细胞粘附分子的表达与结直肠癌转移、预后的关系

细胞粘附分子是参与细胞－细胞以及细胞－基质之间作用的一类粘附物质的总称,包括钙粘附素族,整合素族,免疫球蛋白超家族,选择素族,透明质酸受体类及其它。近年来细胞粘附分子在肿瘤转移中的作用日益引起人们的重视。本文就主要几种粘附分子的表达与结直肠癌转移,预后的关系的研究进展作一综述。     

结直肠癌中VEGF-C和MMP-2蛋白表达量与肿瘤侵袭转移关系的研究

目的:研究VEGF-C、MMP-2在结直肠癌中mRNA和蛋白水平的表达,分析其表达与临床病理特征间关系,探讨其在结直肠癌中的表达及其意义。方法:收集46例常熟市第二人民医院病理科2014年至2017年结直肠癌手术切除的新鲜肿瘤组织及20例癌旁正常组织。采用实时荧光定量逆转录聚合酶链反应方法检测46例结直肠癌与癌旁正常组织中VEGF-C mRNA、MMP-2的表达,应用免疫组织化学方法检测结直肠癌与癌旁正常组织VEGF-C、MMP-2蛋白的表达,分析VEGF-C mRNA、MMP-2 mRNA和蛋白表达与临床病理分期特征间关系。结果:46例结直肠癌中VEGF-C mRNA（P<0.05）、MMP-2 mRNA（P<0.05）转录水平显著高于癌旁正常组织。VEGF-C mRNA转录水平与患者年龄、性别和肿瘤直径等无相关性（P>0.05）,与组织学分级、TNM分期、淋巴结和远处转移等有相关性（P<0.05）;MMP-2 mRNA转录水平与年龄、性别、肿瘤直径、淋巴结和远处转移等无相关性（P>0.05）,而与组织学分级、TNM分期上有统计学差异（P<0.05）。VEGF-C蛋白表达量与性别、肿瘤直径和远处转移无相关性（P>0.05）,而与患者年龄、淋巴结转移、组织学分级和TNM分期等相关（P<0.05）;MMP-2蛋白表达量与年龄、性别、肿瘤直径和远处转移无相关性（P>0.05）,只与组织学分级和TNM分期等相关（P<0.05）。两基因间mRNA转录水平与蛋白表达水平呈线性相关性（P<0.01）。结论:VEGF-C、MMP-2蛋白的高表达与结直肠癌细胞侵袭及转移过程的发生密切相关,可为作潜在靶向标志物,为临床上进一步诊断治疗及预后提供理论依据。     

p53、Bcl-2蛋白在结直肠癌中的表达及其与预后的关系

目的探讨p53、Bcl-2蛋白在结直肠癌组织中的表达及其与预后的关系。方法应用免疫组化SABC法检测120例手术切除的结直肠癌肿瘤组织中p53、Bcl-2蛋白的表达,并对所有手术后病例进行随访,分析5年生存率与p53及Bcl-2阳性表达的关系。结果结直肠癌肿瘤组织中p53、Bcl-2蛋白表达阳性率分别为63.3%、46.7%。p53、Bcl-2蛋白阳性表达均与患者年龄、性别、肿瘤Dukes分期、生长部位、淋巴结是否转移无关（P〉0.05）,与肿瘤分化程度有关（P〈0.05）;Spearman相关性分析表明,在结直肠癌肿瘤组织中p53和Bcl-2的表达呈负相关;患者术后的5年生存率与Bcl-2蛋白表达呈正相关（P〈0.01）;与p53表达呈负相关（P〈0.05）。结论 p53在结直肠癌组织中高表达,而Bcl-2蛋白低表达,且两者成负相关。p53和Bcl-2与患者术后5年生存率均有关,提示检测p53和Bcl-2的表达,对临床判断术后患者的预后有指导意义。     

结直肠癌HER-2表达水平与临床病理特征及预后的相关性

目的:分析HER-2表达水平与结直肠癌临床病理特征及预后的关系,并进一步探讨其在结直肠癌中的作用.方法:收集2012年01月至2016年02月在南京鼓楼医院实施手术治疗结直肠癌患者共640例,对其进行HER-2免疫组化检测,根据免疫组化结果,将患者分为HER-2(0)、HER-2(1+)、HER-2(2+)、HER-2(3+)四组,并对四组患者临床病理特征及生存期进行分析.结果:HER-2表达水平与结直肠患者肿瘤分期、大小、神经侵犯、Lgr5、VEGF、VEGFR2等相关,差异有统计学意义(P<0.05),而与性别、年龄、肿瘤部位、病理类型、分化程度、大体类型、侵袭深度、淋巴结、脉管转移及无病生存期、总生存期无关(P>0.05).结论:HER-2可能与结直肠癌的生长、增殖及侵袭相关,未来或许成为晚期结直肠癌靶向治疗的潜在方向之一.     

