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Advances in Clinical Medicine
Vol. 13  No. 06 ( 2023 ), Article ID: 67741 , 10 pages
10.12677/ACM.2023.1361421

细胞分裂周期相关蛋白5的功能及其在癌症发生中作用的研究进展

范锦博1，田甜1，孙卓1,2

1西安市病原微生物与肿瘤免疫重点实验室，陕西 西安

2西安医学院基础医学研究所，陕西 西安

收稿日期：2023年5月25日；录用日期：2023年6月19日；发布日期：2023年6月28日

摘要

细胞分裂周期相关蛋白5 (CDCA5)又名Sororin，最初作为一种调控细胞周期的蛋白被发现，它在姐妹染色单体粘连、细胞周期调控、DNA损伤修复中具有重要作用。近年来CDCA5在癌症发生发展中的作用被逐渐发现，CDCA5在包括肝细胞癌、肺癌、前列腺癌、卵巢癌、膀胱癌、乳腺癌、胃癌、口腔鳞状细胞癌和食管鳞状细胞癌在内的多种癌症中具有肿瘤促进因子的作用。CDCA5参与癌症发生发展的机制主要有：AKT通路、ERK通路、细胞周期调控、蛋白互作等。CDCA5具有作为多种癌症诊断、预后分子标志物及治疗靶点的应用前景。

关键词

细胞分裂周期相关蛋白5，癌症，姐妹染色单体粘连，肿瘤促进因子

Research Progress of the Function of CDCA5 and Its Role in Cancer Progression

Jinbo Fan1, Tian Tian1, Zhuo Sun1,2

1Xi’an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi’an Shaanxi

2Institute of Basic Medical Sciences, Xi’an Medical University, Xi’an Shaanxi

Received: May 25th, 2023; accepted: Jun. 19th, 2023; published: Jun. 28th, 2023

ABSTRACT

Cell division cycle-associated protein 5 (CDCA5), also called Sororin, was first identified as a regulator of the cell cycle. It plays important roles in sister chromatid cohesion, cell cycle regulation and DNA damage repair. Recently it has been discovered that CDCA5 plays a part in the progression of various types of cancer, it promotes the progression of different types of cancer including hepatocellular carcinoma, lung cancer, prostate cancer, ovarian cancer, bladder cancer, breast cancer, gastric cancer, oral squamous cell carcinoma and esophageal squamous cancer. CDCA5 exerts its cancer promoting functions through several mechanisms, such as the AKT pathway, ERK pathway, cell cycle regulation and protein interactions. CDCA5 has potential to become diagnosis/prognostic marker and target for treatment in many cancer types.

Keywords:Cell Division Cycle-Associated Protein 5, Cancer, Cohesion of Sister Chromatids, Tumor Promoting Factor

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

CDCA5 (Cell division cycle associated protein 5，细胞周期相关蛋白5，别名Sororin)是在2005年的一项对于细胞周期调控蛋白的筛选中作为APC复合物(anaphase-promoting complex，后期促进复合物)的底物被发现的 [1] 。CDCA5蛋白由252个氨基酸组成，分子质量为27 kD，CDCA5可以和PDS5A (PDS5 Cohesin Associated Factor A, PDS5相关因子A)和PDS5B (PDS5 cohesin associated factor B, PDS5相关因子B)相互作用。CDCA5在分裂间期分布于细胞核内，而在分裂期散布在细胞质中。HeLa细胞中，CDCA5的敲低可导致有丝分裂停滞及姐妹染色单体间距增加 [2] 。CDCA5对于哺乳动物早期发育是必需的，纯合子基因敲除小鼠胚胎致死 [3] 。CDCA5最初被发现参与姐妹染色单体粘连和细胞周期调控，而从2018年 [4] 至今CDCA5参与各种癌症发生发展逐渐成为研究热点。截至目前，CDCA5被发现与多种癌症的发生或发展相关，CDCA5影响多种癌细胞的生长、迁移、凋亡和细胞周期调控，在体内移植瘤实验种被证明与多种肿瘤的生长相关。CDCA5作为诊断和预后分子标志物以及治疗靶点的潜力需要更加深入的机制探究。

2. CDCA5在细胞周期中的作用

2.1. CDCA5在姐妹染色单体偶联中的作用

真核细胞有丝分裂过程中经过S期的DNA复制形成两条姐妹染色单体，两条姐妹染色单体在黏连蛋白(cohesin)的作用下粘连在一起，随后在有丝分裂后期两个姐妹染色单体分别进入两个子代细胞。姐妹染色单体的粘连对于有丝分裂顺利进行至关重要，两条DNA链空间上的靠近为DNA同源重组修复提供了结构基础，为姐妹染色单体间的交叉互换提供了结构基础。姐妹染色单体在细胞进入有丝分裂核膜降解时变成显微镜下可见的棒状结构，然而在细胞进入有丝分裂前的几小时内已经可以用FISH (fluorescence in situ hybridization，荧光原位杂交)观测到成对的基因位点 [5] 。

黏连蛋白作用周期分为：黏连蛋白装载、建立姐妹染色单体的粘连、粘连的维持以及黏连蛋白卸载。在DNA复制前，黏连蛋白短暂地与染色体结合 [6] ，WAPL (Wings apart-like protein homolog)促进其动态解离 [7] 。在S期，CDCA5通过抑制WAPL的作用使得部分黏连蛋白与染色体稳定结合 [8] 。CDCA5可以维持从S期到分裂期姐妹染色单体之间的粘连。CDCA5参与粘连的维持和黏连蛋白的卸载等过程，在姐妹染色单体的粘连过程具有重要作用 [9] 。若CDCA5被敲除，则姐妹染色单体间的粘连无法维持，在显微镜下观察时可以看到明显的缝隙。

