ERK5在结直肠癌组织中的表达及其与结直肠癌转移的关系

目的:检测和分析细胞外信号调节激酶5(ERK5)蛋白在原发性结直肠癌组织和癌旁正常黏膜组织中的表达情况及其与结直肠癌临床病理参数的关系,探讨ERK5的临床意义。方法:使用组织芯片和免疫组化的方法检测338例原发性结直肠癌癌组织和80例癌旁正常组织中ERK5的表达,分析ERK5表达与结直肠癌的临床病理参数及预后的相关性。结果:80例癌旁正常黏膜中,ERK5低表达59例(73.8%)、高表达为21例(26.2%);338例结直肠癌组织中ERK5低表达204例(60.4%)、高表达134例(39.6%);二者中的ERK5蛋白表达有显著差异(P0.05)。Kaplan-Meier生存分析显示在结直肠癌组织中ERK5高表达的病人总体5年生存率与低表达组无明显差异(P>0.05)。结论:ERK5蛋白在癌组织中的表达较癌旁正常组织高;发生远处转移的结直肠癌组织中ERK5蛋白的表达水平明显高于未发生远处转移的癌组织中ERK5水平。ERK5可能是一个促进肿瘤远处转移的因子。     

DPD缺乏症与5-FU毒性

5- FU是临床应用最广泛的化疗药物之一 ,二氢嘧啶脱氢酶 (DPD)是其分解代谢的限速酶 ,近来不少研究报道DPD活性部分或完全缺乏可导致严重甚至致死的 5 - FU毒性 ,并已明确其分子遗传学基础为 DPYD基因突变。由于 DPD活性缺乏症者约占人群的 3% ,应当引起足够重视。本文综述了近年来对这一药物遗传病的基础和临床研究进展     

5-FU通过靶向Wnt/β-catenin信号通路对结直肠癌干细胞活性的影响

目的 基于Wnt/β-catenin信号通路探讨5-氟尿嘧啶（5-FU）对结直肠癌干细胞（CRC-CSC）活性的影响。方法 流式细胞术分选CD133标记的CRC-CSC,以不同浓度5-FU(6.25、12.50、25.00μmol/L)处理细胞,对照组以等体积培养液处理。药物作用48 h后,CCK-8法检测细胞增殖,划痕实验检测细胞迁移,流式细胞术检测细胞凋亡,平板克隆实验和球形成实验检测细胞克隆能力及悬浮球形成能力,蛋白免疫印迹法检测Wnt/β-catenin信号通路表达。结果 与对照组比较,高剂量5-FU处理后CRC-CSC细胞增殖能力（24 h、48 h两组分别为0.31±0.03vs. 0.53±0.05;0.37±0.03 vs. 0.61±0.05）和迁移能力（24 h、48 h两组分别为9.63±0.72 vs. 38.69±0.88;16.21±1.17 vs.58.69±1.32）显著增加（P<0.05）,细胞凋亡率（24 h、48 h两组分别为46.91±0.94 vs. 18.46±0.88;55.22±1.24 vs. 28.42±1.18）显著降低（P&...     

外泌体在结直肠癌中的研究进展

近年来,由于对外泌体的不断认识和了解,研究外泌体已成为当下的热点,外泌体是细胞分泌的一种纳米级囊泡结构,可来源于机体正常细胞及肿瘤细胞,在血液、唾液、尿液、母乳等多种体液中均有分布,其参与许多生物学和病理学过程,主要是由于它们在细胞间通讯作用,源自结直肠癌（CRC）细胞的外泌体与肿瘤发生、进展、转移、预后等相关。本文就外泌体在结直肠癌中的研究进展进行综述。     

抗DR5单抗CTB006联合5-FU对结直肠癌细胞系作用研究

目的探讨肿瘤坏死因子相关诱导配体受体（DR5）激动型单抗CTB006对人结直肠痛细胞系SW1116、SW480、SW620、Colo205的影响。方法采用ATPlite法检测CTB006组、5-FU组及两药物合用组作用后的细胞存活率,流式细胞仪技术检测细胞系表面DR5的表达水平,研究两者之间的关系。结果CTB006和5-FU对四种结直肠癌细胞增殖均表现出抑制作用。CTB006对早期细胞SW1116增殖抑制效果欠佳,对中晚期细胞SW480、SW620、Colo205有着良好的增殖抑制作用（P〈0．05）。当联合使用5-FU后,对后三者有明显的协同作用。流式细胞仪检测DR5表达水平,SW1116细胞表达（47．01±30．4）％,SW480细胞表达（76．11±15．1）％,SW620细胞表达（86．77±9.3）％,Col0205细胞表达（93．55±7．9）％。结论CTB006对中晚期结直肠癌杀伤作用较强,联用5-FU具有显著的协同作用。     

