NCOA4介导铁自噬的调控机制及其在结肠炎和结肠炎相关癌症中的研究进展

铁自噬及其参与的铁离子代谢异常是促发铁死亡的重要机制之一。铁自噬的调控主要涉及核受体共激活因子4(NCOA4)转录和蛋白质翻译后修饰。铁死亡在结肠炎和结肠炎相关癌症(CAC)的发生、发展中扮演重要角色,靶向调节铁死亡能缓解结肠炎症反应和诱导肿瘤细胞死亡。本文就NCOA4介导铁自噬的调控机制及其在结肠炎和CAC中的研究进展作一综述,从而为结肠炎及其炎癌转变的研究提供新视角。

芪贞汤对结肠炎相关癌症小鼠肠道细菌诱导的Toll样受体4/核因子κB信号通路的影响

目的探讨芪贞汤对结肠炎相关癌症(CAC)小鼠肠道细菌诱导的Toll样受体4(TLR4)/核因子κB信号通路的影响,为其抗炎抗肿瘤作用提供实验依据。方法将24只C57BL/6J雄性小鼠按照随机数字表法分为空白组、模型对照组、氟尿嘧啶组和芪贞汤组,每组6只。除空白组外,余小鼠采用氧化偶氮甲烷联合葡聚糖硫酸钠周期性诱导建立CAC小鼠模型。空白组与模型对照组以0.9%氯化钠注射液灌胃,余2组以对应药物灌胃,连续给药14 d。采用16S rDNA测序分析各组小鼠肠道菌属特征;运用酶联免疫吸附试验法测定各组小鼠血清中内毒素含量;运用免疫组织化学法检测并比较各组小鼠结肠组织中TLR4和核因子KB p65蛋白表达。结果测序结果显示革兰阴性菌拟杆菌属在模型对照组和氟尿嘧啶组中较多,芪贞汤组多为革兰阳性菌乳球菌属和芽孢杆菌属。模型对照组小鼠内毒素水平、TLR4和核因子κB p65蛋白表达水平明显高于空白组;氟尿嘧啶组和芪贞汤组较模型对照组明显降低[(14.2±3.1)、(8.6±1.8)U/L比(19.0±2.9)U/L,(2.0±1.1)、(1.2±0.7)分比(12.8±2.7)分,(2.3±1.4)、(1.7±0.5)分比(9. 3±2. 3)分],差异均有统计学意义(均P <0.01)。其中芪贞汤组内毒素水平明显低于氟尿嘧啶组,差异有统计学意义(P<0.01)。结论芪贞汤可通过抑制革兰阴性致病菌,减少抗原物质内毒素释放,抑制TLR4/核因子κB信号通路,而发挥抗CAC的作用。

靶向MDSCs免疫治疗结肠炎相关性癌症的研究现状

结肠炎相关性癌症(CAC)是一种特定类型的结直肠癌,由炎症性肠病(IBD)发展而来。髓源性抑制细胞(MDSCs)是一群具有免疫抑制性的髓细胞,肿瘤微环境中的MDSCs在结肠炎相关性癌症的发生发展过程中增殖、激活,抑制T细胞的生成并损害其功能,阻碍结肠炎相关性癌症的免疫治疗效果。本文就MDSCs在炎症性肠病到结肠炎相关性癌症的发生发展过程中的免疫抑制机制,以及目前靶向MDSCs免疫治疗炎症性结直肠癌的药物做一综述,以期为治疗结肠炎相关性癌症提供新的策略。

结肠炎相关肠癌的发病机制及化学防治的研究进展

结肠炎相关肠癌是在炎症性肠病背景下发生的大肠癌,可能是由于肠道慢性持续性炎症导致组织异型增生并最终癌变,其分子机制尚未阐明。结肠炎相关肠癌因其高死亡率和治疗困难而日益受到人们的重视,研究表明应用药物进行化学防治可降低癌变风险。本文就结肠炎相关肠癌发病机制及化学防治的研究进展进行综述。

白细胞介素22与炎症性肠病的研究进展

炎症性肠病(IBD)是一类多种病因引起、异常免疫介导的肠道慢性复发性炎症,主要包括溃疡性结肠炎和克罗恩病。白细胞介素22(IL-22)是一种具有独特生物学特性的细胞因子。在肠道中IL-22具有通过激活STAT3通路来促进黏膜屏障完整性的抗菌肽和黏蛋白表达的能力,并可促进肠上皮细胞再生和增强肠上皮细胞屏障功能。IL-22在IBD患者肠道黏膜中表达水平明显增强,IL-22可促进肠道炎症损伤的修复,但是随着细胞因子等环境变化,如IL-23、T-bet、IL-22结合蛋白的表达水平变化,IL-22表现出了其特征性的双面性,一方面可以促进炎症损伤的修复,另一方面会加重炎症损伤反应。文中阐述IL-22的起源、作用方式以及在临床治疗领域应用的前景。