人类细胞有丝分裂中粘连的解除分为两个阶段：分裂前期染色体臂粘连解除和分裂后期着丝粒粘连解除 [10] 。CDCA5在这两个阶段中都具有重要作用 [11] 。CDK1 (Cyclin-dependent kinase 1，细胞周期蛋白依赖性激酶1)对于CDCA5的磷酸化以及PLK1 (Polo like kinase 1)对于黏连蛋白SA2亚基的磷酸化介导了黏连蛋白从染色体臂上的卸载 [12] [13] 。CDCA5羧基端12个氨基酸可以与黏连蛋白相互作用 [14] 。

2.2. CDCA5在DNA损伤修复中的作用

CDCA5对于G2期正常的DNA双链断裂修复是必需的 [8] 。使用胸腺嘧啶核苷双阻断法将Hela细胞同步在G1/S期，加入依托泊苷诱发DNA双链断裂，使用咖啡因失活DNA损伤检查点，使得DNA双链断裂存在的情况下也可进入分裂期，使用纺锤体毒素诺考达唑将细胞阻断在分裂期，后用染色体分散方法检查DNA双链断裂情况 [7] 。发现在对照组细胞中，只有约35%的细胞含有染色体断裂，然而约有88%CDCA5敲低的细胞含有染色体断裂。证明CDCA5在DNA双链断裂修复中具有重要作用。

2.3. CDCA5在减数分裂中的作用

哺乳动物卵细胞中CDCA5含量降低导致CDK1活性降低，细胞被阻滞在G2/M期 [15] 。CDCA5对于减数分裂中纺锤体组装是必需的。CDCA5可以保护Cyclin B2 (细胞周期蛋白B2)不被泛素化途径降解。

3. CDCA5在癌症发生中的作用

3.1. CDCA5影响多种癌症发生发展

利用生物信息学方法筛选与肺腺癌 [16] [17] [18] [19] 、肝细胞癌 [20] [21] [22] [23] [24] 、前列腺癌 [25] 、结直肠癌 [26] 、乳腺癌 [27] 、卵巢上皮癌 [28] [29] 、胰腺癌 [30] 发展和预后相关的基因中都发现了CDCA5。多项研究表明CDCA5在多种癌症中过表达，起到肿瘤促进因子的作用，如：食管鳞状细胞癌 [31] ，肺癌 [32] ，膀胱癌 [33] ，前列腺癌 [34] [35] ，肾透明细胞癌 [36] ，口腔鳞状细胞癌 [37] ，胃癌 [38] ，胸膜间皮瘤 [39] ，乳腺癌 [40] [41] ，和肝细胞癌 [4] [42] [43] [44] 。

其中大多数研究从表型上描述了CDCA5对不同种类癌细胞生长、凋亡、移植瘤生长的影响，然而机制尚不明确。部分研究对于CDCA5参与癌症发生的机制进行了深入的探究，主要发现的机制有：AKT通路 [45] ，ERK (extracellular regulated protein kinases，细胞外调节蛋白激酶)通路。

CDCA5在多种癌症中有着相似的肿瘤促进因子作用。这种作用表现在几个方面 [4] [33] [41] [46] [47] ：癌组织中CDCA5表达量高于癌旁组织；患者中CDCA5的高表达和较低存活率相关；在癌细胞系中敲低CDCA5使得细胞增殖降低，细胞凋亡增加；在小鼠移植瘤实验中，敲低CDCA5可以抑制癌细胞的生长(表1)。

Table 1. Summary of cancer types and mechanism affected by CDCA5

表1. CDCA5影响的癌症种类及机制总结

3.2. CDCA5参与癌症发生的相关机制

3.2.1. PI3K/AKT通路

PI3K/AKT (phosphatidylinositide 3-kinase磷脂酰肌醇激酶–丝氨酸/苏氨酸激酶AKT)通路参与包括蛋白合成、细胞增殖、细胞凋亡等重要的细胞过程。通路可以被多种信号激活，如：激素，生长因子及细胞外基质成分等。PI3K/AKT通路参与多种癌症发生发展，在抗癌治疗的研究中备受关注。PI3K可以被多种上游信号通路激活，包括胰岛素受体，受体酪氨酸激酶，G蛋白偶联受体，细胞因子受体等。被激活的PI3K进一步激活AKT，AKT激活后可以通过磷酸化和形成复合体等方式改变下游分子的活性。AKT激活可以造成细胞凋亡抑制，细胞增殖加快等。AKT通过与BAX (BCL-2 associated X protein, BCL-2相关X蛋白)结合，抑制其在线粒体外膜穿孔的功能，从而抑制细胞凋亡。AKT激活mTOR (mammalian target of rapamycin，哺乳动物雷帕霉素靶蛋白)信号通路，通过S6K (Ribosomal protein S6 kinase 1，核糖体蛋白S6激酶1基因)翻译因子激活mRNA向蛋白质的翻译过程，从而促进细胞增殖。FOXO (Forkhead box protein O，叉头框蛋白O)可以通过抑制细胞增殖起到肿瘤抑制因子的作用，AKT通过磷酸化FOXO，使其通过泛素化途径降解，从而抑制FOXO的作用。

