Novel cross-talk between IGF-IR and DDR1 regulates IGF-IR trafficking,signaling and biological responses

The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression.Experiments in mouse fibroblasts co-transfected with the human IGF-IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired.These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR.     

Tobacco carcinogen NNK transporter MRP2 regulates CFTR function in lung epithelia: Implications for lung cancer

Lung cancer is the leading cause of cancer death in the United States. About 85% of all lung cancers are linked to tobacco smoke, in which more than 50 lung carcinogens have been identified and one of the most abundant is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The human lung epithelium constitutes the first line of defense against tobacco-specific carcinogens, in which apically-localized receptors, transporters, and ion channels in the airway may play a critical role in this native defense against tobacco smoke. Here we showed that multidrug resistance protein-2 (MRP2) and cystic fibrosis transmembrane conductance regulator (CFTR), two ATP-binding cassette (ABC) transporters, are localized to the apical surfaces of plasma membrane in polarized lung epithelial cells. We observed that there is a functional coupling between CFTR and MRP2 that may be mediated by PDZ proteins. We also observed the existence of a macromolecular complex containing CFTR, MRP2, and PDZ proteins, which might form the basis for the regulatory cooperation between these two ABC transporters. Our results have important implications for cigarette smoke-associated lung diseases (such as smoke-related emphysema, chronic obstructive pulmonary disease, and lung cancer).     

MEMO1共结合IGF-IR介导胃癌细胞侵袭转移

目的:探讨MEMO1（mediator of ErbB2-driven cell motility 1）调控IGF-IR（insulin-like growth factor-I receptor）介导胃癌侵袭转移的分子机制,为临床治疗提供潜在靶点。方法:选取五种不同分化程度胃癌细胞系（MKN-7、NCI-N87、MGC-803、BGC-823、MKN-74）,Western blot检测MEMO1、IGF-IR和E-cad表达差异;Transwell比较五种胃癌细胞系迁移能力;选取MEMO1/IGF-IR高表达细胞系MGC-803,瞬时敲除MEMO1或IGF-IR基因,Western blot检测EMT标志物表达差异;IP实验检测MEMO1与IGF-IR间相互作用;TCGA数据库分析胃癌组织MEMO1和IGF-IR mRNA表达水平与患者预后的关系。结果:基础状态下五种胃癌细胞IGF-IR与MEMO1的表达呈显著正相关,并且两种蛋白的表达强度与胃癌细胞EMT相关;五种胃癌细胞迁移能力MKN-7相似文献   

Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model

Purpose  Dexrazoxane (DZR), a clinically approved cation chelator, is effective in reducing doxorubicin (DOX)-induced heart damage, yet its cardioprotective mechanism is not fully understood. We aimed to investigate the effects of DZR on the activation of Akt and Erk 1/2 signals in a rat model of DOX-induced cardiomyopathy. Methods  Male Sprague–Dawley rats received weekly DOX injection (2.5 mg/kg) for 6 weeks, with or without DZR pretreatment at a dose ratio of 20:1. The ventricular functions of these animals were monitored at week 6, 9 and 11 by echocardiography. At week 11, their heart morphology was studied by light and electron microscopy. Phosphorylation of Akt and Erk in heart tissues was measured by Western blot analysis. Results  DOX caused myocardial damage with compromised left ventricular function, increased myocardium injury and reduced phosphorylation of Akt and Erk. DZR exerted a significant cardioprotective effect in terms of improved fractional shortening, cardiac output and cardiomyopathy score at one or more time points. We also provided the first evidence that dexarazoxane-treated animals had increased levels of Akt and Erk activation, whilst total Akt and Erk remained unchanged. Conclusions  Our results showed that the cardioprotective effect of dexarazoxane has been sustained beyond the treatment period. The data also suggested that activation of the Akt and Erk signaling pathways was regulated in the course of DOX-induced cardiomyopathy and protection by DZR. Ping Xiang and Hai Yan Deng have equal contribution to this study.     

