晚期非小细胞肺癌p53 和ERCC1 表达状态与顺铂为主的 联合方案化疗的近期有效率的相关性研究*

目的:研究晚期非小细胞肺癌不同的p53和ERCC1表达状态与基于顺铂为主的姑息化疗近期有效率的相关性。方法:对经顺铂联合多西他赛或顺铂联合吉西他滨治疗的48例晚期非小细胞肺癌患者进行回顾性分析,利用既往免疫组化资料,观察基于顺铂为主的方案近期有效率(RR)的影响因素及化疗不良反应。结果:全组48例患者均完成至少两周期化疗,并行疗效评价。该组患者化疗的近期有效率为28例(58.3%),RR与不同的转移病灶部位(P=0.042)及病灶数目(P=0.034)有显著差异。该类方案的近期有效率与ERCC1状态(P=0.012)密切相关,而与p53表达状态(P=0.401)无关。毒性反应主要是骨髓抑制、脱发及消化道反应等。结论:晚期非小细胞肺癌ERCC1阴性患者较ERCC1阳性患者运用顺铂为主的联合方案化疗的近期有效率较高。ERCC1可能是顺铂疗效预测的敏感因子。p53的表达状态可能不是该类方案的疗效预测因子。     

Lipase member H is a novel secreted protein selectively upregulated in human lung adenocarcinomas and bronchioloalveolar carcinomas

Lung cancer is one of the most frequent causes of cancer-related death worldwide. However, molecular markers for lung cancer have not been well established. To identify novel genes related to lung cancer development, we surveyed publicly available DNA microarray data on lung cancer tissues. We identified lipase member H (LIPH, also known as mPA-PLA1) as one of the significantly upregulated genes in lung adenocarcinoma. LIPH was expressed in several adenocarcinoma cell lines when they were analyzed by quantitative real-time polymerase chain reaction (qPCR), western blotting, and sandwich enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis detected LIPH expression in most of the adenocarcinomas and bronchioloalveolar carcinomas tissue sections obtained from lung cancer patients. LIPH expression was also observed less frequently in the squamous lung cancer tissue samples. Furthermore, LIPH protein was upregulated in the serum of early- and late-phase lung cancer patients when they were analyzed by ELISA. Interestingly, high serum level of LIPH was correlated with better survival in early phase lung cancer patients after surgery. Thus, LIPH may be a novel molecular biomarker for lung cancer, especially for adenocarcinoma and bronchioloalveolar carcinoma.     

Association of ERCC1-C118T and -C8092A polymorphisms with lung cancer risk and survival of advanced-stage non-small cell lung cancer patients receiving platinum-based chemotherapy: A pooled analysis based on 39 reports

The published data on the predictive role of ERCC1 polymorphisms in lung cancer risk and survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy remains inconsistent. The aim of this meta-analysis was to determine the role of ERCC1 gene polymorphisms (C118T and C8092A) in this clinical situation. Eligible studies were included and assessed for quality using multiple search strategies. Thirty-nine published papers involving 9615 cases (4606 with Stage III/IV disease) and 5542 controls were included in the analysis. Pooled odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate risk. ERCC1-C118T was associated with lung cancer risk. The OR was 0.90 (95% CI: 0.81–0.99, p = 0.043) in an additive genetic model (C allele vs. T allele) and 0.77 (95% CI: 0.63–0.95, p = 0.013) in a recessive genetic model (CC/CT vs. TT). The corresponding risk was 0.74 (95% CI: 0.58–0.94, p = 0.013) based on a homozygous comparison (CC vs. TT). No significant correlation was found for ERCC1 C8092A and there was no obvious relationship between ERCC1 C118T/C8092A polymorphisms and objective response to platinum-based chemotherapy. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was significantly related to ERCC1 C118T (HR: 1.29, 95% CI: 1.07–1.56, p = 0.007, CT/TT vs. CC). There was no relationship between ERCC1 C8092A and survival (HR: 1.32, 95% CI: 0.84–2.10, p = 0.23, CA/AA vs. CC). These findings suggest that ERCC1 C118T polymorphisms may serve as a biomarker for lung cancer risk and have prognostic value in patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based treatment. Further studies with larger numbers of subjects from a worldwide arena are needed to validate the associations.     

