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摘要:目的
探讨局限期（LD）与广泛期（ED）原发性食管小细胞癌（PESCC）患者的临床特点及预后影响因素。
方法回顾性整理72例PESCC患者临床资料和随访信息。采用卡方检验比较LD与ED患者基线资料，Kaplan-Meier方法绘制二者生存曲线，组间生存率比较采用Log-rank检验。单因素和多因素Cox回归方法分析影响LD与ED患者总生存期的因素。
结果49例LD患者和23例ED患者纳入本研究。LD与ED患者的中位生存期分别为18.300月与10.903月（P=0.029）。总蛋白值（TP）（HR=0.890, 95%CI: 0.805~0.983, P=0.022）及化疗周期数（HR=0.388, 95%CI: 0.187~0.807, P=0.011）是LD患者预后独立影响因素；全身免疫炎症指数（SII）（HR=1.002, 95%CI: 1.000~1.004, P=0.007）与C反应蛋白值（CRP）（HR=1.065, 95%CI: 1.021~1.111, P=0.004）是ED患者预后独立影响因素。
结论PESCC恶性程度高，预后差。LD与ED的患者预后影响因素不同。总蛋白值及化疗周期是LD PESCC患者预后独立影响因素；全身免疫炎症指数及C反应蛋白值是ED PESCC患者预后独立影响因素。
Abstract:ObjectiveTo investigate the clinical characteristics and prognostic factors of the limited-stage disease (LD) and extensive-stage disease (ED) of primary esophageal small cell carcinoma (PESCC).
MethodsThe clinical data and follow-up information of 72 patients with PESCC were retrospectively analyzed. Chi-square test was used to compare the baseline data of patients with LD and ED, Kaplan-Meier method was employed to draw the survival curve of both groups, and Log-rank test was employed to compare survival rates between groups. Univariate and multivariate Cox regression methods were used to analyze the factors affecting the overall survival (OS) of patients with LD and ED.
ResultsA total of 49 patients with LD and 23 patients with ED were included in this study. The median survival time of patients with LD was 18.300 months and that of patients with ED was 10.903 months (P=0.029). Total protein (TP) value (HR=0.890, 95%CI: 0.805−0.983, P=0.022) and chemotherapy cycle number (HR=0.388, 95%CI: 0.187−0.807, P=0.011) were independent prognostic factors of patients with LD. Systemic immune-inflammation index (SII) (HR=1.002, 95%CI: 1.000−1.004, P=0.007) and C-reactive protein (CRP) (HR=1.065, 95%CI: 1.021−1.111, P=0.004) were independent prognostic factors of patients with ED.
ConclusionThe malignant degree of PESCC is high, and prognosis is poor. Patients with LD and ED have different prognostic factors. Total protein value and chemotherapy cycle are independent prognostic factors of patients with LD. SII and CRP are independent prognostic factors of patients with ED.
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Key words:
- Primary esophageal small cell carcinoma /
- Limited-disease /
- Extensive-disease /
- Prognosis
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0 引言