芪贞汤对结肠炎相关癌症小鼠肠道细菌丰度及构成的影响

目的:探讨芪贞汤对结肠炎相关癌症(CAC)小鼠肠道细菌丰度及构成的影响,为其发挥抗癌作用提供理论依据。方法:采用氧化偶氮甲烷(AOM)联合葡聚糖硫酸钠(DSS)周期性诱导建立小鼠CAC模型,造模成功后,实验组小鼠用1.26g/kg芪贞汤冻干粉水溶液灌胃,模型组和正常组小鼠用无菌0.9%氯化钠溶液灌胃。治疗结束后提取小鼠肠道微生物总DNA,进行16S r DNA V4区测序,并取结肠进行HE染色进行病理评价。结果:(1)病理评价:模型组小鼠炎性反应病理评分得分3.7分显著高于实验组2.2分(P<0.01);模型组小鼠非典型增生得分(2.8分)显著高于实验组(1.5分)(P<0.01)。(2)菌群测序结果:模型组小鼠肠道菌群丰度降低,芪贞汤治疗后,小鼠肠道菌群丰度提高,相似度上更接近于空白组;多样性检测结果可见实验组相对模型组更接近于空白组,但实验组与模型组之间差距并不显著;在菌群构成方面,模型组多为致病菌占优势地位,治疗组多为益生菌属。结论:芪贞汤可以通过增加益生菌抑制致病菌改善肠道菌群,而发挥抗癌作用。

Inhibition of signal transducer and activator of transcription 3 expression by RNA interference suppresses invasion through inducing anoikis in human colon cancer cells

AIM:To investigate the roles and mechanism of signal transducer and activator of transcription 3 (STAT3) in invasion of human colon cancer cells by RNA interference. METHODS: Small interfering RNA (siRNA) targeting Signal transducer and activator of transcription 3 (STAT3) was transfected into HT29 colon cancer cells. STAT3 protein level and DNA-binding activity of STAT3 was evaluated by western blotting and electrophoretic mobility shift assay (EMSA), respectively. We studied the anchorage-independent growth using colony formation in soft agar, and invasion using the boyden chamber model, anoikis using DNA fragmentation assay and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL), respectively. Western blot assay was used to observe the protein expression of Bcl-xL and survivin in colon cancer HT29 cells. RESULTS: RNA interference (RNAi) mediated by siRNA leads to suppression of STAT3 expression in colon cancer cell lines. Suppression of STAT3 expression by siRNA could inhibit anchorage-independent growth, and invasion ability, and induces anoikis in the colon cancer cell line HT29. It has been shown that knockdown of STAT3 expression by siRNA results in a reduction in expression of Bcl-xL and survivin in HT29 cells. CONCLUSION: These results suggest that STAT3 siRNA can inhibit the invasion ability of colon cancer cells through inducing anoikis, which antiapoptotic genes survivin and Bcl-xL contribute to regulation of anoikis.These studies indicate STAT3 siRNA could be a useful therapeutic tool for the treatment of colon cancer.

Depression and anxiety levels in therapy-nave patients with inflammatory bowel disease and cancer of the colon

AIM: To assess whether depression and anxiety are more expressed in patients with the first episode of inflammatory bowel disease (IBD) than in individuals with newly discovered cancer of the colon (CCa). METHODS: A total of 32 patients with IBD including 13 males and 19 females, aged 27 to 74, and 30 patients with CCa including 20 males and 10 females, aged 39-78, underwent a structured interview, which comprised Hamilton’s Depression Rating Inventory, Hamilton’s Anxiety Rating Inventory and Paykel’s Stressful Events Rating Scale. RESULTS: Patients of the IBD group expressed both depression and anxiety. Depressive mood, sense of guilt, psychomotor retardation and somatic anxiety were also more pronounced in IBD patients. The discriminant function analysis revealed the total depressive score was of high importance for the classification of a newly diagnosed patient into one of the groups. CONCLUSION: Newly diagnosed patients with IBD have higher levels of depression and anxiety. Moreover, a psychiatrist in the treatment team is advisable from the beginning.

Azoxymethane-induced rat aberrant crypt foci:Relevance in studying chemoprevention of colon cancer

The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci （ACF） represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane （AOM）-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.

