Zaidi Afak Rasheed Salman, Dresman Sadie, Burt Charlotte, Rule Simon, McCallum Lynn
School of Biomedical and Healthcare Science, Peninsula Schools of Medicine and Dentistry, Plymouth University, PSQ B413, Drake Circus, Plymouth, PL4 8AA, UK.
Department of Biology, College of Education for Pure Science, University of Diyala, Baquba, Diyala, Iraq.
J Cell Commun Signal. 2019 Sep;13(3):421-434. doi: 10.1007/s12079-018-0494-y. Epub 2018 Nov 21.
Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin's lymphoma characterised by overexpression of cyclin D1. Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease with median survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators in progressive MCL. We have used the human MCL cell lines REC1 < G519 < JVM2 as a model for disease aggression. The magnitude of CCN1 expression in human MCL cells is REC1 > G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1 expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expression of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18-20 and 28-30 kDa) decreased with disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21and p27) are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519 cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27 followed a similar profile of expression as cyclin D1. Conversely, p21 was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellular localization detected p21/ p27 primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction with reduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease and treatment resistance.
套细胞淋巴瘤（MCL）是一种相对罕见的非霍奇金淋巴瘤，其特征为细胞周期蛋白D1过表达。许多患者在3年内出现或进展为晚期疾病。MCL被认为是一种无法治愈的疾病，中位生存期为3至4年。我们研究了CCN1（CYR61）和细胞周期调节因子在进展性MCL中的作用。我们使用人MCL细胞系REC1＜G519＜JVM2作为疾病侵袭的模型。通过RQ-PCR检测，人MCL细胞中CCN1表达量为REC1＞G519＞JVM2细胞，表明CCN1表达随疾病进展而降低。通过蛋白质印迹法研究CCN1异构体表达，结果显示虽然全长CCN1在细胞系中的表达几乎没有改变，但截短形式（18 - 20和28 - 30 kDa）的表达随疾病进展而降低。然后我们证明细胞周期蛋白D1和细胞周期蛋白依赖性激酶抑制剂（p21和p27）也参与疾病进展。细胞周期蛋白D1在REC1细胞中高表达（光密度：1.0），在G519细胞中降至五分之一（光密度：0.2），在JVM2细胞中通过蛋白质印迹法未检测到。p27的表达模式与细胞周期蛋白D1相似。相反，p21在REC1细胞中不存在，在G519和JVM2细胞中表达增加。亚细胞定位检测到p21/p27主要位于细胞质中，细胞核中没有，这与治疗耐药性中作用改变一致。CCN1截短形式的失调与MCL进展相关。结合细胞周期蛋白D1表达降低和p21表达增加，这种分子特征可能描绘了侵袭性疾病和治疗耐药性。