ERCC1和RRM1在非小细胞肺癌组织中的表达及意义

目的:观察非小细胞肺癌中ERCC1和RRM1表达,并探讨其临床意义。方法:选择本院及西安交通大学第一附属胸外二科于2013年1月-2013年6月收治的经术后病理证实为非小细胞癌肺癌患者40例作为研究对象,均采取免疫组化技术测定组织中ERCC1和RRM1表达水平,并分析ERCC1和RRM1表达水平与患者年龄、病理分期、是否淋巴结转移等相关因素之间的关系。结果:40例非小细胞肺癌患者中,ERCC1表达阴性28例(70.0%),阳性12例(30.0%);RRM1表达阴性9例(22.5%),阳性31例(77.5%)。ERCC1和RRM1表达阴性非小细胞肺患者生存期均优于表达阳性患者,均P0.05。患者非小细胞癌TNM分期及淋巴结转移转移情况与ERCC1及RRM1表达情况具有相关性,均P0.05。结论:非小细胞肺癌ERCC1和RRM1表达水平测定有助于预后情况,具有重要临床价值。     

The potential usefulness of monoclonal antibodies in the determination of histologic types of lung cancer in cytologic preparations

Two monoclonal antibodies (MAbs) were tested for their reactivity with antigens of exfoliated malignant cells in respiratory secretions of lung cancer patients. MAb CE 407 was developed from tissue culture cell line SW 756, derived from human uterine cervical squamous cell carcinoma; MAb BL 99-57 was developed from cell line T-24, derived from human transitional cell bladder cancer. MAb CE 407 reacted preferentially with squamous cell carcinomas (80%) and with some (44%) of the adenocarcinomas of the lung; BL 99-57 reacted with 76% of the adenocarcinomas, but only with 27% of the squamous cell carcinomas of the lung. The reactivity of BL 99-57 was more apparent in well-differentiated adenocarcinomas (89% positive), but less in poorly differentiated adenocarcinomas (65% positive). Neither of these antibodies reacted with antigens of small cell anaplastic carcinoma. These two MAbs may be useful in differentiating histologic types of lung cancer in cases that are difficult to diagnose morphologically and/or in which tissue is not available for study.     

血栓调节蛋白在胚胎肺及肺癌中的表达

目的研究血栓调节蛋白(thrombomodulin,TM)在胚胎肺、正常肺组织及肺癌组织中的表达。方法以不同周龄的胚胎肺组织、正常成人肺组织、肺癌组织为研究对象,应用免疫组织化学SP法检测TM的存在。结果8、15、18、21、24、27、29周人胎肺组织中,TM在气管纤毛柱状上皮细胞、I型和Ⅱ型肺泡上皮细胞及软骨、结缔组织均呈阴性表达,围绕肺泡上皮细胞团周围的血管内皮细胞阳性表达。正常成人支气管纤毛柱状上皮细胞、肺泡上皮细胞不表达,但在血管内皮细胞呈阳性表达。TM在鳞状上皮不典型增生的细胞膜和细胞问桥表达,在肺鳞癌表达,阳性率为97．3％(34／35),在癌细胞膜和细胞问桥阳性表达,但腺癌、小细胞癌癌细胞不表达。结论TM在胚胎肺以及成人肺仅见于血管内皮细胞,在支气管上皮、肺泡上皮不表达。与其它的血管内皮细胞标记物不同,TM的表达在肺鳞癌与腺癌表扶明显不同．右助于鉴别肺鳞癌与肺腺癌．     