CDCA5敲低的肾透明细胞癌、肝细胞癌和前列腺癌细胞中，p-AKT (磷酸化的AKT)含量降低 [36] [45] [49] 。CDCA5敲低对于肝细胞癌及膀胱癌细胞增殖的抑制可以通过加入AKT的激活剂SC79部分缓解 [33] [45] 。

CDCA5通过上调CDC2和cyclin B1 (细胞周期蛋白B1)以及激活PI3K/AKT/mTOR通路促进膀胱癌细胞增殖 [33] 。当CDCA5在乳腺癌细胞中被过表达时，p-mTOR (磷酸化的mTOR)的水平有超过2倍的上调，而p-PI3K (磷酸化的PI3K)、p-AKT、以及上皮细胞间充质转化相关标记物也有不同程度的轻微上调 [55] 。

在肝细胞癌细胞系MHCC97-H和Huh7中敲低CDCA5后，p-AKT含量降低，皮下肿瘤中敲低CDCA5后，p-AKT含量降低 [44] ，以上结果提示敲低CDCA5对肝细胞癌细胞系细胞增殖的抑制可能是通过AKT通路。

3.2.2. ERK通路

ERK通路可以被包括生长因子和激素在内的多种细胞外因子激活，最终影响细胞增殖和分化、细胞凋亡等多种细胞过程。首先，受体酪氨酸激酶，G蛋白偶联受体或整合素激活GTP酶Ras (rat sarcoma，大鼠肉瘤)。随后Raf (Rapidly accelerated Fibrosarcoma，快速进展纤维肉瘤)、MEK-1/2 (meiosis-specific serine/threonine-protein kinase 1/2，丝裂原活化蛋白激酶激酶1/2)和ERK依次被激活。激活的ERK可以磷酸化一系列核内转录因子，包括：c-fos，c-jun，Elk-1，c-myc和ATF2 (activating transcription factor 2，激活转录因子2)，这些转录因子可以通过调节相关基因表达参与细胞增殖和分化调控。

在结直肠癌细胞系中敲低CDCA5导致p-ERK1/2 (磷酸化的ERK1/2)及c-jun含量降低，表明ERK信号通路被抑制 [46] 。敲低CDCA5的前列腺癌细胞系中磷酸化的ERK含量降低，而高表达CDCA5的前列腺癌患者ERK磷酸化水平也较高 [34] 。

3.2.3. p53-p21通路

在人类非小细胞肺癌细胞系A549和HCC827中敲低CDCA5后，p53和p21的含量也降低，表明CDCA5可能通过p53-p21通路影响非小细胞肺癌的细胞周期 [48] 。

3.2.4. 细胞周期

处于正常细胞周期中的细胞需要受到一系列细胞周期检查点的调控，以保证DNA复制和细胞分裂的正常进行。细胞周期检查点主要包括G1期、G2期、M期检查点。G1检查点控制细胞能否通过G1期进入DNA合成的S期。G1检查点检测细胞内是否含有DNA损伤，并确认环境中含有足够的营养物质和生长因子以完成DNA复制。G1检查点由CDK4/6-Cyclin D (周期蛋白依赖性激酶4/6-周期蛋白D)和CDK2-CyclinE (周期蛋白依赖性激酶2-周期蛋白E)调控。G2检查点确保所有DNA都已准确复制，并且没有DNA损伤。G2检查点通过CyclinB/CDK1复合物调控，若基因中存在DNA损伤，则会通过包括P53、ATM/ATR等各种信号通路失活Cyclin B/CDK1复合物，细胞周期阻滞在G2/M期。

在一些种类的癌细胞中敲低CDCA5会造成G2/M期阻滞。在肾细胞癌细胞系中敲低CDCA5导致G0/G1期细胞比例降低，G2/M期细胞比例增加 [36] 。敲低CDCA5的稳转前列腺癌细胞系也有相似表型 [34] ，表明细胞周期被阻滞在G2/M期。Cyclin B1含量降低，这与细胞周期被阻断在分裂期之前相关。G2/M期阻滞抑制了肿瘤细胞的增殖。肝细胞癌细胞系中敲低CDCA5导致G2/M期阻滞 [4] [44] [57] [58] 。

在另一些种类的癌细胞中CDCA5与G1/S期阻滞相关。CDCA5过表达和膀胱尿路上皮癌细胞G1/S期阻滞相关 [54] 。胃癌细胞系中敲低CDCA5导致G1期细胞比例升高，即G1/S期阻滞 [50] 。在非小细胞肺癌细胞系中敲低CDCA5引起G1期阻滞 [48] 。

在细胞周期通路中起到重要作用的Cyclin A2 (周期蛋白A2)，cyclin B1，MPIP1 (M-phase inducer phosphatase 1，M期诱导磷酸酶1)和PCNA (proliferating cell nuclear antigen，增值细胞核抗原)，都与CDCA5在食管鳞状细胞癌细胞系中有共表达关系。在CDCA5敲低的细胞系中，以上几种蛋白的表达量降低。提示CDCA5可能通过激活细胞周期通路蛋白促进食管鳞状细胞癌的发展 [31] 。

3.2.5. DNA损伤及修复

在肾细胞癌细胞系中敲低CDCA5后，利用免疫荧光染色及WesternBlot方法发现磷酸化的组蛋白H2AX焦点增加，表明DNA双链断裂增多 [36] 。同时，DNA损伤修复基因BRCA1 (breast cancer 1，乳腺癌一号基因)和p-BRCA1 (磷酸化的BRCA1)表达量降低，提示DNA损伤修复能力降低。