原发性肝癌是一种临床常见的恶性肿瘤，仅有约10%~30%的患者可手术切除[1]，且术后易发生复发转移，五年总生存率仅有5%~16%[2]，放射治疗是中晚期肝癌的一种有效治疗手段[3-4]，但是由于正常肝脏组织的放射耐受性低，肝癌细胞的根治剂量大于其周围正常组织的耐受剂量，常会引起放射性肝损伤，如果能寻找一种有效的放疗增敏剂以提高肝癌细胞的放射敏感度，对于肝癌的放疗将具有重要的意义。
细胞周期蛋白Cyclin G1不仅是一种细胞周期调节蛋白，而且是一种癌基因[5]。Tao等对肝癌全基因组进行细胞群基因分析发现了三种肿瘤驱动基因，而Cyclin G1就是其中之一[6]，目前Cyclin G1的生物学功能仍不十分明确，研究显示Cyclin G1在多种肿瘤中均高表达，而且这种高表达可以促进肿瘤细胞生长，它的沉默则可以抑制肿瘤细胞增殖[7-8]，这说明了Cyclin G1作为一种致癌基因在肝癌的发生中占有重要地位。但是Cyclin G1是否参与了肝癌放疗敏感度的调节仍不明确，本实验通过成克隆分析研究了Cyclin G1对肝癌细胞HepG2放疗敏感度的影响，并进行了初步的机制研究，现报道如下。
1 材料与方法
1.1 材料
人肝癌细胞株HepG2购自中国科学院上海细胞库。RPMI l640培养液及胎牛血清购自美国Gibco公司，0.25%胰酶、磷酸盐缓冲液（PBS）购于美国Hyclone公司，青霉素/链霉素溶液（10 000 u/ml青霉素，10 000 μg/ml链霉素，溶于0.85% NaCl）购于美国Thermo公司。Matrigel胶购于美国BD公司。30%Acrylamide/Bis Solution购于美国Bio-Rad公司，Tris-HCl购于中国Solarbio公司，过硫酸铵（APS）、四甲基乙二胺（TEMED）、SDS-聚丙烯酰胺凝胶（SDS-PAGE）上样缓冲液购于中国Beyoutime公司。Western blot Marker购于美国Thermon公司。pSilencer3.1-H1载体购自美国Invitrogen公司。HIF-1α ELISA试剂盒购于英国Abcam公司，ROS ELISA试剂盒购于美国Neoscientific公司。Bcl-2、Bax及β-actin一抗购于英国Abcam公司。
1.2 方法
1.2.1 细胞培养
培养液为RPMI l640培养液，内含10%胎牛血清，100 u/ml青霉素，100 μg/ml链霉素。将HepG2细胞置于37℃、5%CO2培养箱内培养至对数生长期进行实验，2~3天传代一次，0.25%胰酶细胞消化。
1.2.2 X线照射
使用医用直线加速器（德国Siemens公司，型号：Oncor），应用6MV X射线进行不同剂量照射，剂量率为300 cGy/min，照射野为20 cm×20 cm，照射时机架角转至180，细胞培养皿下垫2.0 cm厚的剂量补偿板，CT（美国GE公司，型号：High-speed-Dual）下定位，并用Pinnacle 3计算机治疗计划系统（Philips公司）对剂量进行调整。
1.2.3 HepG2-Cyclin
G1-siRNA细胞系的构建在Cyclin G1 mRNA上寻找符合特征的靶序列（G1/832: 5’-GCA AGA GCT TGT ATC CAA ATG TTT A-3’），合成Cyclin-siRNA序列并形成双链结构；连接于酶切后的pSilencer3.1-H1载体，转化大肠杆菌感受态细胞，挑取阳性克隆、扩增、提取质粒，测序鉴定。将与人的任何基因序列均无同源关系的DNA序列按上述方法构建重组质粒作为阴性对照。按照LipofectamineTM试剂盒说明书进行转染试验。
1.2.4 q-PCR分析HepG2细胞及HepG2-Cyclin
G1-siRNA细胞常规培养于6孔板中，用TRIzol提取细胞RNA，并反转录成cDNA，β-actin作为内参，在96孔PCR反应板中按说明书依次加入各试剂，制成10 μl的PCR反应体系，反应条件参考试剂盒说明书。每次检测设立3个复孔，至少重复3次。引物由上海生工设计合成。引物序列：Cyclin G1上游引物：5’-AGCTGCAGTCTCTGTCAAG-3’，Cyclin G1下游引物: 5’-ATGTCTCTGTGTCAAAGCCA-3’；β-actin上游引物：5’-AAAGACCTGTACGCCAACAC-3’，β-actin下游引物：5’-GTCATACTCCTGCTTGCTGAT-3’。
1.2.5 成克隆分析
取对数生长期细胞，消化离心制成1×104/ml单细胞悬液，按照预实验结果将不同细胞数接种至6孔板中，具体为：0 Gy及2 Gy的照射剂量均接种200个细胞，4 Gy及6 Gy的照射剂量接种400个细胞，8 Gy的照射剂量接种800个细胞。分为HepG2组，HepG2-Cyclin G1-siRNA组及HepG2-Cyclin G1-siRNA对照组。细胞接种后48 h，实验分别接受0、2、4、6、8 Gy的6 MV的X射线照射，继续培养14 d，-20℃冰甲醇固定10 min，0.05%结晶紫在室温下染色30 min后双蒸水小心洗涤3次，空气干燥。倒置显微镜下进行细胞计数，≥50个细胞集落作为1个克隆。实验重复3次，计算克隆形成率（PE）=克隆数/接种细胞数×100%，存活分数=照射各剂量点PE/0GyPE。按多靶单击模型SF=1-（1-e-K*D）N，使用Graphpad 5软件拟合细胞存活曲线，得出K值和N值，计算单独照射组和联合组的SF2、D0和Dq值，并计算放射增敏比（SER）。
1.2.6 ELISA分析