Significance of Bcl-xL in human colon carcinoma

AIM:To investigate the clinical significance of Bcl-xL gene in the pathogenesis of human colon carcinoma. METHODS:Fifty-six pair tissue samples from patients with colon cancer were collected, and protein level of the Bcl-xL gene was measured by immunohistochemistry method. The correlation of Bcl-xL expression with clinical index was evaluated. After human colon cancer cell line HT29 was transfected with Bcl-xL small interfering RNA (siRNA), the anchorage-independent growth of cancer cells was detected by colony formation in soft agar and invasion ability of cancer cells was determined by a transwell model. RESULTS:The Bcl-xL expression was higher in cancerous tissue samples than in normal tissue samples (38.78 ± 11.36 vs 0.89 ± 0.35, P < 0.001), and was associated with the pathological grade, lymphnode metastasis and Duke’s stage of colorectal carcinoma. Transfection with Bcl-xL siRNA inhibited the colony formation and invasion ability of human colon cancer cell line HT29 in vitro. CONCLUSION:Bcl-xL gene plays an important role in carcinogenesis of human colorectal carcinoma and is associated with malignant biological behaviors of human colorectal carcinoma.

Increased hepcidin expression in colorectal carcinogenesis

AIM:To investigate whether the iron stores regulator hepcidin is implicated in colon cancer-associated anae- mia and whether it might have a role in colorectal car- cinogenesis. METHODS: Mass spectrometry (MALDI-TOF MS and SELDI-TOF MS) was employed to measure hepcidin in urine collected from 56 patients with colorectal cancer. Quantitative Real Time RT-PCR was utilised to determine hepcidin mRNA expression in colorectal cancer tissue. Hepcidin cellular localisation was determined using im- munohistochemistry. RESULTS: We demonstrate that whilst urinary hepcidin expression was not correlated with anaemia it was posi- tively associated with increasing T-stage of colorectal cancer (P < 0.05). Furthermore, we report that hepcidin mRNA is expressed in 34% of colorectal cancer tissue specimens and was correlated with ferroportin repres- sion. This was supported by hepcidin immunoreactivity in colorectal cancer tissue. CONCLUSION: We demonstrate that systemic hepcidin expression is unlikely to be the cause of the systemic anaemia associated with colorectal cancer. However, we demonstrate for the first time that hepcidin is expressed by colorectal cancer tissue and that this may represent a novel oncogenic signalling mechanism.

Matrix metalloproteinase-9-1562C>T polymorphism may increase the risk of lymphatic metastasis of colorectal cancer

AIM. To explore the role of the matrix metalloproteinase-9 （MMP-9） polymorphism in colorectal cancer （CRC） in a northeast Chinese population.METHODS： Genotyping of MNP-9-1562C〉T and 279R〉Q polymorphisms was carried out on blood samples from 137 colorectal cancer patients and 199 controls using polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP）. Multivariate logistic regression models were used to calculate adjusted odds ratios （OR） and 95% confidence intervals （95% CI）.RESULTS： The distribution of IVllVlP-9 -2562C〉T and 279 R〉Q genotype was not significantly associated with the risk of CRC. However, the risk of Ilymph node metastasis of CRC was increased in patients with the -1562T allele （OR = 2.601; 95% CI = 1.160-5.835; P = 0.022）. The frequency of MMP-9 279RR ＋ RQ genotype was higher than the QQ genotype among CRC patients younger than sixty years old （OR = 0.102, 95% CI = 0.013-0.812; P = 0.012）.CONCLUSION： Our results indicated that the MMP-9- 1562C〉T polymorphism affects lymph node metastasis of CRC. In addition, the MMP-9 279R allele may lead to a younger age of onset of colorectal cancer.

Risk of colorectal neoplasm in patients with acromegaly: A meta-analysis

AIM: To examine the risk of colorectal neoplasm in acromegalic patients by meta-analyzing all relevant controlled studies. METHODS: Extensive English language medical literature searches for human studies, up to December 2007, were performed using suitable keywords. Pooled estimates [odds ratio (OR) with 95% confidence intervals (CI)] were obtained using either the fixed or random-effects model as appropriate. Heterogeneity between studies was evaluated with the Cochran Q test whereas the likelihood of publication bias was assessed by constructing funnel plots. Their symmetry was estimated by the adjusted rank correlation test. RESULTS: For hyperplastic polyps the pooled ORs with 95% CI were 3.557 (2.587-4.891) by fixed effects model and 3.703 (2.565-5.347) by random effects model. The Z test values for overall effect were 7.81 and 6.984, respectively (P < 0.0001). For colon adenomas the pooled ORs with 95% CI were 2.486 (1.908-3.238) (fixed effects model) and 2.537 (1.914-3.364) (random effects model). The Z test values were 6.747 and 6.472, respectively (P < 0.0001). For colon cancer the pooled OR with 95% CI was identical for both fixed and random effects model (OR, 4.351; 95% CI, 1.533-12.354; Z = 2.762, P = 0.006]. There was no significant heterogeneity and no publication bias in all the above meta-analyses. CONCLUSION: Acromegaly is associated with an increased risk of colorectal neoplasm.