3.3. CDCA5与其他蛋白的互作

3.3.1. 细胞周期相关蛋白

在胃癌组织中CDK1和CDCA5的表达都上调，且在胃癌细胞系MGC-803中CDK1和CDCA5的表达呈正相关，CDK1或CDCA5抑制会抑制胃癌细胞增殖、克隆形成、迁移能力 [59] 。以上现象提示CDCA5可能通过调节CDK1蛋白促进胃癌发展。

CDCA5敲低的细胞中周期蛋白E1 (CCNE1) mRNA和蛋白含量均降低 [50] 。在CDCA5敲低的细胞中过表达CCNE1可以使得细胞增殖能力部分恢复，而且可以部分恢复G1期阻滞的表型。以上结果提示CDCA5可能通过调节CCNE1促进胃癌细胞增殖 [50] 。

CDK1和CCNB1都是G2/M细胞周期检查点的核心调节蛋白 [60] [61] 。肝细胞癌细胞系中敲低CDCA5导致CDK1和CCNB1的表达量降低，这可能与CDCA5敲低导致的G2/M期阻滞相关 [4] 。

3.3.2. 黏连蛋白相关蛋白

PDS5 (Precocious dissociation of sisters 5)是一种黏连蛋白结合蛋白，对于黏连蛋白复合体具有重要的调节作用，参与姐妹染色单体粘连、DNA损伤修复等过程。脊椎动物中PDS5有两个旁系同源蛋白：PDS5A (PDS5 cohesin-associated factor A)和PDS5B (PDS5 cohesin-associated factor B)。PDS5A在多种癌症中表达量发生变化，如：乳腺癌，肾癌，胃癌，肝癌和结肠癌 [62] 。PDS5A的表达量和世界卫生组织神经胶质瘤级别正相关 [63] 。

乳腺癌细胞中敲低CDCA5使得PDS5A表达量降低 [64] 。PDS5A过表达可以回复CDCA5敲低对于乳腺癌细胞增殖和迁移的影响。CDCA5敲低通过调节PDS5A的含量抑制乳腺癌细胞的恶性进展。

3.3.3. 其他上游作用因子

目前已经发现了几个CDCA5的上游作用因子，包括：E3泛素连接酶接头蛋白SPOP (Speckle-type POZ protein，斑点型锌指结构蛋白) [49] ，转录因子E2F1 [45] ，剪接体复合物互作蛋白SUN2 (SUN domain-containing protein 2，含SUN结构域蛋白2) [65] ，miR-326 [51] ，MIR4435-2HG [66] ，miR-326 [51] ，LINC01515 [53] ，长非编码RNA RHPN1-AS1 [67] 等。

4. CDCA5作为预后标志物或治疗靶点的应用前景

一些研究指出了CDCA5作为诊断和预后标志物及治疗靶点的价值，如在乳腺癌 [27] [68] 、卵巢癌 [52] 、肢端黑色素瘤 [69] 、非小细胞肺癌 [70] 、肝细胞癌中 [4] [23] [42] [44] [57] [58] [71] [72] [73] 。

CDCA5敲低后提高了食管鳞状细胞癌细胞对于顺氯氨铂化疗敏感性 [31] 。CDCA5敲低的细胞相比于未敲低细胞对于顺氯氨铂处理更加敏感，且CDCA5敲低的使用顺氯氨铂处理的细胞活力比单独CDCA5敲低或单独顺氯氨铂处理的细胞低。

5. 结语

CDCA5在多种癌症中的肿瘤促进因子作用在近些年被发现，而对于CDCA5对癌细胞生长、凋亡、细胞周期的调控作用的机制尚不明确。例如，已经在多种癌症细胞中发现敲低CDCA5导致细胞周期阻滞，然而该现象的分子机制尚不明确，即CDCA5通过哪个信号通路或哪种蛋白调节细胞周期调控蛋白，目前研究尚缺乏。在未来的研究中，CDCA5可能会被发现在其他种类的癌症中也起到肿瘤促进因子的作用，但更多的研究应当逐步揭示CDCA5参与癌症发生发展的机制，从而推进其作为诊断、预后标志物及治疗靶点的转化研究。

基金项目

陕西省教育厅专项科研计划项目(21JK0896)；西安医学院博士科研启动基金(2020DOC17)；陕西省自然科学基础研究计划项目(2022JQ-216，2021JQ-774)。

文章引用

范锦博,田 甜,孙 卓. 细胞分裂周期相关蛋白5的功能及其在癌症发生中作用的研究进展
Research Progress of the Function of CDCA5 and Its Role in Cancer Progression[J]. 临床医学进展, 2023, 13(06): 10153-10162. https://doi.org/10.12677/ACM.2023.1361421

参考文献

  1. 1. Rankin, S., Ayad, N.G. and Kirschner, M.W. (2005) Sororin, a Substrate of the Anaphase-Promoting Complex, Is Re-quired for Sister Chromatid Cohesion in Vertebrates. Molecular Cell, 18, 185-200. https://doi.org/10.1016/j.molcel.2005.03.017

  2. 2. Nishiyama, T., Ladurner, R., Schmitz, J., et al. (2010) Sororin Mediates Sister Chromatid Cohesion by Antagonizing Wapl. Cell, 143, 737-749. https://doi.org/10.1016/j.cell.2010.10.031

  3. 3. Ladurner, R., Kreidl, E., Ivanov, M.P., et al. (2016) Sororin Active-ly Maintains Sister Chromatid Cohesion. The EMBO Journal, 35, 635-653. https://doi.org/10.15252/embj.201592532