实验分为六组：HepG2组，HepG2-Cyclin G1-siRNA对照组，HepG2-Cyclin G1-siRNA组，HepG2+X线照射组，HepG2-Cyclin G1-siRNA对照+X线照射组，HepG2-Cyclin G1-siRNA+X线照射组。细胞接种后48 h，更换培养液，予以8 Gy照射，分别于照射后0、24、48、72 h洗涤细胞培养板，HIF-1α及ROS的测定均参照试剂盒要求，依次加入所需试剂，根据OD值绘制标准曲线，并计算所测样品中HIF-1α及ROS含量。
1.2.7 Western blot分析
实验分组同1.2.6。细胞接种后48 h，更换培养液，予以8 Gy照射，照射后48 h提取蛋白，裂解细胞时加入2×loading蛋白上样缓冲液，95℃加热5 min，用10% SDS-PAGE蛋白电泳分离样品，湿转法转至PVDF膜。5%脱脂奶粉室温封闭2 h，加入Bcl-2（1:1 000）、bax（1:1 000）、GAPDH（1:5 000）抗体，4℃孵育过夜，加入辣根过氧化物酶（HRP）标记的二抗室温孵育1 h，ECL化学发光检测显影，在凝胶成像系统上拍照并分析。
1.3 统计学方法
采用SPSS 17.0软件进行分析，数据以均数±标准差表示，多组数据间比较用单因素方差分析（one way ANOVA），如果差异有统计学意义，再采用Student-Newman-Keuls法进行两两比较。检验水准α=0.05。
2 结果
2.1 肝癌细胞中Cyclin G1的表达
通过q-PCR检测发现，HepG2转染Cyclin G1-siRNA后，其Cyclin G1表达量较HepG2-Cyclin G1-siRNA对照组及HepG2组均明显下降，而HepG2-Cyclin G1-siRNA对照组与HepG2组相比，Cyclin G1的表达量没有明显改变，见图 1。
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图 1 Cyclin G1的相对表达量Figure 1 Relative expression of Cyclin G1**: P < 0.001, compared with HepG2 group2.2 Cyclin G1对肝癌细胞放疗敏感度影响
随着放疗剂量的逐渐增加，各组细胞所形成的克隆数逐渐减少，以HepG2-Cyclin G1-siRNA+X线组克隆数下降最为明显，见图 2。根据克隆形成实验的结果，拟合生存曲线见图 3，所得放射生物学参数见表 1，由表 1求得Cyclin G1的相应放射增敏比SERDq为1.41，HepG2-Cyclin G1-siRNA对照组与HepG2组之间差异无统计学意义，说明Cyclin G1对HepG2细胞有放射增敏作用。
表 1 成克隆分析的相关参数Table 1 Parameters in clone forming analysis
2.3 Cyclin G1对肝癌细胞细胞周期的影响
流式细胞分析显示HepG2-Cyclin G1-siRNA细胞中G2/M期细胞比例较HepG2组明显升高，G0/G1期明显下降，而S期改变不明显。2 Gy单次放疗前后细胞比例没有显著改变，见图 4~5。
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图 4 Cyclin G1对肝癌细胞HepG2细胞周期的影响Figure 4 Effect of Cyclin G1 on cell cycle of HepG2 cellsA: HepG2; B: HepG2+X ray; C: HepG2-Cyclin G1-siRNA; D: HepG2-Cyclin G1-siRNA+X ray2.4 Cyclin G1对放射诱导的相关乏氧因子HIF-1α及ROS含量的影响
X线照射可引起肝癌HepG2细胞的HIF-1α升高，照射后48 h达到最高，并且与HepG2组相比差异有统计学意义，72 h后，HIF-1α轻度下降，而Cyclin G1-siRNA引起HIF-1α的含量显著下降，见图 6。ROS含量在X射线照射后表现为轻度升高，与照射前相比差异无统计学意义。过表达Cyclin G1-siRNA可以使ROS含量增加，照射后24 h开始升高，48 h后达到高峰，72 h轻度下降，与HepG2组细胞相比具有统计学意义，见图 7。
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图 6 Cyclin G1及X线照射对肝癌HepG2细胞HIF-1α表达的影响Figure 6 Effect of Cyclin G1 and X-ray on expression of HIF-1α in HepG2 cells**: P < 0.001, compared with HepG2 group in each time point![]()
图 7 CyclinG1及X线照射对肝癌细胞ROS表达的影响Figure 7 Effect of Cyclin G1 and X-ray on expression of ROS in HepG2 cells**: P < 0.001, compared with HepG2 group in each time point2.5 Cyclin G1及X线对肝癌细胞凋亡相关蛋白Bcl-2和Bax表达的影响
Western blot结果显示X线照射及Cyclin G1-siRNA均可使Bcl-2表达下降及Bax表达增加，其中以HepG2-Cyclin G1-siRNA联合X线照射组改变最明显，见图 8。
