Proteomics and Phosphoproteomics Analysis of Effect of Retinoic Acid-Induced Protein 16 Knockout on Human Colon Cancer Cells
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摘要:目的
分析人结肠癌HCT116细胞敲除维甲酸诱导蛋白16（RAI16）后细胞内总蛋白及磷酸化蛋白质表达的差异，探究RAI16影响HCT116细胞蛋白质功能的可能机制及相关信号通路。
方法收集并提取HCT116 KO和WT细胞蛋白，SDS-PAGE检验蛋白提取效果。利用胰蛋白酶酶解蛋白后，标记肽段并进行质谱分析。对鉴定到的差异蛋白及差异磷酸化蛋白质利用GO数据库、KEGG数据库和STRING数据库进行生物信息学分析。
结果SDS-PAGE结果提示蛋白无明显降解，且实验组与对照组部分关键条带有明显差异；按Foldchange≥1.5或Foldchange≤1/1.5且P<0.05为条件进行差异蛋白的筛选，共筛选出147个上调差异蛋白和230个下调差异蛋白；并筛选到106个上调磷酸化位点和217个下调磷酸化位点。将去本底差异磷酸化位点功能GO富集分析，发现差异蛋白主要在核质、细胞核及细胞质组成，RNA、钙黏着蛋白及染色质结合，DNA修复、RNA剪接及DNA为模板转录的正调控等多个方面有显著富集趋势。KEGG富集结果显示，差异蛋白主要在核质转运、剪接体、细胞周期、细胞间紧密连接、病毒致癌作用和癌症中的微小RNA等通路具有显著富集趋势。蛋白互作网络主要以 DDX17、NCL、EEF2、CDK1、SSRP1和SMARCC1为核心蛋白质。统计发现，SKP1、ORC1和BAD等两组学差异变化均上调，且磷酸化差异变化比蛋白差异变化更显著，RBL1、RB1、CDK1、CDC6、MCM4、TFDP1、CHD4和SNW1等两组学差异变化均下调，且磷酸化差异变化比蛋白差异变化更显著。
结论RAI16可能通过SKP1、ORC1、RB1和CDK1等关键蛋白质在多方面生物功能和多条信号通路中发挥作用，影响细胞周期，进而影响癌症发生发展。
Abstract:ObjectiveTo analyze the differences in the expressions of the total and phosphorylated proteins in human colon cancer HCT116 cells after the knockout (KO) of retinoic acid-induced protein 16 (RAI16) and explore the possible mechanism and related signaling pathways affecting its protein function in HCT116 cells.
MethodsHCT116 KO and WT cell proteins were collected and extracted, and the protein extraction efficiency was detected via a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) experiment. After protein digestion, the peptides were labeled with TMT and analyzed via mass spectrometry. We used bioinformatics methods to analyze the identified differential proteins and differentially phosphorylated proteins by using GO, KEGG, and STRING databases.
ResultsThe results of SDS-PAGE showed no evident protein degradation. In addition, some key bands were significantly different between the experimental and control groups. A total of 147 up-regulated and 230 down-regulated differential proteins were screened in accordance with the conditions of Foldchange≥1.5 or Foldchange≤1/1.5 and P<0.05. Meanwhile, 106 up-regulated and 217 down-regulated phosphorylation sites were screened. GO enrichment analysis revealed that the differential proteins were mainly enriched in the composition of nucleoplasm, nucleus and cytoplasm, RNA binding, cadherin and chromatin, DNA repair, RNA splicing, and positive regulation of DNA as template transcription. The results of KEGG enrichment indicated that the differential proteins were mainly enriched in nucleocytoplasmic transport, spliceosomes, cell cycle, cell-cell tight junctions, viral carcinogenesis, microRNAs in cancer, etc. The protein interaction network mainly focused on DDX17, NCL, EEF2, CDK1, SSRP1, and SMARCC1. The statistical findings unveiled the up-regulated changes in the two omics of SKP1, ORC1, and BAD and the down-regulated changes in RBL1, RB1, CDK1, CDC6, MCM4, TFDP1, CHD4, and SNW1. Moreover, the phosphorylation differences were more significant than the protein differences.
ConclusionRAI16 plays the possible crucial role in multiple biological functions and signaling pathways through key proteins, such as SKP1, ORC1, RB1, and CDK1, which affect the cell cycle and thereby the occurrence and development of cancer.