  4. 4. Shen, Z., Yu, X., Zheng, Y., et al. (2018) CDCA5 Regulates Pro-liferation in Hepatocellular Carcinoma and Has Potential as a Negative Prognostic Marker. OncoTargets and Therapy, 11, 891-901. https://doi.org/10.2147/OTT.S154754

  5. 5. Selig, S., Okumura, K., Ward, D.C., et al. (1992) Delineation of DNA Replication Time Zones by Fluorescence in Situ Hybridization. The EMBO Journal, 11, 1217-1225. https://doi.org/10.1002/j.1460-2075.1992.tb05162.x

  6. 6. Gerlich, D., Koch, B., Dupeux, F., et al. (2006) Live-Cell Imaging Reveals a Stable Cohesin-Chromatin Interaction after but Not before DNA Replication. Current Biology, 16, 1571-1578. https://doi.org/10.1016/j.cub.2006.06.068

  7. 7. Kueng, S., Hegemann, B., Peters, B.H., et al. (2006) Wapl Controls the Dynamic Association of Cohesin with Chromatin. Cell, 127, 955-967. https://doi.org/10.1016/j.cell.2006.09.040

  8. 8. Schmitz, J., Watrin, E., Lénárt, P., et al. (2007) Sororin Is Required for Stable Binding of Cohesin to Chromatin and for Sister Chromatid Cohesion in Interphase. Current Biology, 17, 630-636. https://doi.org/10.1016/j.cub.2007.02.029

  9. 9. Zhang, N. and Pati, D. (2012) Sororin Is a Master Regu-lator of Sister Chromatid Cohesion and Separation. Cell Cycle, 11, 2073-2083. https://doi.org/10.4161/cc.20241

  10. 10. Waizenegger, I.C., Hauf, S., Meinke, A., et al. (2000) Two Distinct Path-ways Remove Mammalian Cohesin from Chromosome Arms in Prophase and from Centromeres in Anaphase. Cell, 103, 399-410. https://doi.org/10.1016/S0092-8674(00)00132-X

  11. 11. Liu, H., Rankin, S. and Yu, H. (2013) Phosphoryla-tion-Enabled Binding of SGO1-PP2A to Cohesin Protects Sororin and Centromeric Cohesion during Mitosis. Nature Cell Biology, 15, 40-49. https://doi.org/10.1038/ncb2637

  12. 12. Zhang, N., Panigrahi, A.K., Mao, Q., et al. (2011) Interaction of Sororin Protein with Polo-Like Kinase 1 Mediates Resolution of Chromosomal Arm Cohesion. Journal of Biological Chemistry, 286, 41826-41837. https://doi.org/10.1074/jbc.M111.305888

  13. 13. Dreier, M.R., Bekier, M.E. and Taylor, W.R. (2011) Regulation of Sororin by Cdk1-Mediated Phosphorylation. Journal of Cell Science, 124, 2976-2987. https://doi.org/10.1242/jcs.085431

  14. 14. Zhang, N. and Pati, D. (2015) C-Terminus of Sororin Interacts with SA2 and Regulates Sister Chromatid Cohesion. Cell Cycle, 14, 820-826. https://doi.org/10.1080/15384101.2014.1000206

  15. 15. Zhou, C., Zhang, X., Miao, Y., et al. (2021) The Cohesin Stabilizer Sororin Drives G(2)-M Transition and Spindle Assembly in Mammalian Oocytes. Science Advances, 7, eabg9335. https://doi.org/10.1126/sciadv.abg9335

  16. 16. Xu, Z., Wang, S., Ren, Z., et al. (2022) An Integrated Analysis of Prognostic and Immune Infiltrates for Hub Genes as Potential Survival Indicators in Patients with Lung Ad-enocarcinoma. World Journal of Surgical Oncology, 20, Article No. 99. https://doi.org/10.1186/s12957-022-02543-z

  17. 17. Chen, Y., Jin, L., Jiang, Z., et al. (2021) Identifying and Validat-ing Potential Biomarkers of Early Stage Lung Adenocarcinoma Diagnosis and Prognosis. Frontiers in Oncology, 11, Ar-ticle ID: 644426. https://doi.org/10.3389/fonc.2021.644426

  18. 18. Zeng, H., Ji, J., Song, X., et al. (2020) Stemness Related Genes Revealed by Network Analysis Associated with Tumor Immune Microenvironment and the Clinical Outcome in Lung Adenocarcinoma. Frontiers in Genetics, 11, Article ID: 549213. https://doi.org/10.3389/fgene.2020.549213

  19. 19. Yi, M., Li, T., Qin, S., et al. (2020) Identifying Tumorigenesis and Prognosis-Related Genes of Lung Adenocarcinoma: Based on Weighted Gene Coexpression Network Analysis. BioMed Research International, 2020, Article ID: 4169691. https://doi.org/10.1155/2020/4169691

  20. 20. Jiang, N., Zhang, X., Qin, D., et al. (2021) Identification of Core Genes Related to Progression and Prognosis of Hepatocellular Carcinoma and Small-Molecule Drug Predication. Frontiers in Genetics, 12, Article ID: 608017. https://doi.org/10.3389/fgene.2021.608017

  21. 21. Yu, Z., Ma, X., Zhang, W., et al. (2021) Microarray Data Mining and Preliminary Bioinformatics Analysis of Hepatitis D Virus-Associated Hepatocellular Carcinoma. BioMed Research International, 2021, Article ID: 1093702. https://doi.org/10.1155/2021/1093702

