ABCG2与消化系统肿瘤相关研究进展

临床实践中,很多肿瘤因具有了多药耐药性(MDR)而对抗肿瘤药治疗无效,其中一重要的机制是与多药耐药转运蛋白相关。ABCG2是ABC转运超家族的一个成员,可转运包括拓扑替康、伊立替康等细胞毒药物,但ABCG2具体的蛋白结构及如何转运这些结构不同的底物的机制尚不明确。本文综述近期ABCG2基础研究成果及与消化系统肿瘤相关研究的进展。这些研究提示ABCG2在食管癌、胃癌、肠癌中肿瘤细胞产生多药耐药机制发挥了重要作用,并可能与预后相关。同时ABCG2基因的单核苷酸多态性(SNP)影响ABCG2蛋白的表达、分布和功能,从而可能导致肿瘤对相关药物的耐药性及作为提示预后差的指标。     

食管癌组织中复制蛋白A的表达变化及意义

目的观察食管鳞癌组织中复制蛋白A（RPA）的表达水平变化,并探讨其意义。方法采用免疫组织化学法检测48例食管癌组织及40例癌旁正常组织中的RPA1和RPA2蛋白。结果食管癌组织中RPA1、RPA2蛋白阳性表达率分别为65.25%±0.21%、58.90%±0.19%,与癌旁组织的35.65%±0.16%、16.71%±0.12%相比P均〈0.05。食管癌组织中的RPA1、RPA2表达与肿瘤病理分级、肿瘤浸润深度、淋巴结转移、肿瘤分期相关（P均〈0.05）。结论 食管癌组织中RPA1、RPA2的表达升高。这可能与食管癌的发生、发展有关。     

食管癌活检标本多药耐药基因表达及意义

目的 研究食管癌活检标本中多药耐药基因（multidrug resistance gene １,ＭＤＲ１基因）和多药耐药相关蛋白（multidrug resistance associatid pritein,ＭＲＰ）表达水平,探讨与食管癌临床特征及化疗的相关性。方法 应用逆转录聚合酶链反应（ＲＴ－ＰＣＲ）技术定量分析标本中ＭＤＲ１基因和ＭＲＰ的表达水平。结果 ５８例标本中,ＭＤＲ１基因阳性表达率为８２．８％（４８/５８）,ＭＲＰ表达率为２９．３％（１７/５８）。     

食管癌组织中水通道蛋白3的表达变化及意义

采用免疫组化SP法对56例食管癌组织及45例正常食管组织中水通道蛋白3（AQP3）进行检测。结果显示，食管癌组织中AQP3高表达者41例、低表达者15例，正常食管组织分别为23、22例，两种组织相比，P〈0．05；32例有淋巴结转移食管癌组织中AQP3高表达27例、低表达5例，24例无淋巴结转移者中分别为14、10例，两种组织相比，P〈0．05；21例Ⅰ级食管癌组织中，AQP3高表达11例、低表达10例，20例Ⅱ级者分别为16、4例，15例Ⅲ级者分别为14、1例，三种组织相比，P〈0.05。认为食管癌组织中AQP3的表达可能在食管癌分化和转移过程中发挥作用。     

食管癌组织中WISP3的表达变化及意义

目的探讨人食管癌组织中WISP3的表达变化及其与食管癌临床病理参数的关系。方法采用荧光实时定量RT-PCR和免疫组化法对186例食管癌患者的癌组织和癌旁正常组织中的WISP3进行检测。结果食管癌组织中WISP3 mRNA的ΔCt值为6.31±3.77、WISP3蛋白的阳性表达率为25.63%±7.81%,癌旁正常组织分别为8.93±3.83、7.50%±2.38%,两者相比,P均〈0.01;WISP3 mRNA的表达与食管癌淋巴结转移及肿瘤浸润深度及大小、分期有关（P均〈0.05）;WISP3蛋白表达与食管癌淋巴结转移、肿瘤浸润深度、分期相关（P均〈0.05）,WISP3蛋白是对食管癌患者生存率有影响的因素之一（相对危险度为2.287）。结论WISP3在食管癌中的表达增加,可作为食管癌临床分期、转移潜能及预后的评估指标。     