乳腺癌CXCR1的表达特征及其与新辅助化疗疗效的相关性

目的:研究趋化因子受体CXCR1在乳腺癌组织中的表达特征,并探讨新辅助化疗前后其表达变化与化疗疗效的关系。方法:选取20例正常乳腺组织,20例乳腺纤维腺瘤,104例乳腺癌标本,免疫组化染色后统计每例标本CXCR1的阳性表达积分,分析不同乳腺疾病CXCR1的表达差异。统计新辅助化疗前后乳腺癌标本CXCR1的阳性表达积分的变化,分析其与化疗病理反应的关系。结果:CXCR1在正常乳腺组织、乳腺纤维腺瘤中低表达,在乳腺癌组织上高表达;其表达与患者的年龄、原发肿瘤的大小无关(P0.05),与病理分期、癌细胞的分化程度、淋巴结转移个数、激素受体状态及Her2表达情况相关,P0.05,有统计学意义。新辅助化疗后,癌组织中CXCR1的表达下降,下降幅度越大,其化疗疗效越好。结论:CXCR1的检测对于乳腺疾病的良恶性判断有指导意义,可辅助判断乳腺癌的恶性程度、侵袭性以及预后,CXCR1表达的下降与化疗疗效相关,抑制其表达可能可以提高化疗疗效。     

MNX1-AS1 is a novel biomarker for predicting clinical progression and poor prognosis in lung adenocarcinoma

Motor neuron and pancreas homeobox 1-antisense RNA1 (MNX1-AS1) is a novel long noncoding RNA and has been suggested to be overexpressed in human ovarian cancer and glioma. The role of MNX1-AS1 in lung cancer was still unknown. In our study, we observed levels of MNX1-AS1 expression through analyzing The Cancer Genome Atlas and found MNX1-AS1 expression was highly expressed in lung adenocarcinoma tissues compared with normal lung tissues, but there was no statistical difference between lung squamous cell carcinoma tissues and normal lung tissues. Furthermore, we conducted quantitative real-time polymerase chain reaction, and confirmed that the expression of MNX1-AS1 was definitely higher in lung adenocarcinoma tissue samples, but not in lung squamous cell carcinoma tissue samples. In addition, high MNX1-AS1 expression was found to be associated with the low differentiated degree, advanced clinical stage, big tumor size, lymph node metastasis, and distant metastasis in lung adenocarcinoma patients. High expression of MNX1-AS1 was negatively correlated with overall survival time and served as an independent unfavorable prognostic factor in patients with lung adenocarcinoma. The in vitro functional studies suggested that suppression of MNX1-AS1 inhibited lung adenocarcinoma cell proliferation and migration, and promoted apoptosis. In conclusion, MNX1-AS1 is overexpressed in lung adenocarcinoma, and associated with clinical progression and poor prognosis.     

PTEN、p57／Kip2和CK19在非小细胞肺癌中的表达及意义研究

探讨非小细胞肺癌中PTEN、p57/Kip2和CK19的表达情况和临床意义。选取58例非小细胞肺癌手术切除标本,采用SP法进行免疫组织化学染色。PTEN、p57/Kip2和CK19的阳性表达率分别为44.8%、56.9%和98.3%。PTEN和p57/Kip2在低分化肿瘤中表达显著降低或缺失,在腺癌中的表达强度高于鳞癌;CK19几乎在所有的肺癌组织中均表达,且在腺癌中的表达强度高于鳞癌。PTEN和p57/Kip2的低表达参与肿瘤的生长分化和进展,并提示预后不良。     

非小细胞肺癌组织MMP-2、MMP-9的表达与组织学类型及临床分期的关系

目的:探究非小细胞肺癌组织基质金属蛋白酶-2(MMP-2)、基质金属蛋白酶-9(MMP-9)的表达及其与患者组织学类型及其临床分期的关系。方法:选取2014年1月至2017年1月于我院进行就诊并确诊为非小细胞肺癌的96例患者为实验组,另选取30例肺良性病变患者为对照组,使用免疫组织化学的方法检测患者肺癌组织或肺良性病变组织中MMP-2、MMP-9的表达,并分析MMP-2、MMP-9的表达与患者组织学类型及临床分期之间的关系。结果:非小细胞肺癌组织MMP-2及MMP-9表达水平显著高于肺良性病变组织(P0.05)。非小细胞肺癌鳞癌组织MMP-2、MMP-9表达明显高于腺癌和腺鳞癌(P0.05),而鳞癌与腺鳞癌组织MMP-2、MMP-9表达相比差异无统计学意义(P0.05)。随着非小细胞肺癌临床分期的增加,癌组织MMP-2及MMP-9表达逐渐上升,各分期比较差异均具有统计学意义(P0.05)。结论:MMP-2、MMP-9在非小细胞肺癌组织中的表达水平明显上调,以鳞癌最高,且与临床分期显著相关,提示其对组织学类型、临床分期、病情评估和预后判断均具有一定的参考意义。     