  22. 22. Gao, S., Zhu, D., Zhu, J., et al. (2021) Screening Hub Genes of Hepa-tocellular Carcinoma Based on Public Databases. Computational and Mathematical Methods, 2021, Article ID: 7029130. https://doi.org/10.1155/2021/7029130

  23. 23. Chen, H., Wu, J., Lu, L., et al. (2020) Identification of Hub Genes As-sociated with Immune Infiltration and Predict Prognosis in Hepatocellular Carcinoma via Bioinformatics Approaches. Frontiers in Genetics, 11, Article ID: 575762. https://doi.org/10.3389/fgene.2020.575762

  24. 24. Wan, Z., Zhang, X., Luo, Y., et al. (2019) Identification of Hepa-tocellular Carcinoma-Related Potential Genes and Pathways through Bioinformatic-Based Analyses. Genetic Testing and Molecular Biomarkers, 23, 766-777. https://doi.org/10.1089/gtmb.2019.0063

  25. 25. Liu, Z., Pan, R., Li, W., et al. (2021) Comprehensive Analysis of Cell Cycle-Related Genes in Patients with Prostate Cancer. Frontiers in Oncology, 11, Article ID: 796795. https://doi.org/10.3389/fonc.2021.796795

  26. 26. Lin, K., Zhu, X., Luo, C., et al. (2021) Data Mining Combined with Experiments to Validate CEP55 as a Prognostic Biomarker in Colorectal Cancer. Immunity, Inflammation and Disease, 9, 167-182. https://doi.org/10.1002/iid3.375

  27. 27. Zhou, Q., Ren, J., Hou, J., et al. (2019) Co-Expression Network Analysis Identified Candidate Biomarkers in Association with Progression and Prognosis of Breast Cancer. Journal of Cancer Research and Clinical Oncology, 145, 2383-2396. https://doi.org/10.1007/s00432-019-02974-4

  28. 28. Gui, T., Yao, C., Jia, B., et al. (2021) Identification and Analysis of Genes Associated with Epithelial Ovarian Cancer by Inte-grated Bioinformatics Methods. PLOS ONE, 16, e0253136. https://doi.org/10.1371/journal.pone.0253136

  29. 29. Liu, J., Meng, H., Li, S., et al. (2019) Identification of Potential Biomarkers in Association with Progression and Prognosis in Epithelial Ovarian Cancer by Integrated Bioinformatics Analysis. Frontiers in Genetics, 10, Article No. 1031. https://doi.org/10.3389/fgene.2019.01031

  30. 30. Xing, C., Wang, Z., Zhu, Y., et al. (2021) Integrate Analysis of the Promote Function of Cell Division Cycle-Associated Protein Family to Pancreatic Adenocarcinoma. International Jour-nal of Medical Sciences, 18, 672-684. https://doi.org/10.7150/ijms.53243

  31. 31. Xu, J., Zhu, C., Yu, Y., et al. (2019) Systematic Cancer-Testis Gene Ex-pression Analysis Identified CDCA5 as a Potential Therapeutic Target in Esophageal Squamous Cell Carcinoma. EBio-Medicine, 46, 54-65. https://doi.org/10.1016/j.ebiom.2019.07.030

  32. 32. Nguyen, M.H., Koinuma, J., Ueda, K., et al. (2010) Phosphory-lation and Activation of Cell Division Cycle Associated 5 by Mitogen-Activated Protein Kinase Play a Crucial Role in Human Lung Carcinogenesis. Cancer Research, 70, 5337-5347. https://doi.org/10.1158/0008-5472.CAN-09-4372

  33. 33. Fu, G., Xu, Z., Chen, X., et al. (2020) CDCA5 Functions as a Tumor Promoter in Bladder Cancer by Dysregulating Mitochondria-Mediated Apoptosis, Cell Cycle Regulation and PI3k/AKT/mTOR Pathway Activation. Journal of Cancer, 11, 2408-2420. https://doi.org/10.7150/jca.35372

  34. 34. Ji, J., Shen, T., Li, Y., et al. (2021) CDCA5 Promotes the Progression of Prostate Cancer by Affecting the ERK Signalling Pathway. Oncology Reports, 45, 921-932. https://doi.org/10.3892/or.2021.7920

  35. 35. Chong, Y. and Xue, L. (2021) Downregulation of CDCA5 Can Inhibit Cell Proliferation, Migration, and Invasion, and Induce Apoptosis of Prostate Cancer Cells. Critical Reviews™ in Eu-karyotic Gene Expression, 31, 29-40. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2020036803

  36. 36. Huang, X., Huang, Y., Lv, Z., et al. (2022) Loss of Cell Division Cycle-Associated 5 Promotes Cell Apoptosis by Activating DNA Damage Response in Clear Cell Renal Cell Carcinoma. International Journal of Oncology, 61, Article No. 87. https://doi.org/10.3892/ijo.2022.5377

  37. 37. Tokuzen, N., Nakashiro, K., Tanaka, H., et al. (2016) Therapeutic Po-tential of Targeting Cell Division Cycle Associated 5 for Oral Squamous Cell Carcinoma. Oncotarget, 7, 2343-2353. https://doi.org/10.18632/oncotarget.6148

  38. 38. Chen, T., Huang, Z., Tian, Y., et al. (2017) Role of Triosephosphate Isomerase and Downstream Functional Genes on Gastric Cancer. Oncology Reports, 38, 1822-1832. https://doi.org/10.3892/or.2017.5846