EIF5A2在肿瘤中的作用研究进展

真核细胞翻译起始因子5A2(EIF5A2)是EIF5A家族中高度进化保守的基因之一.EIF5A2作为可能的癌基因在多种人类上皮源性肿瘤内呈高表达,并与肿瘤的分期和/或预后不佳相关.EIF5A2通过多种机制诱导肿瘤发生上皮间质转化进而促进肿瘤侵袭转移.EIF5A-MTA1/C-MYC轴可能是上皮源性肿瘤发生侵袭转移的重要调控通路之一.相关分子机制尚需进一步研究.     

miR-320a、KLF5在结直肠癌中的表达及意义

目的 研究结直肠癌中miR-320a和KLF5的表达,分析二者表达相关性及其临床意义.方法 通过OncomiR公共数据库分析miR-320a在结直肠癌中的表达.通过GEPIA、HPA公共数据库分析结直肠癌中KLF5基因的表达,通过GEPIA分析KLF5表达患者生存期的关系.通过在线预测工具(TargetscanHuma...     

自噬增强结肠癌CD133~+细胞对5-FU的化疗抵抗

目的对5-FU诱导结肠癌CD133+细胞发生自噬的过程进行观察,初步探讨自噬对化疗的影响。方法用MTT法检测细胞增殖抑制率及IC50;用免疫磁珠分选CD133+细胞;用透射电子显微镜(TEM)观察细胞的超微结构,用MDC染色,荧光显微镜观察自噬囊泡;联合应用细胞活性实验、集落形成实验研究自噬对化疗的影响。结果不同浓度5-FU处理后,人结肠癌SW480细胞活性明显受到抑制,其半数抑制浓度IC50为(1.09±0.18)μg/mL。CD133+胞质出现大量的自噬体及自噬囊泡;相比较单独给予5-FU,联合给予5-FU及3-MA,CD133+细胞活性由(81.8±4.6)%下降到(56.3±5.5)%(P<0.05),集落形成率由(81.1±3.4)%下降(64.4±4.8)%(P<0.05)。结论 5-FU可诱导结肠癌CD133+细胞发生自噬;自噬的抑制能够增强5-FU对结肠癌CD133+细胞的细胞毒效应。     

Combination of Targeting Gene-ViroTherapy with 5-FU enhances antitumor efficacy in malignant colorectal carcinoma.

To improve the therapeutic effect of ONYX015, an E1B55kD-deleted replication-competent adenovirus, ZD55 was constructed and armed with the therapeutic gene hTRAIL to form ZD55-hTRAIL, which was used for cancer therapy and which we call Targeting Gene-ViroTherapy. In vitro experiments with SW620, HCT116, and HT29 colorectal carcinoma cell lines demonstrated that they were all sensitive to ZD55-hTRAIL, and especially sensitive to ZD55-hTRAIL plus 5-fluorouracil (5-FU) treatment. In the SW620 xenograft tumor model, various treatment groups showed marked differences at week 11, with the tumor volume for the phosphate-buffered saline (PBS) treatment group >1700 mm3, for 5-FU > 1300 mm3, for ONYX015 1051.3 mm3, for ZD55-hTRAIL 600.05 mm3, and for ZD55-hTRAIL plus 5-FU 230.2 mm3. At the end of week 14, tumor-bearing mice in the other groups almost all died, whereas all the mice in the combined treatment group were alive, with one mouse tumor free. By transmission electron microscopy (TEM) assay, most tumor cells treated with ONYX015 or with ZD55-hTRAIL singly or in combination with 5-FU were lysed due to viral propagation. RT-PCR analysis and immunohistochemistry examination revealed that hTRAIL was expressed in ZD55-hTRAIL-treated SW620 tumor tissue. Furthermore, no detectable hepatoxicity was found by serum enzyme level analysis. These results suggest that ZD55-hTRAIL alone or in combination with 5-FU may have potential clinical implications.     