Prognostic implication of HSPA (HSP70) in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy

Neoadjuvant chemotherapy is used in patients with locally advanced breast cancer to reduce tumor size before surgery. Unfortunately, resistance to chemotherapy may arise from a variety of mechanisms. Heat shock proteins (HSPs), which are highly expressed in mammary tumor cells, have been implicated in anticancer drug resistance. In spite of the widely described value of HSPs as molecular markers in cancer, their implications in breast tumors treated with anthracycline-based neoadjuvant chemotherapy has been poorly explored. In this study, we have evaluated, by immunohistochemistry, the expression of HSP27 (HSPB1) and HSP70 (HSPA) in serial biopsies from locally advanced breast cancer patients (n = 60) treated with doxorubicin (DOX)- or epirubicin (EPI)-based monochemotherapy. Serial biopsies were taken at days 1, 3, 7, and 21, and compared with prechemotherapy and surgical biopsies. After surgery, the patients received additional chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil. High nuclear HSPB1 and HSPA expressions were found in invasive cells after DOX/EPI administration (P < 0.001), but the drug did not affect the cytoplasmic expression of the HSPs. Infiltrating lymphocytes showed high nuclear HSPA (P < 0.01) levels at postchemotherapy. No correlations were found between HSPs expression and the clinical and pathological response to neoadjuvant therapy. However, in postchemotherapy biopsies, high nuclear (>31 % of the cells) and cytoplasmic HSPA expressions (>11 % of the tumor cells) were associated with better DFS (P = 0.0348 and P = 0.0118, respectively). We conclude that HSPA expression may be a useful prognostic marker in breast cancer patients treated with neoadjuvant DOX/EPI chemotherapy indicating the need to change the administered drugs after surgery for overcoming drug resistance.     

Gene expression and pathologic response to neoadjuvant chemotherapy in breast cancer

Pathologic complete response after neoadjuvant systemic treatment appears to be a valid surrogate for better overall survival in breast cancer patients. Currently, together with standard clinicopathologic assessment, novel molecular biomarkers are being exhaustively tested in order to look into the heterogeneity of breast cancer. The aim of our study was to examine an association between 23-gene real-time-PCR expression assay including ABCB1, ABCC1, BAX, BBC3, BCL2, CASP3, CYP2D6, ERCC1, FOXC1, GAPDH, IGF1R, IRF1, MAP2, MAPK 8, MAPK9, MKI67, MMP9, NCOA3, PARP1, PIK3CA, TGFB3, TOP2A, and YWHAZ receptor status of breast cancer core biopsies sampled before neoadjuvant chemotherapy (anthracycline and taxanes) and pathologic response. Core-needle biopsies were collected from 42 female patients with inoperable locally advanced breast cancer or resectable tumors suitable for downstaging, before any treatment. Expressions of 23 genes were determined by means of TagMan low density arrays. Analysis of variance was used to select genes with discriminatory potential between receptor subtypes. We introduced a correction for false discovery rates (presented as q values) due to multiple hypothesis testing. Statistical analysis showed that seven genes out of a 23-gene real-time-PCR expression assay differed significantly in relation to pathologic response regardless of breast cancer subtypes. Among these genes, we identified: BAX (p = 0.0146), CYP2D6 (p = 0.0063), ERCC1 (p = 0.0231), FOXC1 (p = 0.0048), IRF1 (p = 0.0022), MAP2 (p = 0.0011), and MKI67 (p = 0.0332). The assessment of core biopsy gene profiles and receptor-based subtypes, before neoadjuvant therapy seems to predict response or resistance and to define new signaling pathways to provide more powerful classifiers in breast cancer, hence the need for further research.     