食管癌组织中Ebp1蛋白表达及意义

目的探讨Ebpc蛋白在食管癌发生、发展中的作用。方法采用免疫组化染色法检测220例食管癌患者的癌组织及其癌旁正常食管组织中Ebp1蛋白表达水平。结果食管癌组织中Ebp1蛋白阳性率显著高于正常食管组织（t=23．140,P=0．000）。单因素分析显示,与Ebp1mRNA表达高度相关的临床参数包括年龄、家族史、淋巴结转移、病理分级、浸润深度和临床分期;多因素分析结果表明,家族史、淋巴结转移、肿瘤体积、浸润深度、病理分级均是Ebp1蛋白表达的危险因素。结论Ebp1在食管癌发生、发展过程中起重要作用,可作为食管癌病情进展监测、转移潜能及预后评估方面的一个靶基因。     

食管癌组织MCM2的表达及意义

目的探讨MCM2作为细胞新增殖指标的可靠性及其对判断食管鳞癌预后的意义。方法采用免疫组化法检测134例食管鳞癌组织中MCM2及增殖细胞核抗原（PCNA）的表达．分析它们的相关性及与食管鳞癌分化、分期和预后的关系。结果MCM2的表达强弱与食管癌的分化程度密切相关。分化越低,表达越明显（P〈0．01）;表达强弱与食管癌的临床分期无关。MCM2与PCNA呈显著正相关（r=0．701,P〈0．01）。COX回归模型显示肿瘤分期、MCM2为独立的预后指标。结论MCM2可作为判断食管鳞癌增殖速率和预后的独立指标,其高表达提示预后不良。     

食管鳞癌组织中p34^cdc2的表达变化及意义

目的观察人食管鳞癌组织中细胞分裂周期蛋白p34^cdc2的表达,并探讨其临床意义。方法利用组织芯片技术结合免疫组化及蛋白免疫印迹法检测138例食管癌患者肿瘤组织和配对正常食管黏膜组织中的p34^cdc2蛋白。结果p34^cdc2在食管鳞癌组织的表达明显高于配对正常黏膜组织,P〈0.01。p34^cdc2表达与食管鳞癌临床分期、淋巴结转移有关（P均〈0.05）,与分化程度和肿瘤浸润深度等无关（P均〉0.05）。结论食管癌组织中p34^cdc2表达升高。p34^cdc2可促进食管癌的发生与发展。     

食管癌P-糖蛋白的表达及化疗耐药性

目前已阐明,mdr-1基因扩增产物P-糖蛋白(P-glycoprotein,P-gp)的过度表达,是化疗失败的直接原因,更有作者认为,肿瘤组织中mdr-1基因表达也是肿瘤恶性的生物学指标。然而,对于食管癌组织中mdr-1基因表达的研究国内外均鲜见报道。本文研究58例食管癌标本mdr-1的表达情况,为临床化疗提供依据。     

宫颈鳞癌组织中P-gp、LRP的表达及临床意义

目的探讨多药耐药基因蛋白（P-gp）和肺耐药蛋白（LRP）在宫颈鳞癌组织中的表达及指导宫颈癌化疗的意义。方法采用Real time RT-PCR和MaxVision免疫组化法检测30份宫颈鳞癌组织（宫颈癌组）及30份正常宫颈组织（正常组）中P-gp编码基因（mdr1）、LRP编码基因（lrp）表达量及P-gp、LRP阳性率,并分析mdr1与lrp的相关性,P-gp、LRP之间及与宫颈鳞癌临床病理参数的相关性。结果宫颈癌组及正常组mdr1 mRNA表达量分别为45.830±0.570、43.567±0.151,lrp mRNA表达量分别为49.989±0.762、45.138±0.550,P-gp阳性表达率分别为83.3%、20%,LRP阳性表达率分别为86.7%、26.7%,组间比较P均〈0.01;mdr1 mRNA、lrp mRNA及P-gp、LRP表达均无相关性（P〉0.05）。结论联合检测P-gp和LRP在宫颈鳞癌组织中的表达,对宫颈鳞癌化疗药物的选择有重要参考价值。     

Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma

In the light of increasing evidence supporting cancer stem cells (CSCs) theory, the expression of two stem cell markers, CD133 and adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2), in esophageal squamous cell carcinoma (ESCC) was investigated, and their prognostic values were evaluated. Paraffin-embedded tissue sections of 110 ESCC patients were investigated using Immunohistochemistry. The association of CD133 and ABCG2 expression with clinicopathologic characteristics was analyzed by χ(2) test. Survival analysis was carried out using Kaplan-Meier method and Cox proportional hazards model. CD133 and ABCG2 expression were detected in 27.3% and 15.5% of ESCC patients, respectively. The presence of CD133-positive cancer cells was associated with tumor cell differentiation (P= 0.008) but not significantly related to the survival of ESCC patients (P= 0.085). ABCG2 expression was not associated with clinicopathologic characteristics but was a significant prognostic factor for adverse overall survival of ESCC patients (P= 0.005). The median overall survival time for ESCC patients with and without ABCG2 expression were 21.8 and >49.3 months, respectively. A combined analysis of CD133 and ABCG2 expression did not show that ESCC patients with coexpression of these two markers had a worse prognosis than those with only ABCG2 expression (P= 0.934). Moreover, ABCG2 expression was revealed to be an independent prognostic factor along with tumor node metastasis stage in multivariate analysis (hazard ratio of ABCG2, 3.38; 95% confidence interval, 1.61～7.09; P= 0.001). By survival analysis based on tumor node metastasis stage of ESCC, the association between ABCG2 expression and the patients' prognosis was found significant in the group of relatively early stage (P= 0.005) and marginally significant in the group of relatively late stage (P= 0.058). This is the first time to report the presence of CD133-positive cancer cells in ESCC but not supporting its prognostic value and validity as a CSC marker for ESCC. ABCG2 expression was found to correlate with the survival of ESCC patients, especially those at relatively early stage, suggesting that ABCG2-positive cancer cells may represent a pool of CSCs in ESCC, and relatively early-stage patients with ABCG2 expression may deserve more intensive or targeted therapy.     

非小细胞肺癌中 ALDH1 和 ABCG2 的表达及其临床意义简

目的 检测ALDH1和ABCG2在人非小细胞肺癌组织中的表达状况,探讨二者的相关性及其与临床病理特征的关系.方法采用免疫组化 ElivisionTM plus法检测60例NSCLC和30例癌旁正常肺组织中ALDH1、ABCG2的表达情况.结果 在癌旁正常肺组织中ALDH1、ABCG2的表达率分别为10%、0%,在NSCLC 组织中分别为63.3%、48.3%,差异有显著（P＜0.05）;其阳性表达与肿瘤细胞分化程度、临床分期、淋巴结转移（P均＜ 0.05）; ALDH1的表达与ABCG2的表达无明显相关（P＞0.05）.结论 ALDH1、ABCG2的表达在NSCLC的发生、发展中起重要作用,可以作为预后判断的指标.     

Role of ABCG2 expression driven by cisplatin in platinumcontaining chemotherapy for gastric cancer

AIM:To investigate the relationship between increases in expression time of ABCG2 mRNA driven by cisplatin and efficacy of platinum-containing chemotherapy for gastric cancer.METHODS:Tumor specimens and normal control tissues were collected from 78 patients with gastric cancer treated from January 2008 to December 2011.Fresh tumor tissue obtained from the surgically resected specimens was tested within 6 h.Polymerase chain reaction products were run on 2%agarose gels and analyzed under ultraviolet light after ethidium bromide staining.Increases in ABCG2 mRNA expression time cisplatin,and were divided into terciles and compared in relation to clinical outcomes.RESULTS:Among groups classified by expression time of ABCG2 mRNA,no significant differences in baseline clinical characteristics and pathological findings were detected.The median overall time was 14.2(95%CI:9.7-18.6),11.4(95%CI:6.3-16.5)and 8.1(95%CI:5.4-10.8)in patients with low,intermediate and high increases in ABCG2 mRNA expression times(P<0.05),respectively.Median survival associated with performance status and tumor node metastasis(TNM)stage showed a similar trend,with longer survival and higher risk for mortality associated with lower performance status score and TNM stage.In a multivariate analysis for survival with Cox proportional-hazards model,increased ABCG2 mRNA expression time was an independent predictor for overall survival.Overall survival was longer with increased ABCG2 mRNA expression times≤0.71 than increased ABCG2 mRNA expression times>0.71,with a hazard ratio for death of 0.855(95%CI:0.615-0.962,P=0.038).CONCLUSION:Increased ABCG2 mRNA expression time driven by cisplatin is associated with survival of gastric cancer patients,and this may help modify the therapeutic strategies.     