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Key words:
- Colon cancer /
- Retinoic acid-induced protein 16 /
- HCT116 cells /
- Phosphoproteomics
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0 引言
艾滋病病毒（human immunodeficiency virus, HIV）会降低人体的免疫功能，增加人体患各种恶性肿瘤的风险[1]，特别是引入联合抗反转录病毒疗法之后，艾滋病（acquired immune deficiency syndrome, AIDS）患者/HIV感染者的病程不断延长，而恶性肿瘤也逐渐成为此类患者死亡的重要病因之一[2]。近年来，我国HIV/AIDS患者人数在不断增加，HIV/AIDS合并恶性肿瘤（简称：艾滋病合并恶性肿瘤）的人数也随之增加[3-4]。我国对于艾滋病合并恶性肿瘤的规范性诊断和治疗工作开展较晚[5]，加之临床上重治疗、轻随访，对于该类患者的大样本生存预后的研究报道较少。因此，本研究旨在更好地了解此类患者的临床特点，探讨患者生存预后情况及其影响因素，为进一步诊治提供参考依据。
1 资料与方法
1.1 资料
回顾性分析2013年1月1日—2020年12月31日在重庆大学附属肿瘤医院住院的354例艾滋病合并恶性肿瘤患者资料。所有患者HIV抗体检测均为阳性，均经病理确诊为恶性肿瘤，疾病编码以医院当年病案室专职编码员填写的ICD编码为依据。纳入标准：（1）首次确诊艾滋病合并恶性肿瘤患者；（2）年龄≥18岁；（3）住院治疗患者。排除标准：（1）非HIV或非恶性肿瘤患者；（2）门诊诊疗患者；（3）重复入院患者。本研究符合《赫尔辛基宣言》的要求，研究数据库已做隐私保密处理。
1.2 方法
收集患者的人口学特征（包括年龄、性别、职业、婚姻状况等）、医保信息（包括医疗保险类型、自费比例等）、住院治疗（包括确诊艾滋病合并恶性肿瘤后的住院治疗次数、平均住院天数、直接医疗总花费、是否接受手术/放疗/化疗、有无遵医嘱离院等）以及随访等预后相关信息。多因素分析采用Cox回归模型，利用条件向前法筛选变量，确定α=0.20，分类变量以哑变量的形式纳入模型，参照组为每个变量的第一个亚组，其他变量直接纳入模型进行分析。
1.3 统计学方法
采用R4.0.2，（https://www.r-project.org）统计软件进行统计分析，正态计量资料采用均数±标准差（x±s），计数资料采用绝对数（%）表示；采用Kaplan-Meier法计算平均生存时间、生存率并绘制生存曲线；单因素分析采用Log rank检验进行生存分析；多因素分析采用Cox比例风险回归模型进行分析；P < 0.05为差异有统计学意义。
2 结果
2.1 患者临床特征
患者平均年龄54.10±12.96岁（23~87岁）；男女患者比例为2.1:1；所有患者中，合并淋巴瘤的患者最多，其次是肺癌和宫颈癌；从医保类型分布情况来看，城镇居民医保的患者最多。治疗数据显示：大部分患者只在医院接受一次住院治疗，确诊后在院的直接医疗费用在3万以上的有151例，占42.66%；分别接受过手术、放疗、化疗的患者占30%左右；27.97%的患者有过未遵医嘱出院的行为，见表 1。
表 1 艾滋病合并恶性肿瘤患者的临床特征Table 1 Clinical characteristics of patients with AIDS-related malignant tumor
2.2 患者生存情况
随访数据显示，54例（占15.25%）患者失访，104例（占29.38%）患者死亡，所有研究对象的平均生存时间为58.42月（95%CI: 53.11~63.73），1、3、5年观察生存率分别为78.48%、62.13%、55.31%。
单因素分析结果显示：不同恶性肿瘤类型、年龄、性别、医疗保险类型、确诊合并HIV后的住院次数、平均住院天数、直接总医疗费用、自费比例、是否放疗、有无遵医嘱离院患者的预后差异均有统计学差异，见表 2。
表 2 艾滋病合并恶性肿瘤患者预后的单因素分析Table 2 Survival of patients with AIDS-related malignant tumor: univariate analysis
2.3 影响艾滋病合并恶性肿瘤患者预后的多因素分析
多因素分析结果显示，性别、入院次数、平均住院天数、自费比例以及有无遵医嘱离院是影响患者生存预后的独立危险因素。可以认为男性患者发生死亡的风险是女性2.02倍；住院次数1次的发生死亡的风险是2次及以上的1.70倍，平均住院天数在8天及以上的患者发生死亡的风险是住院天数≤4天的2.91倍，自费比例≤40%的患者发生死亡的风险是 > 40%患者的1.52倍，遵医嘱离院的患者发生死亡的风险是未遵医嘱离院患者的2.38倍，见表 3。
表 3 影响艾滋病合并恶性肿瘤患者预后的多因素分析Table 3 Multivariate analysis of prognosis of patients with AIDS-related malignant tumor
将多因素分析有统计学差异的变量逐个绘制生存曲线图，结果显示女性患者生存预后好于男性，2次及以上的患者生存预后好于只有1次入院记录的患者，平均住院日在8天以上患者生存预后最差，自费比例 > 40%的患者生存预后逊于≤40%的患者，遵医嘱离院的患者生存预后好于未遵医嘱离院的患者，见图 1。
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图 1 不同患者的Kaplan-Meier生存曲线A: survival of all and different gender patients; B: survival of patients with different admissions; C: survival of patients with different length of stay; D: survival of patients with different proportion of out-ofpocket; E: survival of patients leaving hospital according to medical advice.Figure 1 Kaplan-Meier survival curves of different groups of patients3 讨论