结直肠癌组织中IGF-I和IGF-IR的表达及临床意义

目的探讨胰岛素样生长因子-I(IGF-I)及其受体(IGF-IR)在结直肠癌发病机制中的作用及临床意义。方法应用实时荧光定量RT-PCR法对40例结直肠癌癌组织、癌旁2 cm、10 cm组织和10例非肿瘤患者的正常结直肠组织标本进行IGF-I、IGF-IR定量测定,并将其结果与患者年龄、性别、淋巴结转移、肿瘤浸润深度、分化程度、病理分型和Dukes分期情况进行综合分析。结果结直肠癌组织IGF-I及IGF-IR的表达量显著高于正常组织中的表达量(P<0.05);IGF-I、IGF-IR在Dukes C D期、淋巴结转移组、侵及全层组表达量高于Dukes A B期、无淋巴结转移组、未侵及全层组(P<0.05)。结论IGF-I、IGF-IR在结直肠癌组织中高表达,提示IGF-I、IGF-IR与结直肠癌的发生、发展密切相关;IGF-I、IGF-IR在Dukes C D期、淋巴结转移组及浸润全层组中有高表达,提示IGF-I、IGF-IR与结直肠癌的浸润转移密切相关。     

Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9

Celecoxib is a potent nonsteroid antiinflammatory drug (NSAID) that has shown great promise in cancer chemoprevention and treatment. The tumor suppression activity of celecoxib and other NSAIDs have been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is a specific inhibitor of cyclooxygenase (COX)-2, recent data indicate that its apoptotic properties may also be mediated through COX-independent pathways. In our study, we evaluated second generation celecoxib derivatives, lacking COX-2 inhibitory activity, in a premalignant and malignant human oral cell culture model to determine their potential anticancer effect and mechanisms responsible for the COX-independent apoptotic activity. Celecoxib and its derivatives delayed the progression of cells through the G(2)/M phase and induced apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced apoptosis and cell cycle delay. Apoptosis and cell cycle arrest appeared to be independent of derivative induced inhibition of PDK1 and phosphorylation of Akt and Erk1/2. Derivatives induced apoptosis was mediated by the cleavage and activation of caspase-9 and caspase-3, but not caspase 8, implicating the mitochondrial pathway for apoptosis induction. Inhibitors of caspase-3 and caspase-9 and cyclosporin A, a mitochondrial membrane potential stabilizer, attenuated derivative induced apoptosis. Inhibition of caspase-3 prevented the activation of caspase 8, while the inhibition of caspase-9 inhibitor blocked activation of both caspase 3 and 8 by the derivatives. Apoptosis was independent of Bcl-2. These results indicate that the second generation celecoxib derivatives induce apoptosis in human oral cancer lines by the disruption of mitochondrial membrane potential activating caspase 9 and downstream caspase 3 and 8. This suggests that the modification of the celecoxib structure can lead to highly effective COX-independent growth inhibitory and apoptotic agents in chemoprevention and therapy.     

Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): a model for human lung cancer

Research into dietary chemoprevention against lung carcinogenesis has been limited by the lack of appropriate animal models that closely mimic smoking-related human lung cancer. Ferrets (Mustela putorius furo) have been used to study the biologic activities of carotenoids against smoke-induced lung lesions, but this model has yet to be thoroughly established and validated. To determine the appropriateness of the ferret as a model for human lung cancer, we have performed a 6-month in vivo study in ferrets exposed to both tobacco smoke and a carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) found in cigarette smoke. Results showed that six out 12 ferrets exposed to both NNK injection and cigarette smoke developed grossly identifiable lung tumors whereas none of nine ferrets from the sham treatment group developed any lung lesions. The histopathological types of these tumors (squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma) in ferret lungs are very similar to those in humans. In addition, 10 out of 12 ferrets exposed to both NNK and cigarette smoke developed preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) with complex growth patterns whereas the sham group did not show any of these lesions. Furthermore, the expression of proliferating cellular nuclear antigen increased markedly in both gross tumors and preneoplastic lesions in the lungs. In summary, the development of both preneoplastic lesions and gross lung tumors in ferrets provides an excellent and unique model for studying lung cancer chemoprevention with agents such as carotenoids, and for studying the molecular mechanism of carcinogenesis in the earlier stages of smoke-related lung cancer.     