  39. 39. Kato, T., Lee, D., Wu, L., et al. (2016) SORORIN and PLK1 as Poten-tial Therapeutic Targets in Malignant Pleural Mesothelioma. International Journal of Oncology, 49, 2411-2420. https://doi.org/10.3892/ijo.2016.3765

  40. 40. Li, Y., Peng, W., Deng, Y., et al. (2022) Effect of CDCA5 on Prolifera-tion and Metastasis of Triple Negative Breast Cancer Cells under shRNA Interference Technology. Journal of Oncology, 2022, Article ID: 9038230. https://doi.org/10.1155/2022/9038230

  41. 41. Hu, H., Xiang, Y., Zhang, X.Y., et al. (2022) CDCA5 Promotes the Progression of Breast Cancer and Serves as a Potential Prognostic Biomarker. Oncology Reports, 48, 172. https://doi.org/10.3892/or.2022.8387

  42. 42. Hou, S., Chen, X., Li, M., et al. (2020) Higher Expression of Cell Divi-sion Cycle-Associated Protein 5 Predicts Poorer Survival Outcomes in Hepatocellular Carcinoma. Aging (Albany NY), 12, 14542-14555. https://doi.org/10.18632/aging.103501

  43. 43. Bai, L., Ren, Y. and Cui, T. (2020) Overexpression of CDCA5, KIF4A, TPX2, and FOXM1 Coregulated Cell Cycle and Promoted Hepatocellular Carcinoma Development. Journal of Computational Biology, 27, 965-974. https://doi.org/10.1089/cmb.2019.0254

  44. 44. Wang, J., Xia, C., Pu, M., et al. (2018) Silencing of CDCA5 Inhibits Cancer Progression and Serves as a Prognostic Biomarker for Hepatocellular Carcinoma. Oncology Reports, 40, 1875-1884. https://doi.org/10.3892/or.2018.6579

  45. 45. Chen, H., Chen, J., Zhao, L., et al. (2019) CDCA5, Tran-scribed by E2F1, Promotes Oncogenesis by Enhancing Cell Proliferation and Inhibiting Apoptosis via the AKT Pathway in Hepatocellular Carcinoma. Journal of Cancer, 10, 1846-1854. https://doi.org/10.7150/jca.28809

  46. 46. Shen, A., Liu, L., Chen, H., et al. (2019) Cell Division Cycle Associated 5 Promotes Colorectal Cancer Progression by Activating the ERK Signaling Pathway. Oncogenesis, 8, Article No. 19. https://doi.org/10.1038/s41389-019-0123-5

  47. 47. Kariri, Y.A., Joseph, C., Alsaleem, M.A., et al. (2022) Mechanis-tic and Clinical Evidence Supports a Key Role for Cell Division Cycle Associated 5 (CDCA5) as an Independent Predic-tor of Outcome in Invasive Breast Cancer. Cancers (Basel), 14, Article No. 5643. https://doi.org/10.3390/cancers14225643

  48. 48. Shen, W., Tong, D., Chen, J., et al. (2022) Silencing Oncogene Cell Division Cycle Associated 5 Induces Apoptosis and G1 Phase Arrest of Non-Small Cell Lung Cancer Cells via p53-p21 Signaling Pathway. Journal of Clinical Laboratory Analysis, 36, e24396. https://doi.org/10.1002/jcla.24396

  49. 49. Luo, Z., Wang, J., Zhu, Y., et al. (2021) SPOP Promotes CDCA5 Degra-dation to Regulate Prostate Cancer Progression via the AKT Pathway. Neoplasia, 23, 1037-1047. https://doi.org/10.1016/j.neo.2021.08.002

  50. 50. Zhang, Z., Shen, M. and Zhou, G. (2018) Upregulation of CDCA5 Promotes Gastric Cancer Malignant Progression via Influencing Cyclin E1. Biochemical and Biophysical Research Communications, 496, 482-489. https://doi.org/10.1016/j.bbrc.2018.01.046

  51. 51. Gao, A., Hu, Y. and Zhu, W. (2021) CDCA5 Is Negatively Regu-lated by miR-326 and Boosts Ovarian Cancer Progression. Journal of BUON, 26, 544-552.

  52. 52. Chen, C., Chen, S., Luo, M., et al. (2020) The Role of the CDCA Gene Family in Ovarian Cancer. Annals of Translational Medicine, 8, 190. https://doi.org/10.21037/atm.2020.01.99

  53. 53. Liu, D., Gong, H., Tao, Z., et al. (2021) LINC01515 Promotes Na-sopharyngeal Carcinoma Progression by Serving as a Sponge for miR-325 to Up-Regulate CDCA5. Journal of Molecu-lar Histology, 52, 577-587. https://doi.org/10.1007/s10735-021-09969-x

  54. 54. Chang, I.W., Lin, V.C., He, H.L., et al. (2015) CDCA5 Overex-pression Is an Indicator of Poor Prognosis in Patients with Urothelial Carcinomas of the Upper Urinary Tract and Uri-nary Bladder. American Journal of Translational Research, 7, 710-722.