5-FU诱导人肝细胞癌MDR的比较蛋白质组学研究

目的 寻找与人肝细胞癌多药耐药相关的蛋白质分子,为进一步研究人肝细胞癌多药耐药机制提供依据.方法 体外培养人肝癌细胞Bel-7402及其耐5-氟尿嘧啶(5-FU)细胞Bel-FU,MTF法检测Bel-FU的多药耐药性,双向凝胶电泳技术分析细胞Bel-7402与Bel-FU之间的差异表达蛋白,经MALDI-TOF/TOF质谱鉴定.Western blot验证2-DE及质谱的检测结果.结果 与Bel-7402比较,Bel-FU中有24个蛋白表达上调,其中包括FAK、TM3、ORP150、CRT、hnRNP K、80K-H protein、EF-1-D、phosphoprotein等,12个蛋白表达下调.Western blot法检测到蛋白FAK、CRT在Bel-FU中高表达,与2-DE结果一致.结论 通过建立人肝癌细胞Bel-7402及其耐5-氟尿嘧啶细胞Bel-FU的2-DE图谱筛选了多药耐药相关的差异蛋白,为人肝细胞癌MDR的分子机制研究奠定了基础.     

Semaphorin5A在大肠癌组织中的表达及临床意义

目的检测神经导向分子Semaphorin5A在大肠癌组织中表达,并探讨其在大肠癌发生发展中的意义。方法选取43例大肠癌组织和22例正常大肠粘膜组织,采用免疫组织化学、Western blot和real-time PCR方法检测Semaphorin5A在大肠癌组织及其正常大肠粘膜组织中的表达,并分析其与临床病理特征之间的相关性。结果大肠癌组织中Semaphorin5A的蛋白与mRNA表达水平显著高于正常大肠粘膜组织(P0.05);Semaphorin5A的表达与大肠癌Dukes分期、淋巴结转移、组织学分型有关,与年龄、性别无关。结论Semaphorin5A可能与大肠癌的发生发展密切相关。     

胰腺癌组织中SERPINB5的表达及意义

目的探讨SERPINB5在胰腺癌中的表达及其临床意义。方法利用组织芯片技术及免疫组化SP法检测SERPINB5在胰腺癌、癌旁组织与慢性胰腺炎组织中的表达,分析它与胰腺癌的临床病理指标间的相关性。结果 47例胰腺癌组织中SERPINB5的阳性表达率为85.11%(40/47),而16例癌旁及慢性胰腺炎组织中SERPINB5的阳性表达率为25%(4/16),两者比较差异有统计学意义(P<0.05);SERPINB5在胰腺癌组织中的表达与患者性别、年龄、肿瘤部位、肿瘤组织学类型及神经浸润均无关(P均>0.05)。结论 SERPINB5阳性表达与胰腺癌相关,提示SERPINB5可能在胰腺癌的发生、发展中起重要作用。     

Expression of MUC5AC in colorectal carcinoma and relationship with prognosis

Overexpression and alterations in the glycosylation of gastric mucins have been described in colorectal carcinoma. The purpose of our study was to confirm aberrant expression of MUC5AC in colorectal carcinoma, to investigate relationships between clinicopathological parameters and MUC5AC expression, and to determine if MUC5AC expression may be a prognostic factor for colorectal carcinoma. Immunohistochemical staining using an antibody against MUC5AC tandem repeat epitopes was performed on colorectal tumor specimens (n = 41), their metastatic tumors in regional lymph nodes (n = 21) and normal colonic mucosa (n = 41). We also documented clinicopathological parameters such as the age and sex of the patient, location, size, Dukes stage, histological type and grade of the tumor, pre-sence and number of metastatic lymph nodes, lymphatic, venous and perineural invasion, presence of preoperative and postoperative metastatic tumors and tumor recurrence. MUC5AC was expressed in 34.1% of tumor samples, 24.4% of normal colonic mucosa samples and 19% of lymph node metastases. MUC5AC showed ectopic expression in colorectal carcinoma and was also expressed strongly in mucinous carcinoma (60%). The number of tumors that expressed MUC5AC was lower in patients older than 60 years, in rectum-localized tumors and in patients who had evidence of recurrence and/or metastasis in the postoperative period. The patients with MUC5AC-negative tumors had a lower incidence of being disease free and of overall survival. In conclusion, the patients with MUC5AC-negative tumors had poor clinicopathological parameters and showed worse survival than patients with MUC5AC-positive tumors. Absence of MUC5AC expression in tumors can be a prognostic factor for more aggressive colorectal carcinoma.     

Modeling 5-FU clearance during a chronomodulated infusion

Drugs pharmacokinetic control is a usual practice in case of flat continuous infusions. It enables among others, to modulate delivered doses when drug concentrations in blood appear too high. With chronotherapy, this possibility becomes more difficult because of sinusoidal outflows of infusion. We propose here a method that enables this follow-up, established through the study of 21 metastatic colorectal cancer patients, treated with a chronomodulated infusion of high dose 5-fluoro-uracil (5-FU) and folinic acid. This pharmacokinetic follow-up permitted the modelisation of 5-FU clearance and the calculation of an index, which was, in our study, correlated to the treatment response and also to main encountered toxicities.     

