Differential Expression of Calcium Channels and Signaling Pathways in Hematologic Cancers

Cell surface calcium (Ca2+) channels permit Ca2+ ion influx, with Ca2+ taking part in cellular functions such as proliferation, survival, and activation. The expression of voltage-dependent Ca2+ (CaV) channels may modulate the growth of hematologic cancers. Profile analysis of Ca2+ channels, with a focus on the L-type CaV channels, was performed on RNA sequencing data from lymphoma and leukemia cell lines and samples derived from patients with diffuse large B cell lymphoma (DLBCL). CaV1.2 expression was found to be elevated in classical Hodgkin lymphoma (CHL) cell lines when compared to other B cell lymphoma cell lines. In our analysis comparing activated B cell-like DLBCL (ABC-DLBCL) and germinal centre B cell-like DLBCL (GCB-DLBCL) patient samples, ABC-DLBCL revealed stronger expression of CaV1.3, whereas CaV1.1, CaV1.2, and CaV1.4 showed greater expression levels in GCB-DLBCL. As Ca2+ is known to bind to calmodulin, leading to calcineurin activation and the passage of nuclear factor of activated T cells (NFAT) to the cell nucleus, pathways for calcineurin, calmodulin, NFAT, and Ca2+ signaling were also analyzed by gene set enrichment analysis. The NFAT and Ca2+ signaling pathways were found to be upregulated in the CHL cell lines relative to other B cell lymphoma cell lines. Furthermore, the calmodulin and Ca2+ signaling pathways were shown to be downregulated in the ABC-DLBCL patient samples. The findings of this study suggest that L-type CaV channels and Ca2+-related pathways could serve as differentiating components for biologic therapies to target hematological cancers. RNASeq analysis of 44 cell lines derived from lymphoma samples.

细胞表面钙（Ca²⁺）通道介导钙离子内流，Ca²⁺参与细胞增殖、存活与活化等多种细胞生命活动。电压门控钙（CaV）通道的表达或可调控血液恶性肿瘤的生长进程。本研究基于淋巴瘤、白血病细胞系及弥漫大B细胞淋巴瘤（DLBCL）患者样本的RNA测序数据，开展钙通道表达谱分析，重点聚焦L型CaV通道。研究发现，相较于其他B细胞淋巴瘤细胞系，经典型霍奇金淋巴瘤（CHL）细胞系中CaV1.2的表达水平显著升高。在对比活化B细胞样DLBCL（ABC-DLBCL）与生发中心B细胞样DLBCL（GCB-DLBCL）患者样本的分析中，ABC-DLBCL样本的CaV1.3表达水平更高，而GCB-DLBCL样本则呈现CaV1.1、CaV1.2及CaV1.4的高表达。鉴于Ca²⁺可与钙调蛋白（calmodulin）结合，进而激活钙调磷酸酶（calcineurin）并促使活化T细胞核因子（NFAT）转位入核，本研究同时通过基因集富集分析，对钙调磷酸酶、钙调蛋白、NFAT及Ca²⁺信号通路展开了分析。结果显示，相较于其他B细胞淋巴瘤细胞系，CHL细胞系中的NFAT与Ca²⁺信号通路呈上调状态。此外，ABC-DLBCL患者样本中的钙调蛋白与Ca²⁺信号通路呈下调状态。本研究结果表明，L型CaV通道及Ca²⁺相关信号通路或可作为血液恶性肿瘤靶向生物治疗的差异化靶点与标志物。本研究对44株淋巴瘤来源细胞系开展了RNA测序分析。