随着我国艾滋病防控工作的进一步推进以及检测覆盖面的扩大，每年新诊断的艾滋病患者人数也在不断增加。据估计，2018年我国艾滋病新发感染人数为8万，而现存活人数达到125万，且未来几年将持续增加[6-7]。随着医疗技术的进步，艾滋病患者的生命周期会不断延长，艾滋病合并恶性肿瘤的人数也会不断增加，本次研究数据也证实了该趋势。目前国内对于艾滋病合并恶性肿瘤患者的治疗情况以及该类型患者的预后情况的研究报道不多，因此，本研究利用重庆大学附属肿瘤医院的电子病历信息系统以及随访系统，纳入HIV合并肿瘤真实世界最大病例数，回顾性地研究该类型患者的临床特点及生存预后情况。研究病例数据量较大，随访时间较长，能在一定程度上反映真实情况，为该类型患者防治工作的进一步开展提供有效依据。
艾滋病合并恶性肿瘤可以分为艾滋病相关肿瘤和非艾滋病相关肿瘤，其中艾滋病相关肿瘤主要包括卡波西肉瘤、非霍奇金淋巴瘤及浸润性宫颈癌三种级别，非艾滋病相关肿瘤主要包括肺癌、肝癌、肛门癌、皮肤癌、结直肠癌以及霍奇金淋巴瘤等[8-9]。本研究结果显示患者以艾滋病相关肿瘤为主，与国内其他研究结论一致[10-12]。具体以合并淋巴瘤最多（占28.25%），其次是肺癌（占14.97%）和宫颈癌（占14.12%），这与国内外其他研究报道有所区别[13-15]，可能与不同地区的恶性肿瘤疾病构成及流行趋势不同有关，比如有些肿瘤在某些地区高发，有的医院收治的患者多，艾滋病合并该类肿瘤的患者也会相应增加。实际调查中也发现部分科室不太愿意收治艾滋病合并恶性肿瘤的患者，具体表现在门诊中发现该类患者就不收入住院治疗或者是入院发现后要求患者转院治疗。
本研究显示患者年龄以46岁及以上患者居多，性别以男性为主，与国内外研究一致[16-17]，这也与恶性肿瘤发病特点一致[18]。建议临床上要加强对中老年患者艾滋病病史的询问和HIV抗体筛查。59.04%的患者只有一次入院治疗的记录、平均住院日≤4天以及直接医疗花费在1万元及以下等数据提示该类患者接受专业的抗肿瘤治疗不足。建议医院加强院感管理，设置专有病房，减少暴露风险，同时也要加强对患者的宣教和保护患者的利益。
本研究结果显示总体患者的5年观察生存率为55.31%，与国内其他研究报道的恶性肿瘤5年生存率基本一致[19]。而单艾滋病患者及时接受抗病毒治疗能够有效控制病情，5年生存率能达到98%左右[20-21]。提示艾滋病病毒只要经过系统治疗，不会影响患者抗肿瘤治疗的疗效，但具体还需要做进一步的研究来论证。多因素分析显示男性患者死亡风险高于女性，这与其他研究报道男性HIV患者死亡率高于女性结论一致[16]。可能与不同性别的患者接受抗病毒或抗肿瘤治疗的依从性或者与两性间的生活习惯不同等有关，需要进一步论证。住院次数及平均住院天数也是影响患者生存预后的因素。肿瘤患者需要定期复查，有些治疗比如放疗、化疗也是周期性的，患者需要重复住院。患者出院应该听从医嘱，如果患者没有定期住院治疗或者住院天数不够，以及患者没有遵从医嘱自行出院，可以认为患者接受治疗不足或者是治疗依从性不好，进而影响患者的预后。自费比例 > 40%的患者预后要好于≤40%的患者，提示要加大医保的投入，提高患者医疗保险比例。另外，由于本次研究对象为艾滋病合并恶性肿瘤患者的特殊人群，患者诊疗行为及预后会受到社会、经济以及医疗技术发展等多方因素影响，而本研究为单中心回顾性研究，因此建议后期联合传染病医院以及疾控中心等机构开展多中心研究。
综上所述，艾滋病合并恶性肿瘤患者的生存预后影响因素较多。只要接受系统的抗艾滋病病毒治疗，艾滋病病毒对恶性肿瘤的生存预后影响较小。因此，建议加强对患者的宣教，早发现、早系统治疗。同时也建议医院开展抗艾滋病和抗肿瘤双重治疗，做好院感防护，提高患者的生存质量。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：陈奕孛：收集标本、实施实验、论文撰写苗 根：收集标本、标本前处理、数据整理王 文：设计实验、结果分析、论文修改丁翠玲、戚中田：设计实验、论文审校 -
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图 1 蛋白质及磷酸化蛋白质样本质控评估
Figure 1 Quality control evaluation of protein and phosphorylated protein samples
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图 4 差异蛋白功能KEGG富集分析
Figure 4 KEGG enrichment analysis of differential protein functions
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图 7 差异磷酸化蛋白功能GO富集分析
Figure 7 GO enrichment analysis of differential phosphorylated protein functions
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图 8 差异磷酸化蛋白功能KEGG富集分析
Figure 8 KEGG enrichment analysis of differential phosphorylated protein functions
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图 10 去本底蛋白修饰位点功能富集分析
Figure 10 Functional enrichment analysis of modified sites inbackground-removal proteins