Inactivation of Rac1 reduces Trastuzumab resistance in PTEN deficient and insulin-like growth factor I receptor overexpressing human breast cancer SKBR3 cells

Drug resistance remains to be a big challenge in applying anti-HER2 monoclonal antibody Trastuzumab for treating breast cancer with HER2 overexpression. Amplification of insulin-like growth factor I receptor (IGF-IR) and deletion of tumor suppressor phosphatase and tensin homolog (PTEN) are implicated in Trastuzumab resistance, however, the underlying mechanisms have not been clearly defined. Activation of Rac1, a member of Rho GTPase family, is capable of causing cytoskeleton reorganization, regulating gene expression and promoting cell proliferation. To investigate the mechanism of Trastuzumab resistance, PTEN knockdown and IGF-IR overexpressing stable cell lines were generated in HER2 overexpression human breast cancer SKBR3 cells. Rac1 was highly activated in PTEN deficient and IGF-IR overexpressing Trastuzumab-resistant cells in a HER2-independent manner. Inactivation of Rac1 by using a Rac1 inhibitor NSC23766 or siRNA knocking down the expression of Tiam1, a guanine nucleotide exchange factor for Rac, significantly reduced Trastuzumab resistance in SKBR3 cells. Inhibition of Rac1 had no effect on the levels of phosphor-HER2 and phosphor-Akt, but significantly decreased the levels of cyclin D1 in Trastuzumab-resistant cells. Inhibition of Akt with an Akt inhibitor also significantly reduced Trastuzumab resistance. However, simultaneous inhibition of both Rac1 and Akt resulted in a significantly more decrease of Trastuzumab resistance than inactivation of Rac1 or Akt alone. These results suggest that Rac1 activation is critically involved in Trastuzumab resistance caused by PTEN deletion or IGF-IR overexpression. Simultaneous inhibition of Rac1 and Akt may represent a promising strategy in reducing Trastuzumab resistance in HER2 overexpression breast cancer.     

Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells

In this study, we have characterized a panel of NSCLC cell lines with differential sensitivity to gefitinib for activating mutations in egfr, pik3ca, and k-ras, and basal protein expression levels of PTEN. The egfr mutant NSCLC cell line H1650 as well as the egfr wild type cell lines H292 and A431 were highly sensitive to gefitinib treatment, indicating that other factors determine gefitinib-sensitivity in egfr wild type cells. Activating k-ras mutations were specifically detected in gefitinib-resistant cells, suggesting that the occurrence of k-ras mutations is correlated with resistance to EGFR antagonists. No pik3ca mutations were detected within the panel of cell lines, and PTEN protein expression levels did not correlate with gefitinib sensitivity. Gefitinib effectively blocked Akt and Erk phosphorylation in two gefitinib-sensitive NSCLC cell lines, further supporting our previous findings that persistent activity of the PI3K/Akt and/or Ras/Erk pathways is associated with gefitinib-resistance of NSCLC cell lines. Gefitinib-resistant NSCLC cell lines, showing EGFR-independent activity of the PI3K/Akt or Ras/Erk pathways, were treated with gefitinib in combination with specific inhibitors of mTOR, P13K, Ras, and MEK. Additive cytotoxicity was observed in A549 cells co-treated with gefitinib and the MEK inhibitor U0126 or the farnesyl transferase inhibitor SCH66336 and in H460 cells treated with gefitinib and the PI3K inhibitor LY294002, but not in H460 cells treated with gefitinib and rapamycin. These data suggest that combination treatment of NSCLC cells with gefitinib and specific inhibitors of the PI3K/Akt and Ras/Erk pathways may provide a successful strategy.     

Epidermal growth factor receptor mutations and response to chemotherapy in patients with non-small-cell lung cancer

BACKGROUND: The association of epidermal growth factor receptor (EGFR) mutations with the response to conventional cytotoxic chemotherapeutic agents in non-small-cell lung cancer patients has not been investigated. We retrospectively analyzed the associations between response to chemotherapy and molecular markers associated with gefitinib responsiveness including EGFR mutations. METHODS: EGFR (exons 18, 19 and 21) and K-ras mutations (exon 2) were studied by direct sequencing and p-Erk and p-Akt expressions were studied by immunohistochemistry in archival paraffin embedded tissues. Response rate (RR) and time-to-progression (TTP) of prior chemotherapy by platinum, paclitaxel and gemcitabine were analyzed with respect to the presence of EGFR and K-ras mutations, and p-Erk and p-Akt expressions. RESULTS: Of 90 patients investigated, 75 received platinums and 45 received paclitaxel as first-line chemotherapy agents. The RRS and TTPS of platinum- and paclitaxel-containing regimens were not affected by EGFR or K-ras mutations, nor by p-Erk or p-Akt expression. Fifty-seven patients received gemcitabine as first- or second-line chemotherapy. RR was not affected by EGFR or K-ras mutations or by p-Akt expression. However, all responders to gemcitabine exhibited (+) p-Erk expression [RR 30.6% for p-Erk (+) versus 0% for p-Erk (-), P = 0.01]. TTP was not affected by EGFR or K-ras mutations or by p-Erk or p-Akt expression. CONCLUSIONS: EGFR mutations did not affect response to conventional chemotherapeutic agents, namely platinums, paclitaxel and gemcitabine. Our results also suggest that it may be undesirable to use gemcitabine in patients with tumors not expressing p-Erk.     