Immunohystochemical expression of cancer/testis antigens (MAGE-A3/4, NY-ESO-1) in non-small cell lung cancer: the relationship with clinical-pathological features

The aim of this study was to explore the expression of cancer/testis tumor associated antigens (C/T TAAs) MAGE-A 3/4 and NY-ESO-1 in lung squamous cell carcinoma and adenocarcinoma, and to evaluate their association with the standard clinical-pathological features of surgically treated lung cancer patients. The study included 80 patients with non-small cell lung cancer (40 adenocarcinomas, 40 squamous cell carcinomas) who had undergone surgery in the period between 2002 and 2005. The MAGE-A3/4 and NY-ESO-1 antigen expression was analyzed immunohistochemically (IHC). The results showed MAGE-A3/4 and NY-ESO-1 positive staining in 65.1% and 23.3% of squamous cell carcinomas and 18.9% and 10.8% of adenocarcinomas, respectively. A statistically higher MAGE-A3/4 expression was observed in planocellular bronchial carcinoma (p < 0.001), while no difference was found in the expression of NY-ESO-1 in adenocarcinoma and planocellular carcinoma (p = 0.144). A significant association was found between the MAGE-A3/4 expression and presence of tumor necrosis in squamous cell cancer specimens (p = 0.001), but not in adenocarcinoma (p = 0.033). A statistically significant association was noted between the NY-ESO-1 expression and positive hilar and mediastinal lymph nodes in adenocarcinoma (p = 0.025) whereas it was not the case in squamous cell carcinoma. Non-small cell lung cancer frequently expresses cancer/testis tumor associated antigens. Our results demonstrate that the MAGE-A3/4 and NY-ESO-1 expression was significant associated with prognostic factors of poor outcome of disease (presence of tumor necrosis and lymph node metastasis). As C/T antigens are important for inducing a specific immune reaction in lung cancer patients, there is an intention to form a subgroup of patients in the future, whose treatment would be enhanced by specific immunotherapy based on the observed scientific results.     

Arf6, RalA and BIRC5 protein expression in non small cell lung cancer

Evaluation of tumor markers expression pattern which determines individual progression parameters is one of the major topics in molecular oncopathology research. This work presents research on expression analysis of several Ras-Ral associated signal transduction pathway proteins (Arf6, RalA and BIRC5) in accordance with clinical criteria in non small cell lung cancer patients. Using Western-blot analysis and RT-PCR Arf6, RalA and BIRC5 expression has been analyzed in parallel in 53 non small cell lung cancer samples of different origin. Arf6 protein expression was elevated in 55% non small cell lung cancer tumor samples in comparison with normal tissue. In the group of squamous cell lung cancer Arf6 expression elevation was observed more often. RalA protein expression was decreased in comparison to normal tissue samples in 64% of non small cell lung cancer regardless to morphological structure. Correlation between RalA protein expression decrease and absence of regional metastases was revealed for squamous cell lung cancer. BIRC5 protein expression in tumor samples versus corresponding normal tissue was 1.3 times more often elevated in the squamous cell lung cancer group (in 76% tumor samples). At the same time elevation of BIRC5 expression was fixed only in 63% of adenocarcinoma tumor samples. A statistically significant decrease (p = 0.0158) of RalA protein expression and increase (p = 0.0498) of Arf6 protein expression in comparison with normal tissue was found for T1-2N0M0 and T1-2N1-2M0 groups of squamous cell lung cancer correspondingly.     

DNA repair gene expression level in peripheral blood and tumour tissue from non-small cell lung cancer and head and neck squamous cell cancer patients

BackgroundThe nucleotide excision repair pathway is crucial for cellular DNA integrity and the ERCC1 helicase is also potentially involved in resistance to platinum-based chemotherapy, and high levels of ERCC1 mRNA in tumours have been associated with cisplatin resistance in different human cancers. The aim of this work was to investigate the correlation between DNA repair gene expression levels in tumour tissue, normal tissue and peripheral blood samples from patients with two common human cancers, non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (HNSCC), to test if blood gene expression could be a proxy for tumour tissue gene expression to predict response to platinum-based chemotherapy.MethodsUsing RT-qPCR we determined ERCC1, ERCC2, ERCC4, XPA, XPC, XRCC1, XRCC3, APEX, OGG1, MGMT mRNA levels in fresh NSCLC, normal lung and HNSCC tissue, as well as blood, from NSCLC and HNSCC patients who were treated surgically.ResultsTarget gene expression in NSCLC and HNSCC tissue was higher than in blood. A statistically significant correlation (p < 0.05) was found between target gene mRNA expression in tumour tissue and blood, in particular ERCC1, MGMT, XPC, XRCC1 and XRCC3 in NSCLC and APEX, ERCC1, ERCC2, ERCC4, XRCC1 and XRCC3 in HNSCC.ConclusionsThe existence of a significant correlation between blood and tumour tissue expression of some genes of clinical interest, such as ERCC1 in NSCLC and HNSCC, could allow the introduction in clinical practice of a simple test that would measure mRNA levels of DNA repair genes in peripheral blood samples instead of tissue samples to determine prognostic and predictive factors in NSCLC and HNSCC patients.     