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图 11 去本底蛋白修饰位点蛋白互作网络
Figure 11 Protein interaction network of modified sites in background-removal proteins
表 1 HCT116细胞敲除RAI16后差异表达显著的关键蛋白质
Table 1 Differentially expressed key proteins after RAI16 knockout in HCT116 cells
Gene name Product Regulation STAT1 Signal transducer and activator of transcription 1-alpha/beta Up CYP24A1 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Up ITGB1 Integrin beta-1 Down DAPK1 Death-associated protein kinase 1 Up FGFR2 Fibroblast growth factor receptor 2 Up SMAD3 Mothers against decapentaplegic homolog 3 Up CDK6 Cyclin-dependent kinase 6 Down NOTCH1 Neurogenic locus notch homolog protein 1 Down CDKN1A Cyclin-dependent kinase inhibitor 1 Up RAD51 DNA repair protein RAD51 homolog 1 Down 
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表 2 HCT116细胞敲除RAI16后差异表达显著的关键磷酸化蛋白质
Table 2 Differentially expressed key phosphorylated proteins after RAI16 knockout in HCT116 cells
Gene name Product Regulation CDK1 Cyclin-dependent kinase 1 Down SKP1 S-phase kinase-associated protein 1 Up ORC1 Origin recognition complex subunit 1 Up CDC20 Cell division cycle protein 20 homolog Down RB1 Retinoblastoma-associated protein Down PTTG1 Securin Down RBL1 Retinoblastoma-like protein 1 Down
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表 3 HCT116细胞敲除RAI16后差异表达显著的去本底蛋白修饰位点
Table 3 Differentially expressed key modified sites in background-removal proteins after RAI16 knockout in HCT116 cells
Gene name class Product NEGG description SKP1 Phospho-more up S-phase kinase-associated protein 1 Modification-dependent protein catabolic process ORC1 Phospho-more up Origin recognition complex subunit 1 DNA replication RBL1 Phospho-more down Retinoblastoma-like protein 1 Regulation of cell cycle RB1 Phospho-more down Retinoblastoma-associated protein Regulation of cell cycle CDK1 Phospho-more down Cyclin-dependent kinase 1 Cyclin-dependent protein serine/threonine kinase activity CDC6 Phospho-more down Cell division control protein 6 homolog DNA replication initiation MCM4 Phospho-more down DNA replication licensing factor MCM4 DNA replication initiation TFDP1 Phospho-more down Transcription factor Dp-1 Cell cycle CHD4 Phospho-more down Chromodomain-helicase-DNA-binding protein 4 Peripheral T cell tolerance induction BAD Phospho-more up Bcl2-associated agonist of cell death Positive regulation of intrinsic apoptotic signaling pathway in response to osmotic stress SNW1 Phospho-more down SNW domain-containing protein 1 Generation of catalytic spliceosome for second transesterification step
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