检测肺癌中辅助性T细胞(Th1/Th2)的临床意义

目的探讨辅助性T细胞Th1和Th2细胞因子对肺癌患者的临床意义,为肿瘤的免疫治疗提供依据.方法采用放射免疫(RIA)和酶联免疫吸附法(ELISA)检测86例肺癌患者、59例肺良性病患者及45例正常对照辅助性T细胞分泌的细胞因子.以IL-2和TNF-α的水平代表Th1型细胞因子,IL-4、IL-6和IL-8的水平代表Th2型细胞因子.结果肺癌患者IL-2[(24.6±12.0)μg/L]的水平显著低于肺良性病患者[(71.1±25.4)μg/L](t=3.82,P＜0.01)和正常对照[(69.3±19.5)μg/L](t=2.76,P＜0.01),IL-6[(0.13±0.04)μg/L]的水平显著低于正常对照[(0.23±0.05)μg/L)(t=3.39,P＜0.01),IL-4[(254.2±78.0)μg/L]、IL-8[(0.49±0.16)ug/L]、TNF-α[(2.76±1.12)μg/L]的水平明显高于肺良性病患者[(63.6±18.6)μg/L,(0.36±0.18)μg/L,(0.96±0.20)μg/L]及正常对照[(60.9±19.6)μg/L,(0.35±0.07)μg/L,(0.93±0.19)ug/L](t值分别为4.10、4.89和3.76,P均＜0.01),肺良性病患者和正常对照之间的IL-2、TNF-α、IL-4、IL-8均未见明显差异(P＞0.05),肺癌组IL-6的水平与肺良性病组[(0.15±0.0)4)μg/L]无明显差异(P＞0.05),肺良性病组IL-6的水平与正常对照组[(0.23±0.05)μg/L]有明显差异(P＜0.05).肺癌患者不同组织类型间及不同TNM分期间细胞因子比较无显著性差异(P＞0.05).结论肺癌患者机体T辅助细胞Th1/Th2细胞因子失衡,可能在肺癌的发病机理中起着某种作用.通过纠正这些免疫失常可能成为肺癌治疗的重要手段.     

ABL2在肺癌中的作用及机制研究

目的 探究ABL2在肺癌中的作用及其机制。方法 采用Realtime PCR方法检测ABL2在肺癌组织和癌旁组织中的表达情况。然后建立稳定低表达ABL2的肺腺癌A549细胞株;通过MTT、细胞迁移和克隆形成实验检测细胞增殖和迁移能力的变化情况;Western blot检测EMT、凋亡和PI3K/AKT信号通路相关蛋白的表达情况。结果 肺癌组织中ABL2的表达水平明显高于癌旁组织(P＜0.001)。在A549细胞系中沉默ABL2后,与对照组相比,48 h后细胞的迁移能力减弱(P＜0.001),从第3天开始细胞的生长速度开始明显减缓(P＜0.05),15天后形成的平均克隆数也减少(P＜0.01)。Western blot结果显示,沉默ABL2后上皮细胞标志物E-cadherin表达升高(P＜0.001),间质细胞标志物N-cadherin(P＜0.001)、Vimentin(P＜0.01)及Snail(P＜0.001)表达降低。凋亡相关蛋白Bcl-XL表达下降(P＜0.01),BAX表达上调(P＜0.001)。PI3K/AKT信号通路相关蛋白PI3K P110(P＜0.05)、AKT(P＜0.01)和p-AKT(P＜0.05)蛋白的表达都明显降低。结论 沉默ABL2基因能够通过PI3K/AKT信号通路促进细胞凋亡,抑制肺癌细胞的增殖和迁移。     

以PD-1/PD-L1为靶点的肺癌免疫治疗临床研究进展

免疫检查点的研究在近几年实现突破性进展,PD-1/PD-L1信号通路与免疫逃逸机制密切相关,针对阻断PD-1/PD-L1 通路免疫检查点的治疗在肺癌中取得明显效果。从Checkmate-017、Checkmate-057研究到KEYNOTE-010研究和OAK研究,逐 步奠定了PD1/PD-L1抑制剂作为化疗失败晚期NSCLC的标准治疗的地位;PD-1/PD-L1抑制剂可联合其他治疗方式,包括放疗、 化疗、靶向治疗以及其他免疫治疗等方式,在肺癌综合治疗中起到协同作用,从而提高了疗效。免疫检查点抑制剂带来了肺癌治 疗模式的改变,也对肿瘤疗效评价模式、治疗相关不良反应的处理带来挑战。另外,免疫检查点抑制剂的研发也有力地推动了精 准医疗的进展。     