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图 8 Cyclin G1及X线对肝癌细胞HepG2凋亡相关蛋白表达的影响Figure 8 Effect of Cyclin G1 and X-ray on expression of apoptosis-related proteins in HepG2 cells1: HepG2; 2: HepG2+X ray; 3: HepG2-Cyclin G1-siRNA; 4: HepG2-Cyclin G1-siRNA+X ray; 5: HepG2-Cyclin G1-siRNA control; 6: HepG2-Cyclin G1-siRNA control+X ray3 讨论
放射治疗的生物学基础是粒子辐射通过直接或间接作用引起生物组织的DNA损伤进而杀伤或杀死肿瘤细胞。放疗增敏主要是采用一些化学物质或生物分子以提高放射治疗疗效，目前放疗增敏的主要方向包括改善细胞乏氧以及调控细胞周期，同时细胞再氧合以及细胞周期的再分布也是放射治疗的主要理论基础。Cyclin G1是肝癌癌基因的一种，同时又是细胞周期调控因子，在化疗方面，下调Cyclin G1的表达可以通过细胞周期调节来促进紫杉醇的化疗敏感度。Kimura等研究表明Cyclin G1参与了放疗诱导的细胞周期阻滞（G2/M期阻滞）过程，Cyclin G1基因缺失的小鼠及其胚胎成纤维细胞的放疗敏感度明显增强[9]，本研究发现转染Cyclin G1-siRNA后，HepG2细胞表达Cyclin G1明显下降，而下调Cyclin G1的表达可以提高肝癌细胞的放疗敏感度，同时G2/M期细胞比例增加，而G0/G1期细胞比例减少，与文献报道相符。这一结果说明通过下调Cyclin G1的表达诱导的放疗敏感度增高，可能是通过细胞周期调控引起的。
实体瘤乏氧是放射治疗失败的主要原因之一，克服细胞乏氧是改善放疗抵抗及提高放疗疗效的一种有效途径。目前克服乏氧的药物主要包括硝基咪唑类化合物、糖酵解抑制剂以及HIF-1α抑制剂等。其中HIF-1α是近年来研究最多的一种乏氧相关因子，其通过调控血管内皮生长因子的表达参与肿瘤血管生成，并与肝癌的放疗疗效及临床预后相关[10-11]。在放射治疗的研究中发现，HIF-1α在放疗过程中表达较放疗前升高，抑制HIF-1α的表达或活性可以增加肿瘤的放射敏感度[12-14]，而本研究显示Cyclin G1-siRNA可以使HIF-1α表达下降，说明Cyclin G1-siRNA增加肝癌细胞放疗敏感度的作用部分是通过下调HIF-1α来实现的。
电离辐射对生物的损伤既有损伤DNA的直接作用，也有辐射产生大量自由基的间接作用，其中电离辐射的间接作用是引起损伤的重要方面[15]。ROS是一类活性氧自由基分子的集合体，生理状况下作为细胞内氧化还原信使，其生成和清除均保持着动态平衡，应激状态下这一平衡状态被打破，并最终引起细胞凋亡，ROS含量越高导致细胞的损伤越大，在放射治疗中，可通过增加ROS含量来提高肿瘤细胞的放疗敏感度[16-17]。本实验发现X线照射后ROS含量轻度升高，与对照组相比差异无统计学意义，而下调Cyclin G1的表达则可使ROS含量明显增加，尤其是合并X线照射后ROS含量增加更为明显，表明Cyclin G1-siRNA对HepG2细胞产生放射增敏效应的机制之一有可能是通过ROS含量的增加而实现的。
大量的研究发现，细胞的放射敏感度与凋亡有关[18-20]。本研究亦进行了相关探索，发现X线辐射可引起Bcl-2表达下降及Bax表达增加，其中Bcl-2为抑制凋亡基因，而Bax为促凋亡基因。说明了X线辐射本身可以诱导HepG2细胞的凋亡，而下调Cyclin G1的表达则可使这一作用加强，说明了Cyclin G1可能通过诱导凋亡来增加肝癌细胞的放射敏感度。
综上所述，通过转染Cyclin G1-siRNA可以增加肝癌细胞系HepG2的放射敏感度，其机制可能与细胞周期调控、HIF-1α调节、ROS含量及凋亡相关蛋白表达有关，但其具体机制以及是否与肝癌患者的放射敏感度相关仍不明确，还需要进一步的研究证实。
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：全 敏：试验设计、数据收集、文章撰写唐嘉源：数据整理、文献检索陈 红：选题、研究方法设计、文章审阅 -
表 1 LD与ED患者基线资料差异对比
Table 1 Comparison of baseline data between LD and ED patients
Variables LD patients
(n = 49)ED patients
(n = 23)χ2 P Gender 0.421 0.421 Male 37 20 Female 12 3 Age(years) 2.500 0.114 <65 31 10 ≥65 18 13 Smoking history 0.533 0.465 Yes 32 17 No 17 6 Drinking history 0.659 0.417 Yes 27 15 No 22 8 Family history <0.001 0.992 Yes 8 3 No 41 20 BMI 0.827 0.363 <24 37 15 ≥24 12 8 First symptom 0.125 0.723 Dysphagia 34 15 Others 15 8 Notes: BMI: body mass index; Others: hoarse, pain, neck mass, epigastric discomfort. 