Molecular mechanisms and clinical implications of miRNAs in drug resistance of esophageal cancer

Introduction: With the increasing incidence of esophageal cancer, drug resistance is becoming a major obstacle to successful cancer therapy since chemotherapy is regarded as a curative approach to inhibit cancer cell proliferation. Despite the great progress in anticancer treatment achieved during the last decades, the mechanisms of multidrug resistance have not been completely elucidated. Recently, accumulating studies and pre-clinical reports highlighted the role of miRNAs in the drug resistance of esophageal cancer.

Areas covered: In this review, we mainly summarized the current advances of miRNAs in esophageal cancer and the mechanisms underlying drug resistance. We also reviewed the potential role of miRNAs as biomarkers for predicting drug response and prognosis. Finally, we envisaged the future orientation and challenges in translating the existing knowledge of drug resistance related miRNAs into clinical applications.

Expert commentary: Based on the current knowledge of certain miRNAs, we believe that miRNAs would be helpful to overcome the drug resistance and provide personalized treatment for patients with esophageal cancer. The aims of this study were to provide a comprehensive summary on the emerging role of miRNAs in the drug resistance of esophageal cancer and attract broad attention of more researchers on this field.     

Clinical significance of the ABCB1 and ABCG2 gene expression levels in acute lymphoblastic leukemia

Objectives: Acute lymphoblastic leukemia (ALL) is a clonal disease that accounts for 20% of acute leukemias in adults. A high percentage of adult patients (ranging from 70 to 80%) reach complete remission; however, the 5-year survival rate is only 20–40%. One of the main obstacles to treatment success is the drug resistance of leukemic cells. Therefore, our research group analyzed the ABCB1 and ABCG2 gene expression levels in 61 patients diagnosed with ALL and assessed whether the levels affected the clinical parameters and 40-month survival rate.

Methods: The ABCB1 and ABCG2 gene expression levels were analyzed using real-time polymerase chain reaction in 61 patients diagnosed with ALL and 99 healthy donors as controls. The association between ABCB1 and ABCG2 gene expression levels and clinical variables was determined using the Chi-square test and Fisher’s exact test. Overall survival (OS) was determined using the Kaplan–Meier method.

Results: The results showed high ABCB1 and ABCG2 gene levels, which were 4.5 and 2.3 times the levels of healthy donors, respectively. A total of 52% of the study patients expressed high ABCB1 levels and were significantly associated with the high-risk patient group and a decreased 40-month survival rate of 78%. Only 49% of the patients expressed high ABCG2 gene levels. No association was found between the clinical parameters and the ABCG2 gene expression levels.

Conclusions: Early detection of ABCB1 gene expression levels could be important for the diagnosis and monitoring of ALL patients.     

Clinicopathological significance of cyclooxygenase‐2 and cell cycle‐regulatory proteins expression in patients with esophageal squamous cell carcinoma

The aim of this study was to examine the expression of the molecular markers cyclooxygenase‐2 (COX‐2), Ki‐67, cyclin A, and p27 in patients with esophageal squamous cell carcinoma (ESCC), to ascertain the relationship of these makers with the clinicopathological significance of the patients, and to assess the additional prognostic value of the expression profile of these proteins for ESCC patients. The expression levels of COX‐2, Ki‐67, cyclin A, and p27 proteins of a series of primarily resected ESCC samples were determined by immunohistochemistry method. Clinicopathological and molecular factors affecting survival were analyzed by multivariate analysis. A total of 78 specimens were included in this study. Expression of COX‐2 was observed in 43 (55.1%) cases, and high levels of expression of Ki‐67, p27, and cyclin A were observed in 57 (73.0%), 33 (42.3%), 43 (55.1%) cases, respectively. The results of univariate survival analysis indicated that more advanced tumor stage, lymph node involvement, systemic dissemination, the levels of expression of COX‐2, Ki‐67, cyclin A, and p27 were associated with survival (all P‐value < 0.05). Multifactorial survival analysis revealed that only lymph node involvement, over‐expression of cyclin A, and low p27 expression were associated with the survival of the patients (hazard ratios = 2.83, 4.7, 2.9, respectively; P= 0.025, 0.042, 0.005, respectively). Among the molecular markers assessed, the expression of cell proliferation markers cyclin A and p27 are independent prognostic factors in patients with ESCC, whereas neither COX‐2 nor Ki‐67 is of independent prognostic value.