SOX2蛋白在结直肠癌中的表达及临床意义

目的 研究SOX2蛋白在结直肠癌中的表达及临床意义.方法 收集80例结直肠癌手术标本及20例正常的肠黏膜标本,采用免疫组化法检测SOX2蛋白在标本中的表达情况.结果 SOX2蛋白在正常肠黏膜中不表达,在结直肠癌中高表达,表达率为41.3％.SOX2表达水平与TNM分期、肿瘤浸润深度、淋巴结转移、组织学分化程度、Ki-6...     

乙型肝炎表面抗原、癌胚抗原与结直肠癌肝转移和预后的关系

目的 探讨HBsAg、CEA与结直肠癌肝转移和预后的关系。方法 回顾性分析2所医院1990年1月－1995年12月间收治的58 结直肠癌的病例资料，并对其HBsAg、CEA进行测定，分别观察它们与肝转移和预后的关系。结果 HBsAg阳性得肝转移率明显低于HBsAg阴性者（P＜0.05）；CEA阳性者与CEA阴性者的肝转移率无显著性差异（P＞0.05），但CEA阳性者的5年生存率（31.3%）明显低于CEA阴性者（84.2%）（P＜0.01）。结论 结直肠癌很少转移至感染乙型肝炎病毒的肝脏，CEA不能作为判断结直肠癌肝转移倾向的指标，但可以作为判断结直肠癌预后的指标之一。     

结直肠癌临床病理分期与预后的关系

结直肠癌的预后受诸多因素的影响,其中TNM分期是最为重要的因素。TNM分期的提出是根据肿瘤发展的生物学规律总结出来的,而大宗的临床统计分析数据促成了TNM分期的不断完善和更新。文章就新近的几个大宗临床荟萃分析结果作一综述,阐述结直肠癌TNM分期与预后的关系。     

直肠癌组织中mTOR和VEGF的表达与侵袭转移及预后的关系

目的 探讨直肠癌组织中哺乳动物雷帕霉素靶蛋白（mTOR）和血管内皮生长因子（VEGF）的表达,并分析其与侵袭转移和预后的关系。方法 采用免疫组化SP法检测mTOR和VEGF在60例直肠癌、30例直肠腺瘤及10例正常直肠黏膜组织中的表达,并对直肠癌中两者与临床病理特征、预后及两者间的相关性进行分析。结果 mTOR在直肠癌中的阳性表达率为60.0％（36／60）,高于直肠腺瘤和直肠正常黏膜组织的36.7％（11／30）和10.0％（1／10）,差异均有统计学意义（P＜0.05）;其表达与直肠癌患者的术前CEA水平、分化程度、TNM分期、淋巴结转移和远处转移有关（P＜0.05）,而与年龄、性别、肿瘤部位和肿瘤形态无关（P＞0.05）。VEGF在直肠癌中的阳性表达率为70.0％（42／60）,显著高于直肠腺瘤和直肠正常黏膜组织的46.7％（14／30）和20.0％（2／10）,差异均有统计学意义（P＜0.05）;其表达与直肠癌患者的TNM分期、淋巴结转移和远处转移有关（P＜0.05）,而与年龄、性别、肿瘤部位、肿瘤形态、术前CEA水平和分化程度无关（P＞0.05）。两者在直肠癌组织中的表达呈正相关（r=0.393,P=0.002）。60例直肠癌患者的中位生存期为39.2个月,1、2、3年生存率分别为89.4%、76.6%和55.3%。单因素生存分析显示,术前CEA水平、TNM分期、淋巴结转移、远处转移与直肠癌预后有关（P＜0.05）,而年龄、性别、肿瘤部位、分化程度、肿瘤形态、VEGF、mTOR与直肠癌预后无关（P＞0.05）。结论 直肠癌组织中 mTOR、VEGF均呈高表达,且呈正相关,二者在直肠癌侵袭转移中可能发挥重要作用。     

结直肠癌组织中SKP2表达及其与MVD、FAK的关系

[目的]探讨S期激酶相关蛋白2(SKP2)与黏着斑激酶(FAK)、微血管密度(MVD)在结直肠癌组织中的表达意义及相互关系。[方法]免疫组化S-P法检测62例结直肠癌和正常黏膜组织标本中SKP2和FAK、MVD的表达。[结果]结直肠癌组织中SKP2的阳性率为61.29%;而对应癌旁非瘤正常组织中阳性率为9.68%,有显著性差异(P<0.05)。结直肠癌组织中SKP2的表达与分化程度、浸润深度有明显相关性;而与性别、年龄、病灶部位、大体类型、病灶大小、有无淋巴结转移无明显相关性。SKP2表达与FAK表达呈正相关(r=0.46,P<0.01);SKP2阳性表达组的MVD标记数50.41±11.07明显高于阴性表达组43.06±9.78(P<0.01)。[结论]SKP2在结直肠癌组织表达上调且与分化程度、浸润深度有关,SKP2与FAK表达及癌组织的MVD呈正相关,三者的表达可以作为评价肿瘤恶性程度的重要参考指标。     