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表 2 PESCC患者一般连续性变量统计描述
Table 2 Statistical description of general continuity variables in patients with PESCC
Variables Mean value Standard deviation Age 64.39 7.734 BMI 22.74 3.234 Focal length 6.39 2.778 NEUT# 4.00 1.205 LYMPH# 1.59 0.657 PLT 193.74 61.699 Mono# 0.42 0.168 NLR 2.87 1.428 PLR 136.90 61.24 SII 557.75 372.882 PNI 45.744 9.366 CRP 7.24 13.497 TP 65.34 4.745 ALB 39.44 3.151 Notes: NEUT#: neutrophil count; LYMPH#: lymphocyte count; PLT: platelet count; MONO#: monocyte count; TP: total protein; ALB: serum albumin.
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表 3 LD与ED患者总生存期的Cox单因素生存分析
Table 3 Cox univariate survival analysis of overall survival of patients with LD and ED
Variables LD patients ED patients HR 95%CI P HR 95%CI P Gender 1.160 0.527-2.551 0.713 0.840 0.240-2.935 0.785 Age 1.034 0.983-1.087 0.195 1.040 0.967-1.118 0.287 Smoking history 1.269 0.624-2.580 0.511 0.771 0.288-2.063 0.605 Drinking history 1.085 0.560-2.100 0.809 0.539 0.211-1.376 0.196 Family history 0.503 0.194-1.302 0.157 0.721 0.164-3.157 0.664 BMI 0.591 0.268-1.302 0.192 0.880 0.759-1.019 0.088 Focal length 1.039 0.927-1.165 0.509 0.954 0.830-1.097 0.507 NEUT# 0.899 0.663-1.219 0.494 1.469 0.875-2.464 0.146 LYMPH# 0.785 0.474-1.300 0.346 0.521 0.217-1.247 0.143 PLT 0.997 0.990-1.003 0.328 1.001 0.993-1.009 0.809 Mono# 0.871 0.129-5.897 0.888 1.115 0.040-30.957 0.949 NLR 1.016 0.815-1.266 0.887 1.819 1.216-2.719 0.004 PLR 1.001 0.995-1.006 0.853 1.011 1.003-1.019 0.009 SII 1.000 0.999-1.001 0.741 1.002 1.001-1.004 0.003 PNI 0.950 0.921-0.979 0.001 0.941 0.857-1.034 0.207 TP 0.915 0.849-0.987 0.022 1.029 0.926-1.142 0.597 ALB 0.937 0.847-1.037 0.209 0.942 0.794-1.119 0.497 CRP 1.020 0.974-1.068 0.395 1.059 1.009-1.112 0.021 Treatment mode* 0.934 0.490-1.782 0.836 - - - Treatment mode** 0.503 0.247-1.024 0.058 0.800 0.331-1.033 0.620 Chemotherapy cycle 0.454 0.230-0.897 0.023 1.324 0.538-3.260 0.542 Notes: *: surgical vs. nonsurgical treatment; **: combination therapy vs. monotherapy; -: not applicable.
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表 4 影响LD与ED患者总生存期的Cox多因素生存分析
Table 4 Cox multifactor survival analysis of overall survival of patients with LD and ED
Variables B SE Wald DF P HR 95%CI LD TP −0.117 0.051 5.226 1 0.022 0.890 0.805-0.983 Chemotherapy cycle −0.946 0.373 6.427 1 0.011 0.388 0.187-0.807 ED SII 0.002 0.001 7.362 1 0.007 1.002 1.000-1.004 CRP 0.063 0.022 8.511 1 0.004 1.065 1.021-1.111
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