肿瘤细胞治疗研究
英文原题：T and NK cell lymphoma cell lines do not rely on ZAP-70 for survival.
B细胞受体（BCR）信号对B细胞淋巴瘤的生存至关重要，是Ibrutinib等药物的治疗靶点。
B细胞受体（BCR）信号对B细胞淋巴瘤的生存至关重要，是Ibrutinib等药物的治疗靶点。然而，T细胞受体（TCR）信号在T/自然杀伤（NK）淋巴瘤生存中的作用尚不清楚。ZAP-70（zeta相关蛋白-70）是一种细胞质酪氨酸激酶，在T细胞受体（TCR）信号中起关键作用。它也被证明在正常NK细胞信号传导和激活中发挥作用。免疫组化已在外周T细胞淋巴瘤（PTCL）和NK细胞淋巴瘤（NKTCL）中检测到ZAP-70高表达。因此，我们通过ZAP-70信号研究了TCR通路在介导这些恶性肿瘤增殖和生存中的作用。ZAP-70蛋白在T细胞淋巴瘤细胞系（JURKAT和KARPAS-299）和NKTCL细胞系（KHYG-1、HANK-1、NK-YS、SNK-1和SNK-6）中高表达，但在多个B细胞淋巴瘤细胞系中不表达。siRNA敲低ZAP-70抑制了ZAP-70底物SLP76、LAT和p38MAPK的磷酸化，但未影响这些细胞系的细胞活力或诱导凋亡。同样，虽然ZAP-70的稳定过表达介导TCR通路中靶底物磷酸化增加，但并未促进NKTCL细胞系生存或生长的增加。表皮生长因子受体（EGFR）抑制剂Gefitinib对ZAP-70具有脱靶活性，在ZAP-70过表达（OE）或敲低（KD）细胞系之间也未显示出任何差异性细胞杀伤。全转录组RNA测序突出表明，ZAP-70 KD在三种不同的T/NK细胞系中诱导的差异基因表达极少。重要的是，ZAP-70 KD未显著富集任何下游TCR相关基因和通路。总之，这表明ZAP-70在T/NK淋巴瘤中的高表达和持续信号传导对细胞存活或下游TCR介导的信号传导和基因表达并非关键。因此，ZAP-70可能不是T/NK细胞恶性肿瘤的合适治疗靶点。
B-cell receptor (BCR) signalling is critical for the survival of B-cell lymphomas and is a therapeutic target of drugs such as Ibrutinib. However, the role of T-cell receptor (TCR) signalling in the survival of T/Natural Killer (NK) lymphomas is not clear. ZAP-70 (zeta associated protein-70) is a cytoplasmic tyrosine kinase with a critical role in T-cell receptor (TCR) signalling. It has also been shown to play a role in normal NK cell signalling and activation. High ZAP-70 expression has been detected by immunohistochemistry in peripheral T cell lymphoma (PTCL) and NK cell lymphomas (NKTCL). We therefore, studied the role of TCR pathways in mediating the proliferation and survival of these malignancies through ZAP-70 signalling. ZAP-70 protein was highly expressed in T cell lymphoma cell lines (JURKAT and KARPAS-299) and NKTCL cell lines (KHYG-1, HANK-1, NK-YS, SNK-1 and SNK-6), but not in multiple B-cell lymphoma cell lines. siRNA depletion of ZAP-70 suppressed the phosphorylation of ZAP-70 substrates, SLP76, LAT and p38MAPK, but did not affect cell viability or induce apoptosis in these cell lines. Similarly, while stable overexpression of ZAP-70 mediates increased phosphorylation of target substrates in the TCR pathway, it does not promote increased survival or growth of NKTCL cell lines. The epidermal growth factor receptor (EGFR) inhibitor Gefitinib, which has off-target activity against ZAP-70, also did not show any differential cell kill between ZAP-70 overexpressing (OE) or knockdown (KD) cell lines. Whole transcriptome RNA sequencing highlighted that there was very minimal differential gene expression in three different T/NK cell lines induced by ZAP-70 KD. Importantly, ZAP-70 KD did not significantly enrich for any downstream TCR related genes and pathways. Altogether, this suggests that high expression and constitutive signalling of ZAP-70 in T/NK lymphoma is not critical for cell survival or downstream TCR-mediated signalling and gene expression. ZAP-70 therefore may not be a suitable therapeutic target in T/NK cell malignancies.
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