RHGAPs分子与结直肠癌侵袭及转移关系的研究进展

Rho家族参与细胞形态、细胞骨架重组、细胞与基质黏附、细胞周期、细胞凋亡等过程。ARHGAPs作为Rho家族的分子开关,可以极大地提高Rho蛋白内在的RhoGTPase活性,负性调控Rho蛋白,在多种恶性肿瘤的侵袭和转移中发挥重要作用。在结直肠癌组织中,一些ARHGAPs表现出抑制肿瘤侵袭和转移的作用,值得进一步深入研究。     

High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer

Increased expression of tumour-associated trypsin inhibitor (TATI) in tumour tissue and/or serum has been associated with poor survival in various cancer forms. Moreover, a proinvasive function of TATI has been shown in colon cancer cell lines. In this study, we have examined the prognostic significance of tumour-specific TATI expression in colorectal cancer, assessed by immunohistochemistry (IHC) on tissue microarrays (TMAs) with tumour specimens from two independent patient cohorts. Kaplan–Meier analysis and Cox proportional hazards modelling were used to estimate time to recurrence, disease-free survival and overall survival. In both cohorts, a high (>50% of tumour cells) TATI expression was an independent predictor of a significantly shorter overall survival. In cohort II, in multivariate analysis including age, gender, disease stage, differentiation grade, vascular invasion and carcinoembryonal antigen (CEA), high TATI expression was associated with a significantly decreased overall survival (HR=1.82; 95% CI=1.19–2.79) and disease-free survival (HR=1.56; 95% CI=1.05–2.32) in curatively treated patients. Moreover, there was an increased risk for liver metastasis in both cohorts that remained significant in multivariate analysis in cohort II (HR=2.85; 95% CI=1.43–5.66). In conclusion, high TATI expression is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer.     

RhoGDI2 confers gastric cancer cells resistance against cisplatin-induced apoptosis by upregulation of Bcl-2 expression

Rho GDP dissociation inhibitor (RhoGDI)2 has been identified as a regulator of Rho family GTPase. Recently, we suggested that RhoGDI2 could promote tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that RhoGDI2 contributes to another important feature of aggressive cancers, i.e., resistance to chemotherapeutic agents such as cisplatin. Forced expression of RhoGDI2 attenuated cisplatin-induced apoptosis, whereas RhoGDI2 depletion showed opposite effects in vitro. Moreover, the increased anti-apoptotic effect of RhoGDI2 on cisplatin was further validated in RhoGDI2-overexpressing SNU-484 xenograft model in nude mice. Furthermore, we identified Bcl-2 as a major determinant of RhoGDI2-mediated cisplatin resistance in gastric cancer cells. Depletion of Bcl-2 expression significantly increased cisplatin-induced apoptosis in RhoGDI2-overexpressing gastric cancer cells, whereas overexpression of Bcl-2 blocked cisplatin-induced apoptosis in RhoGDI2-depleted gastric cancer cells. Overall, these findings establish RhoGDI2 as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk in gastric cancer.     

Pgp检测和进展期大肠癌化疗及临床预后的关系

目的　了解Pgp检测和进展期大肠癌患者化疗及预后的关系。 方法　 44例进展期大肠癌患者手术标本 ,通过免疫组化技术检测Pgp表达情况 ,所有患者均进行临床密切随访。 结果　 44例患者中 ,Pgp表达阳性 2 4例 ,Pgp阳性率 54 .5 % (2 4 /4 4 ) ,其中术前化疗≥ 2个疗程者 ,其Pgp阳性率显著高于未化疗和行一疗程化疗者 ,且Pgp阳性者临床预后较差。 结论　大肠癌患者化疗后存在多药耐药 (MDR)现象 ,且与临床预后有关     

SOX2在结直肠癌表达的临床观察

目的：观察SOX2在结直肠癌组织的表达情况,探讨SOX2在结直肠癌中表达的临床意义。方法收集103例有60～125个月（中位随访时间84个月）随访资料的结直肠癌及其相应的正常结直肠黏膜标本,应用免疫组化方法检测SOX2的表达,分析SOX2表达与临床特征的关系。结果结直肠癌组织中SOX2蛋白的表达率显著高于癌旁正常肠黏膜（P＜0.001）;SOX2表达与结直肠癌分化程度显著负相关（P＜0.01）,与结直肠癌TNM分期、淋巴结转移个数及远处转移程度正相关（P＜0.05）。SOX2表达与结直肠癌患者术后5年生存率和3年无瘤生存率也具有相关性（P＜0.05）。结论 SOX2蛋白异常表达可作为提示结直肠癌预后判断的重要参考指标。     

Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis

Background:

Five-year survival after resection of colorectal cancer liver metastasis (CRLCM) is <30%. We recently found that aurora kinase A (AURKA) drives 20q gain-associated tumour progression and is associated with disease recurrence. This study evaluates the prognostic value of AURKA expression in CRCLM of patients who underwent liver resection.