Euphol from Tapinanthus sp. Induces Apoptosis and Affects Signaling Proteins in Glioblastoma and Prostate Cancer Cells

Background: Plants play an important role in cancer therapy. They are source of natural molecules which can induce apoptosis in cancer cells by affecting molecular mechanisms implicated in cancer progression. The MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways are two classical signaling pathways implicated in cancer progression and constitute therapeutic targets against cancer. This study aimed to evaluate the effect of euphol on MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways in glioblastoma and prostate cancer cells. Euphol is a tetracyclique triterpene alcohol isolated from Tapinanthus sp. which is a hemi parasitic plant belonging to Loranthaceae family. Methods: Plant powder was extracted by maceration and euphol was isolated and described using respectively column chromatography separation on silica gel and spectroscopic data. Cytotoxic effect of euphol was evaluated using XTT assay and its effect on MAP Kinase/ERK1/2 and PI3K/AKT protein expression was investigated by Western immunoblot analysis. Apotosis was analyzed by evaluating caspase-3/7 activity. Results: Our investigations demonstrated that this compound has an important cytotoxic effect on C6 and U87 MG glioblastoma (GBM) cells and PC-3 prostate cancer cells. Furthermore, euphol-induced apoptosis revealed by elevated caspase 3/7 activity, was correlated with a significant inhibition of MAP kinase/Erk 1/2 and PI3K/Akt signaling pathway in glioblastoma U87 MG cells. The reverse effect was observed in C6 glioblastoma cells, where apoptosis was correlated with a long-lasting activation of Erk 1/2.  In PC-3 cells, euphol had no or limited effect on Erk 1/2 and Akt activity. Conclusion: These results indicate that euphol induces cell death in glioblastoma and prostate cancer cells and regulates significantly Erk1/2 and Akt activity in glioblastoma cells.     

Syndecan-1, a key regulator of cell viability in endometrial cancer

Syndecan-1 is one of the major proteoglycans on cell surfaces involved in major biological processes. Although loss of syndecan-1 correlates well with the gain of cancerous characteristics in a wide range of cancers, increased expression of syndecan-1 also coincides with adverse outcomes in some cancers, including breast, ovarian and pancreatic cancers. For this Janus-faced attitude of syndecan-1, we sought to examine expression patterns of syndecan-1 in endometrial carcinoma (EC) and gain insight into the roles of syndecan-1. Immunohistochemical examinations of 109 endometrial tissue samples from myoma, hyperplasia and EC uteri revealed that syndecan-1 expression was significantly upregulated in EC compared with hyperplasia (p < 0.001). To evaluate pathophysiological functions of syndecan-1, its expression level was altered, and subsequent outcomes were examined using human endometrial cancer cell lines such as HEC-1A, AN3CA and KLE cells. Overexpression of syndecan-1 increased the growth of HEC-1A cells regardless of anchorage dependence while silencing syndecan-1 by antisense RNAs caused apoptotic cell death. Consistent with decreased viability, the loss of syndecan-1 was also accompanied by a decrease in the activation of Erk and Akt and a concomitant decrease in the phosphorylation of PTEN and PDK1, which are known as negative and positive regulators of Akt activation, respectively. These down-regulatory effects were reversed upon overexpression of syndecan-1. Collectively together, the aforementioned findings lend support to the notion that upregulation of syndecan-1 may be a critical element for endometrial cancers in maintaining their viability and thus can serve as a cancer specific therapeutic and diagnostic marker.     

SIRT1 in B[a]P-induced lung tumorigenesis

Benzo[a]pyrene (B[a]P) is a carcinogen in cigarette smoke. We found that B[a]P induced SIRT1 in human bronchial epithelial BEAS-2B cell. SIRT1 was overexpressed in the lung of B[a]P-exposed mice and in human lung cancer biopsies. SIRT1 up-regulated TNF-α and β-catenin and down-regulated the membrane fraction of E-cadherin. In addition, SIRT1 promoted invasion, migration and tumorigenesis of BEAS-2B cells in nude mice upon B[a]P exposure. Thus, SIRT1 is involved in B[a]P-induced transformation associated with activation of the TNF-α/β-catenin axis and is as a potential therapeutic target for lung cancer.     