大肠癌的细胞遗传学研究

目的研究大肠癌的发生机理,期望发现与大肠癌发生有关的染色体脆性位点,以指导大肠癌高危人群的筛查和防治。方法对２０例大肠癌手术切除瘤组织及４例大肠癌细胞系进行了细胞遗传学研究。结果发现癌细胞多为异倍体,染色体数目以亚二倍体居多,常见１３号染色体增多及１７、１号染色体丢失;结构畸变较常累及１号染色体,以１ｑ２１,１ｐ１３区的裂隙、断裂、末端丢失最为常见。对比大肠癌细胞染色体高度非随机断裂点与脆性位点和目前所确认的癌基因位点,发现三者同位或毗邻的位点为１ｑ２１。结论１ｑ２１可能与大肠癌的发生有关,并对大肠癌高危人群的筛查和防治有一定的指导意义。     

Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation

AIMS: Chromosomal gains and losses were surveyed by comparative genomic hybridisation (CGH) in a series of colorectal adenomas and carcinomas, in search of high risk genomic changes involved in colorectal carcinogenesis. METHODS: Nine colorectal adenomas and 14 carcinomas were analysed by CGH, and DNA ploidy was assessed with both flow and image cytometry. RESULTS: In the nine adenomas analysed, an average of 6.6 (range 1 to 11) chromosomal aberrations were identified. In the 14 carcinomas an average of 11.9 (range 5 to 17) events were found per tumour. In the adenomas the number of gains and losses was in balance (3.6 v 3.0) while in carcinomas gains occurred more often than losses (8.2 v 3.7). Frequent gains involved 13q, 7p, 8q, and 20q, whereas losses most often occurred at 18q, 4q, and 8p. Gains of 13q, 8q, and 20q, and loss of 18q occurred more often in carcinomas than in adenomas (p = 0.005, p = 0.05, p = 0.05, and p = 0.02, respectively). Aneuploid tumours showed more gains than losses (mean 9.3 v 4.9, p = 0.02), in contrast to diploid tumours where gains and losses were nearly balanced (mean 3.1 v 4.1, p = 0.5). CONCLUSIONS: The most striking difference between chromosomal aberrations in colorectal adenomas and carcinomas, as detected by CGH, is an increased number of chromosomal gains that show a nonrandom distribution. Gains of 13q and also of 20q and 8q seem especially to be involved in the progression of adenomas to carcinomas, possibly owing to low level overexpression of oncogenes at these loci.     

Intracavitary 5-fluoro-uracil (5-FU) in combination with systemic chemotherapy

In 23 patients with peritoneal, pleural oder pericardial metastases the efficacy of intracavitary tumor therapy was investigated. 5-FU was administered intracavitary in all patients combined with systemic chemotherapy. 8 partial responses (34%) were achieved.     

Overexpression of EIF-5A2 is associated with metastasis of human colorectal carcinoma

Our previous study has suggested an oncogenic role of eIF-5A2 in ovarian tumorigenesis. Abnormalities of eIF-5A2, however, in colorectal carcinoma are unclear. In this study, amplification and overexpression of eIF-5A2 in colorectal carcinoma were studied by fluorescence in situ hybridization and immunohistochemistry using colorectal carcinoma tissue microarrays, including 139 primary colorectal carcinomas and their adjacent normal mucosa, 22 paired premalignant adenomas, and 42 metastatic tumors. The immunohistochemistry results showed that overexpression of EIF-5A2 was detected in none of normal epithelial mucosa, 35.3% of colorectal adenomas, 53.2% of primary colorectal carcinomas, and 67.6% of metastases. Amplification of eIF-5A2 was detected in 15.8% (16/101) of informative colorectal carcinomas, and most of them showed overexpression of EIF-5A2. In primary colorectal carcinomas, the frequency of EIF-5A2 overexpression was significantly higher in colorectal carcinomas with lymphovascular invasion (61.2%) than that in colorectal carcinomas without lymphovascular invasion (36.6%, P < .05). In addition, significant positive associations were found between EIF-5A2 overexpression and the tumors' later pN and pM stages, as well as increased tumor cell proliferation (P < .05). These findings suggest that overexpression of EIF-5A2 in colorectal carcinomas may be important in the acquisition of a metastatic phenotype and plays an important role in colorectal carcinoma development and progression.