作用网络显示DLBCL中STAT3和CCL4过表达。机制上，STAT3激活CCL4转录以诱导Wnt/β-连环蛋白通路。预后分析显示，STAT3和CCL4高表达患者的总生存期比STAT3和CCL4低表达患者更差。此外，沉默STAT3可逆转DLBCL细胞的恶性表型。CCL4过表达部分削弱了si-STAT3介导的对DLBCL细胞的抗肿瘤作用。肿瘤异种移植模型显示，si-STAT3在体内抑制肿瘤生长，并降低肿瘤组织中的增殖和促有丝分裂活性，这与体外数据一致。因此，本研究提供了新的证据，表明STAT3和CCL4可能是治疗DLBCL的新预后生物标志物和治疗靶点。