整合素连接激酶在非小细胞肺癌中的表达及意义

目的了解整合素连接激酶(intergrin-linked kinase ILK)在非小细胞肺癌中的表达情况．与临床病理特征之间的关系及与非小细胞肺癌患预后的关系并探讨其意义。方法采用免疫组织化学SP法和免疫蛋白印迹法检测ILK在101例非小细胞肺癌(60例鳞癌,41例腺癌)中的表达。结果(1)ILK在非小细胞肺癌组织中的表达高于正常组织且在鳞癌组织中ILK的表达随着分化程度的降低而提高;(2)ILK的表达与临床分期,淋巴结转移等临床病理特征之间无联系(3)ILK的不同表达与非小细胞肺癌患的预后无关。结论目前国内外尚未有ILK在肺癌中的研究,我们的研究表明ILK在非小细胞肺癌中的表达与非小细胞肺癌组织的组织类型来源和恶性程度有关,并可能参与了非小细胞肺癌的发生发展过程。     

Arf6, RalA,and BIRC5 protein expression in nonsmall cell lung cancer

Evaluation of tumor marker expression pattern that determines individual progression parameters is one of the major topics in molecular oncopathology research. This work represents research on expression analysis of several Ras-Ral associated signal transduction pathway proteins (Arf6, RalA, and BIRC5) in accordance with clinical criteria in nonsmall cell lung cancer patients. Using Western-blot analysis and RT-PCR Arf6, RalA, and BIRC5, expression has been analyzed in 53 nonsmall cell lung cancer samples of different origin. Arf6 protein expression was increased in 55% nonsmall cell lung cancer tumor samples in comparison with normal tissue. In the group of squamous cell lung cancer, increase of Arf6 expression was observed more often. RalA protein expression was decreased in comparison to normal tissue samples in 64% of nonsmall cell lung cancer regardless of morphological structure. Correlation between the decrease of RalA protein expression and the absence of regional metastases was revealed for squamous cell lung cancer. BIRC5 protein expression in tumor samples versus corresponding normal tissue was 1.3 times more often elevated in the squamous cell lung cancer group (in 76% tumor samples). At the same time, increase of BIRC5 expression was detected only in 63% of adenocarcinoma tumor samples. A statistically significant decrease (p = 0.015) of RalA protein expression and the increase (p = 0.049) of Arf6 protein expression in comparison with normal tissue was found in T_1–2N₀M₀ and T_1–2N_1–2M₀ groups of squamous cell lung cancer, respectively.     

非小细胞肺癌组织中mir-483-5p的差异表达

目的:寻找非小细胞肺癌组织中微小RNA(miRNA)表达谱的差异,并鉴定非小细胞肺癌组织与癌旁组织差异表达的miRNA。方法:应用miRNA芯片分别检测非小细胞肺癌组织与癌旁组织的miRNA表达丰度,并比较两者中差异表达的miRNA;挑选mir-483-5p通过荧光定量PCR进行验证。结果:非小细胞肺癌组织与癌旁组织检测的miRNA表达谱存在较大差异。其中,鳞癌组织中有16条miRNA上调,22条miRNA下调;腺癌组织中有40条miRNA上调,51条miRNA下调。对mir-483-5p进行了定量PCR验证,发现其在非小细胞肺癌组织中的表达丰度显著高于癌旁的正常组织。结论:mir-483-5p在非小细胞肺癌组织中高表达。