Obesity and colorectal cancer risk: A meta-analysis of cohort studies

TO evaluate the association between obesity and colorectal cancer risk. METHODS： We searched PubMed, EMBASE, and the Cochrane Library up to January 1, 2007. Cohort studies permitting the assessment of causal association between obesity and colorectal cancer, with clear definition of obesity and well-defined outcome of colorectal cancer were eligible. Study design, sample size at baseline, mean follow-up time, co-activators and study results were extracted. Pooled standardized effect sizes were calculated.

HER2 aberrations and heterogeneity in cancers of the digestive system: Implications for pathologists and gastroenterologists

Management of cancers of the digestive system has progressed rapidly into the molecular era. Despite the significant recent achievements in the diagnosis and treatment of these patients, the number of deaths for these tumors has currently plateaued. Many investigations have assessed the role of HER2 in tumors of the digestive system in both prognostic and therapeutic settings, with heterogeneous results. Novel testing and treatment guidelines are emerging, in particular in gastric and colorectal cancers. However, further advances are needed. In this review we provide a comprehensive overview of the current state-ofknowledge of HER2 alterations in the most common tumors of the digestive system and discuss the operational implications of HER2 testing.

Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer

AIM： To investigate the association between common single nucleotide polymorphisms （SNPs） in inflammatory response-related genes such as interleukin （IL）-6, IL-8, tumor necrosis factor α （TNFα）, peroxisome proliferators-activated receptor γ （PPARγ）, intercellular adhesion molecule-1 （ICAM-1） and the risk of colorectal cancer （CRC） in a group of Greek patients. METHODS： The study group consisted of 222 CRC patients and 200 healthy controls. Genotyping was performed using allele-specific PCR of PRC-RFLP and the results were confirmed by sequencing. We studied the association of SNPs in the IL-6 （-174G 〉 C）, IL-8 （-251T 〉 A）, TNFα （-308G 〉 A）, ICAM-1 （R241G and K469E）, and PPARγ （Pro12Ala） genes and the risk of CRC. RESULTS： The IL-6 -174G, R241 and K469 alleles of ICAM-1 were associated with increased risk of CRC （OR = 1.77, 95% CI： 1.34-2.34; OR = 1.83, 95% CI： 1.23-2.72; and OR = 1.35, 95% CI： 1.03-1.77 respectively）. The IL-8 and TNFα polymorphisms had no effect. Whereas the PPARγ Pro12 genotype was associated with increased risk of disease （OR = 1.78, 95% CI： 1.25-2.49）. CONCLUSION： The association between common SNPs in immunologic response-related genes and CRC is reported in the present study. Apart from shedding light on the mechanisms of malignancy initiation and progression, SNPs may improve appropriate screening for sub-populations at risk.

E-cadherin expression pattern in primary colorectal carcinomas and their metastases reflects disease outcome

AIM： To investigate the changes that occur in E-cadherin expression during the process of metastasis in colorectal cancer.METHODS： E-cadherin expression was detected by immunohistochemistry and two indices of expression were calculated which reflected the level of expression and the locations （membrane and cytoplasm）. Univariate and multivariate survival analyses were used to assess the value of these two E-cadherin indices as predictors of both disease-free （DFS） and disease-specific （DSS） survival. RESULTS： E-cadherin membrane index （MI）, but not cytoplasmic index （CI）, was significantly higher in primary tumors than their metastases （P = 0.0001）. Furthermore, both primary tumor MI and CI were higher among the patients who developed subsequent metastasis （P = 0.022 and P = 0.007, respectively）. Interestingly, both indices were higher in liver metastase compared to other anatomic sites （MI, P = 0.034 and CI, P = 0.022）. The CI of the primary tumors was a significant predictor of DFS （P = 0.042, univariate analysis）, with a strong inverse correlation between CI and DFS （P = 0.006, multivariate analysis）. Finally, the MI of primary tumor proved to be a significant independent predictor of DSS, with higher indices being associated with a more favorable outcome （P = 0.016）. CONCLUSION： Examination of E-cadherin expression and distribution in colorectal tumors can be extremely valuable in predicting disease recurrence. The observation that aberrant cytoplasmic expression of E-cadherin can predict disease recurrence is obviously of great importance for both patients and clinicians, and significantly affects decisions concerning the therapy and management of the patients.

Surveillance colonoscopy practice in Lynch syndrome in the Netherlands:A nationwide survey

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is the most common genetic disorder predisposing to colorectal cancer. As regular colonoscopic surveillance has been shown to reduce the incidence of colorectal cancer, this strategy is recommended worldwide. Recently, several advances in colonoscopic techniques have improved detection rates of neoplasia in Lynch syndrome. In this nationwide survey, we evaluated current surveillance colonoscopy practices for Lynch syndrome in the Netherlands and the extent to which advanced techniques have been adopted in routine clinical practice.