Methods:

Tissue microarrays (TMAs) were generated using formalin-fixed paraffin-embedded CRCLM and matched primary tumour from a multi-institutional cohort of patients with CRCLM who underwent liver resection between 1990 and 2010. Tissue microarrays were stained for AURKA using immunohistochemistry, and a hazard rate ratio (HRR) for the association between overall survival (OS) and nuclear AURKA expression in CRCLM was calculated. Results were validated by 500-fold cross-validation.

Results:

The expression of AURKA was evaluated in CRCLM of 343 patients. High AURKA expression was associated with poor OS (HRR 1.55, P<0.01), with a cross-validated average HRR of 1.57 (P=0.02). Average HRR was adjusted for the established prognostic clinicopathological variables in a multivariate analysis (average HRR 1.66; P=0.02). The expression of AURKA in CRCLM was correlated to its expression in corresponding primary tumour (P<0.01).

Conclusion:

The expression of AURKA protein is a molecular biomarker with prognostic value for patients with CRCLM, independent of established clinicopathological variables.     

Diabetes and prognosis in older persons with colorectal cancer

Background:

Epidemiological studies have reported that diabetes significantly increases overall mortality in patients with colorectal cancer. However, it is unclear whether diabetes increases colorectal cancer-specific mortality. We used the US Surveillance Epidemiology and End Results (SEER) database linked with Medicare claims data to assess the influence of pre-existing diabetes on prognosis of patients with colorectal cancer.

Methods:

Data from 61 213 patients aged 67 or older with colorectal cancer diagnosed between 2003 and 2009 were extracted and prospectively followed through the date of death or the end of 2012 if the patient was still alive. Diabetes cases with and without complications were identified based on an algorithm developed for the Chronic Condition Data Warehouse (CCW). Cox models were used to estimate hazard ratios (HRs) for total mortality. The proportional subdistribution hazards model proposed by Fine and Gray was used to estimate HRs for colorectal cancer-specific mortality.

Results:

Compared with patients without diabetes, colorectal cancer patients with pre-existing diabetes had significantly higher risk of overall mortality (HR=1.20, 95 % confidence interval (95% CI): 1.17–1.23). The HR for overall mortality was more pronounced for patients who had diabetes with complications (HR=1.50, 95% CI: 1.42–1.58). However, diabetes was not associated with increased colorectal cancer-specific mortality after accounting for non-colorectal cancer outcomes as competing risk.

Conclusions:

Pre-existing diabetes increased risk of total mortality among patients with colorectal cancer, especially among cancer patients who had diabetes with complications. The increased risk of total mortality associated with diabetes was primarily explained by increased cardiovascular-specific mortality, not by increased colorectal cancer-specific mortality.     

VEGF‐C mediates RhoGDI2‐induced gastric cancer cell metastasis and cisplatin resistance

Rho GDP dissociation inhibitor 2 (RhoGDI2) expression is correlated with tumor growth, metastasis and chemoresistance in gastric cancer. However, the mechanisms by which RhoGDI2 promotes tumor cell survival and metastasis remain unclear. In this study, we clearly demonstrate that RhoGDI2 upregulates VEGF‐C expression and RhoGDI2 expression is positively correlated with VEGF‐C expression in human gastric tumor tissues as well as parental gastric cancer cell lines. VEGF‐C depletion suppressed RhoGDI2‐induced gastric cancer metastasis and sensitized RhoGDI2‐overexpressing cells to cisplatin‐induced apoptosis in vitro and in vivo. Secreted VEGF‐C enhanced gastric cancer cell invasion and conferred cisplatin resistance to RhoGDI2‐overexpressing cells. We also show that RhoGDI2 positively regulates Rac1 activity in gastric cancer cells. Inhibition of Rac1 expression suppressed RhoGDI2‐induced VEGF‐C expression, and this inhibition was associated with decreased invasiveness and increased sensitivity to cisplatin in RhoGDI2‐overexpressing cells. Our results indicate that RhoGDI2 might be a potential therapeutic target for simultaneously reducing metastasis risk and enhancing chemotherapy efficacy in gastric cancer.