  55. 55. Jin, X., Wang, D., Lei, M., et al. (2022) TPI1 Activates the PI3K/AKT/mTOR Signaling Pathway to Induce Breast Cancer Progression by Stabilizing CDCA5. Journal of Translational Medicine, 20, Article No. 191. https://doi.org/10.1186/s12967-022-03370-2

  56. 56. Wu, Z.H., Fang, M. and Zhou, Y. (2020) Comprehensive Anal-ysis of the Expression and Prognosis for CDCAs in Head and Neck Squamous Cell Carcinoma. PLOS ONE, 15, e0236678. https://doi.org/10.1371/journal.pone.0236678

  57. 57. Tian, Y., Wu, J., Chagas, C., et al. (2018) CDCA5 Overexpression Is an Indicator of Poor Prognosis in Patients with Hepatocellular Carcinoma (HCC). BMC Cancer, 18, Article No. 1187. https://doi.org/10.1186/s12885-018-5072-4

  58. 58. Cai, C., Wang, W. and Tu, Z. (2019) Aberrantly DNA Methylated-Differentially Expressed Genes and Pathways in Hepatocellular Carcinoma. Journal of Cancer, 10, 355-366. https://doi.org/10.7150/jca.27832

  59. 59. Huang, Z., Zhang, S., Du, J., et al. (2020) Cyclin-Dependent Ki-nase 1 (CDK1) Is Co-Expressed with CDCA5: Their Functions in Gastric Cancer Cell Line MGC-803. Medical Science Monitor, 26, e923664. https://doi.org/10.12659/MSM.923664

  60. 60. Wang, Z., Fan, M., Candas, D., et al. (2014) Cyclin B1/Cdk1 Coordi-nates Mitochondrial Respiration for Cell-Cycle G2/M Progression. Developmental Cell, 29, 217-232. https://doi.org/10.1016/j.devcel.2014.03.012

  61. 61. Fang, Y., Yu, H., Liang, X., et al. (2014) Chk1-Induced CCNB1 Overexpression Promotes Cell Proliferation and Tumor Growth in Human Colorectal Cancer. Cancer Biology & Therapy, 15, 1268-1279. https://doi.org/10.4161/cbt.29691

  62. 62. Zhang, N., Coutinho, L.E. and Pati, D. (2021) PDS5A and PDS5B in Co-hesin Function and Human Disease. International Journal of Molecular Sciences, 22, Article No. 5868. https://doi.org/10.3390/ijms22115868

  63. 63. Hagemann, C., Weigelin, B., Schommer, S., et al. (2011) The Cohe-sin-Interacting Protein, Precocious Dissociation of Sisters 5A/Sister Chromatid Cohesion Protein 112, Is Up-Regulated in Human Astrocytic Tumors. International Journal of Molecular Medicine, 27, 39-51. https://doi.org/10.3892/ijmm.2010.551

  64. 64. Wang, Y., Yao, J., Zhu, Y., et al. (2022) Knockdown of CDCA5 Suppresses Malignant Progression of Breast Cancer Cells by Regulating PDS5A. Molecular Medicine Reports, 25, Arti-cle No. 209. https://doi.org/10.3892/mmr.2022.12725

  65. 65. Koedoot, E., van Steijn, E., Vermeer, M., et al. (2021) Splicing Fac-tors Control Triple-Negative Breast Cancer Cell Mitosis through SUN2 Interaction and Sororin Intron Retention. Journal of Experimental & Clinical Cancer Research, 40, Article No. 82. https://doi.org/10.1186/s13046-021-01863-4

  66. 66. Yang, T., Li, Y., Wang, G., et al. (2022) lncRNA MIR4435-2HG Accelerates the Development of Bladder Cancer through Enhancing IQGAP3 and CDCA5 Expression. BioMed Research International, 2022, Article ID: 3858249. https://doi.org/10.1155/2022/3858249

  67. 67. Zhang, X., Yan, Z., Wang, L., et al. (2020) STAT1-Induced Upregula-tion of lncRNA RHPN1-AS1 Predicts a Poor Prognosis of Hepatocellular Carcinoma and Contributes to Tumor Pro-gression via the miR-485/CDCA5 Axis. Journal of Cellular Biochemistry, 121, 4741-4755. https://doi.org/10.1002/jcb.29689

  68. 68. Fu, Y., Zhou, Q.Z., Zhang, X.L., et al. (2019) Identification of Hub Genes Using Co-Expression Network Analysis in Breast Cancer as a Tool to Predict Different Stages. Medical Science Monitor, 25, 8873-8890. https://doi.org/10.12659/MSM.919046

  69. 69. Xu, T., Ma, M., Dai, J., et al. (2018) Gene Expression Screening Identifies CDCA5 as a Potential Therapeutic Target in Acral Melanoma. Human Pathology, 75, 137-145. https://doi.org/10.1016/j.humpath.2018.02.009

  70. 70. Wu, Q., Zhang, B., Sun, Y., et al. (2019) Identification of Novel Biomarkers and Candidate Small Molecule Drugs in Non-Small-Cell Lung Cancer by Integrated Microarray Analysis. OncoTargets and Therapy, 12, 3545-3563. https://doi.org/10.2147/OTT.S198621

  71. 71. Wu, B., Huang, Y., Luo, Y., et al. (2020) The Diagnostic and Prognos-tic Value of Cell Division Cycle Associated Gene Family in Hepatocellular Carcinoma. Journal of Cancer, 11, 5727-5737. https://doi.org/10.7150/jca.46554

  72. 72. Wang, Y., Yang, Y., Gao, H., et al. (2020) Comprehensive Analysis of CDCAs Methylation and Immune Infiltrates in Hepatocellular Carcinoma. Frontiers in Oncology, 10, Article ID: 566183. https://doi.org/10.3389/fonc.2020.566183

  73. 73. Lin, Y., Liang, R., Ye, J., et al. (2019) A Twenty Gene-Based Gene Set Variation Score Reflects the Pathological Progression from Cirrhosis to Hepatocellular Carcinoma. Aging (Albany NY), 11, 11157-11169. https://doi.org/10.18632/aging.102518

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