Beta-2 adrenergic receptor gene (ADRB2) polymorphism and risk for lung adenocarcinoma: a case-control study in a Chinese population

The incidence of lung adenocarcinoma (AC) has been increasing over recent decades. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent carcinogens and reproducibly induces a high incidence of lung AC in laboratory animals. In addition to its genotoxic effects, NNK has also epigenetic effects on lung cells by functioning as an agonist for beta adrenergic receptors and stimulating the signal pathways that lead to lung AC. Beta-2 adrenergic receptor (ADRB2) expressed on bronchial smooth muscle is a well-defined target for asthma treatment that has epidemiological implications in lung cancer development. And biochemical effect and pharmacogenetic relevance of regulatory and coding variants of ADRB2 have been well documented. Aiming to test whether the genetic variants of ADRB2 modify risk of lung AC, we compared the manifestation of three common single nucleotide polymorphisms (SNPs) of ADRB2 (G-1023A, G-654A, and A46G (Gly16Arg)) between 313 patients with lung AC and 321 controls. Overall association was not observed between risk and either individual of the three SNPs or their combined haplotypes. However, in the subgroup of young subjects ≤50 years old, significant association was observed for G-1023A (allele based OR, 1.82; 95% CI, 1.12–2.95), A46G (Gly16Arg) (allele based OR, 0.64; 95% CI, 0.40–1.03), and the haplotype A⁻¹⁰²³A⁴⁶ (OR 2.62; 95% CI 1.30–5.27). Our results do not support a major independent role of ADRB2 polymorphisms in lung AC risk, suggesting that functional variants of other genes involved in the NNK epigenetic pathway of carcinogenesis should be investigated.     

肺癌相关的 Slit2－Robo1信号通路的研究进展

恶性肿瘤的生长和转移离不开新生血管的形成。 Slit2－Robo1信号通路最初是在神经系统中被发现,且在轴突导向生长和神经细胞迁移过程中发挥重要作用,血管系统和神经系统的结构和功能具有相似之处,近年来研究发现Slit2－Robo1信号通路在血管系统,特别是肿瘤血管中具有重要的作用,并在不同肿瘤中发挥的作用不同,已发现Slit2－Robo1可以抑制乳腺癌脑转移的扩散,同时,Slit2－Robo1也可以促进黑素瘤中的肿瘤生长。本文对与肺癌相关的Slit2－Robo1信号通路现状做一综述。     

人肺癌细胞株中hnRNP A2/B1表达的研究

目的 研究人肺癌细胞株中核内不均一核糖核蛋白(hnRNP)A2/B1及hnRNP B1的表达。方法 采用特异性hnRNP A2／B2及hnRNP B1引物,应用RT-PCR方法研究肺癌细胞株hnRNP A2／B1 mRNA的表达,以抗hnRNP B1单克隆抗体免疫细胞化学染色方法研究肺癌细胞hnRNP A2/B1蛋白的亚细胞定位。结果 RT—PCR显示人肺腺癌细胞株SPC-A1及Y-90,小细胞肺癌细胞株NCI-H446及鳞癌细胞株A431均表达hnRNP A2／B1及hnRNP B1,其PCR产物分子量分别在661及1039bp左右,与预期大小的hnRNP A2/B1 cDNA片断相符。免疫细胞化学研究发现,肺腺癌细胞株SPC—A1及Y-90．小细胞肺癌细胞株NCI—H446及鳞癌A431的细胞浆及细胞核内均可见特异的hnRNP B1染色,鳞癌A43l及小细胞肺癌NCI—H446 hnRNP B1染色较肺腺癌细胞株SPC—A1及Y-90明显。结论 肺癌细胞株hnRNP A2／B1及hnRNP B1表达明显增高。     

采用改进方法检测肺癌组织端粒酶活性

用改进的ＴＲＡＰ法检测肺癌的端粒酶活性,探讨端粒酶活性与肺癌的关系。方法：用培养瓶替代液氮瓶收集标本,采用ＴＲＡＰ改进方法,内含３６ｐｂ质控模板预防假阴性,增加强物长度避免二聚体形成,且使反应一步完成,并用银染法显示检测结果,对４５例病理确诊的肺癌手术标本及一株肺癌细胞株的端粒酶活性进行检测。