肺癌与甲状腺转录因子-1的研究进展

肺癌是目前全世界发病率最高的恶性肿瘤,其病死率也居于前列.因此,对肺癌的早期诊断及早期治疗对于降低肺癌患者的病死率以及改善患者生存质量至关重要.传统的肺癌诊断方法包括影像学检查以及病理学检查,现在仍然被临床所采用.但鉴于以上检查手段的敏感性、特异性、适用度等方面存在一定局限,近年来有关肺癌早期诊断、治疗及预后的分子标志物的研究愈来愈受到关注.本文就甲状腺转录因子-1的生物作用及其在肺癌诊断、治疗及预后方面的研究进展作一综述.     

Low dose radioiodide thyroid ablation in postsurgical patients with thyroid cancer

Sixty-four patients with well-differentiated carcinoma of the thyroid were treated with initial high (80 to 100 mCi) or low (less than 30 mCi) doses of I¹³¹ after bilateral subtotal thyroidectomy. A total of 36 patients in the various histologic categories were initially treated with the low dose of I¹³¹ (group 1), and a total of 28 patients were treated with the higher dose (group 2). Disease-free criteria were no visible tissue in the neck or body, a protein-bound radioactive iodine (PBI¹³¹) of less than 0.005 per cent per liter at seven days and/or whole body retention of less than 3 per cent at seven days. Of the patients receiving less than 30 mCi (group 1), 56 per cent with papillary carcinoma, 67 per cent with follicular carcinoma and 56 per cent with mixed carcinoma of the thyroid were rendered disease-free after this initial dose. Of the patients receiving the higher dose of I¹³¹ (group 2), 67 per cent with papillary carcinoma, 50 per cent with follicular carcinoma and 67 per cent with mixed carcinoma of the thyroid were rendered disease-free after this initial dose. Disease-free mean follow-up time was 5.17 years (group 1) and 5.82 years (group 2). There was no statistical difference in these mean follow-up times, nor was there a statistical difference in the net (total minus initial) dose of I¹³¹ needed to render the patient disease-free. These data demonstrate that low dose I¹³¹ therapy is as effective as the larger more routine doses of I¹³¹ given in this disease.     

Adenovirus-mediated E2F-1 gene transfer in nonsmall-cell lung cancer induces cell growth arrest and apoptosis.

Since overexpression of E2F-1 has been shown to induce apoptosis, the ability of adenovirus-mediated transfer of E2F-1 to inhibit tumour growth in nonsmall-cell lung cancer cell lines was investigated. Three cell lines with various genomic status were infected with AdE2F. Cell proliferation and viability were determined by trypan blue exclusion. Apoptosis induction was assessed by flow cytometry and poly-adenosine diphosphate-ribose-polymerase cleavage assay. In vivo, the effect of E2F-1 on tumour growth was determined in severe combined immunodeficiency (SCID) mice. The current experiments showed that overexpression of E2F-1 suppressed tumour cell growth. The population of apoptotic cells was dramatically increased 96 h after infection with AdE2F. Inhibition of cell growth and induction of apoptosis was not dependent on genomic status. Moreover, treatment of implanted tumours in SCID mice with AdE2F inhibited tumour growth. These data suggest that adenovirus-mediated E2F-1 gene therapy may be effective in the treatment of nonsmall-cell lung cancer.     

Inhibition of N-glycan processing affects iodide organification in porcine thyroid cells

The N-glycan-processing inhibitors swainsonine (Sw) and deoxymannojirimycin (dMM) were used to study the influence of N-glycans on iodide organification in cultured porcine thyroid cells. Incubations with [125I]NaI were followed by determination of labeled trichloroacetic acid-insoluble material in culture media, follicular contents and cells. In controls, most of this material was in the follicular contents. With Sw and dMM, total acid-insoluble material was less than 10% of control. Iodide uptake was slightly inhibited and hydrogen peroxide release was not affected by inhibitors. Cell-surface thyroid peroxidase (TPO) activity, assayed by its ability to iodinate bovine serum albumin, was strongly inhibited. Pronase glycopeptide analysis indicated that with drugs the content in complex-type N-glycans was strongly decreased while that in hybrid or oligomannosidic type was increased. In conclusion, inhibition of N-glycan processing prevents iodide organification in cultured porcine thyroid cells by decreasing the recovery of cell-surface TPO activity.     

Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin

Iodide uptake by the thyroid is mediated by the sodium/iodide symporter. Upon iodide uptake, thyroperoxidase catalyzes iodination of tyrosine residues in thyroglobulin, retaining iodide within thyroid follicles. Dedifferentiation-induced loss of these functions in cancers, rendering them unresponsive to radioiodide, occurs with most poorly differentiated and anaplastic tumors. We focused on the histone deacetylase (HDAC) inhibitors (HDACI) as a way to induce differentiation of thyroid cancer cells. We assessed re-expression of thyroid-specific genes mRNA induced by HDACI using quantitative RT-PCR and immunostaining in poorly differentiated papillary and anaplastic thyroid cancer cells. HDACI induced expression of thyroid-specific gene mRNAs and proteins, and accumulation of radioiodide through iodination of generic cellular proteins were detected. HDACI-treated tumors could specifically accumulate (125)I as revealed by imaging experiments and radioiodide concentration in vivo. In an attempt to determine the mechanism by which these gene expressions occurred, we detected the inhibition of protein synthesis by cycloheximide, which up-regulated the expression of thyroperoxidase and thyroglobulin mRNA in HDACI-treated cells and down-regulated that of sodium/iodide symporter mRNA. Together, our results suggest that HDACI-induced expression of thyroid-specific genes, some of which is mediated by some protein synthesis, may contribute to development of novel strategy against thyroid cancer.     

甲状腺转录因子1和表面活性蛋白在肺硬化性血管瘤中表达的意义

目的　探讨甲状腺转录因子 1(TTF 1)和表面活性蛋白A、B(SP A ,SP B)在肺硬化性血管瘤 (PSH)中表达的生物学意义。方法　用免疫组织化学的方法 ,检测 4 2例经外科手术切除、病理诊断的PSH标本中TTF 1、SP A、SP B和上皮膜抗原 (EMA)、波形蛋白 (vimentin)、广谱角蛋白(pancytokeratin)、角蛋白 7(CK7)、CK5 / 6、钙结合蛋白 (calretinin)、S 10 0蛋白、神经元特异性烯醇化酶(NSE)、突触素 (Syn)、嗜铬素A(CgA)、CD3 4 、Ⅷ因子相关抗原 (F Ⅷ )、平滑肌肌动蛋白 (SMA)的表达状况 ,其中 10例进行透射电镜观察。结果　病理组织学上肿瘤主要由多角形细胞和立方细胞组成 ;免疫组织化学显示 95 % (4 0 / 4 2 )患者立方细胞和多角形细胞共同表达TTF 1、88% (37/ 4 2 )表达EMA、5 7% (2 4 / 4 2 )表达vimentin ,93% (39/ 4 2 )患者立方细胞表达SP A、81% (34/ 4 2 )表达SP B、10 0 %(4 2 / 4 2 )表达 pancytokeratin ;2 4 % (10 / 4 2 )患者多角形细胞散在表达Syn、14 % (6 / 4 2 )表达NSE、12 %(5 / 4 2 )表达S 10 0和 12 % (5 / 4 2 )表达CgA ;TTF 1和EMA在这两种细胞之间的表达状况差异无显著性 (χ2 分别为 0 0 0 0和 3 4 0 3,P >0 0 5 ) ,vimentin在这两种细胞之间的表达差异有显著性 (χ2 =10 118,P <     

Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas

Primary cutaneous lymphomas have been successfully treated with interferons (IFNs), counterbalancing the T-helper 2 (Th2)-skewing state. We undertook a phase 1, open-label, dose-escalating trial of repeated intratumoral administration of TG1042 in patients with advanced primary cutaneous T-cell lymphomas (CTCLs) and multilesional cutaneous B-cell lymphomas (CBCLs). TG1042 is a third-generation, nonreplicating human adenovirus vector containing a human IFN-gamma cDNA insert. Nine patients (7 CTCL, 2 CBCL) were enrolled at the following TG1042 doses: 3 x 10(9), 3 x 10(10), and 3 x 10(11) total particles. Local clinical response was observed in 5 of 9 treated patients (3 patients with complete response [CR] and 2 patients with partial response [PR]). Out of these, 3 patients showed systemic CR with the clearance of other noninjected skin lesions. Clinical response lasted for a median of 3 months (range, 1-6 months). Adverse events were mostly of grades 1 and 2. Seven of 9 treated patients had a detectable TG1042-derived IFN-gamma message in injected lesions after the first treatment cycle. A TG1042-IFN-gamma message was also detectable after several treatment cycles. We demonstrate the induction of humoral immune response to lymphoma tumor-antigen se70-2 after treatment. Our study shows that intralesional injections of TG1042 are both safe and well tolerated.     

Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells

Statins show antiproliferative activity in various cancer cells. The aim of this study was to evaluate the effects of rosuvastatin treatment on papillary thyroid carcinoma. The papillary thyroid carcinoma (B-CPAP) and normal (Nthy-ori 3-1) thyroid cell lines were treated with rosuvastatin at 12.5, 18.5, 25, 50, 100, and 200 μM concentrations. After 48 and 72 h of rosuvastatin treatment, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Ki-67 immunolabeling, FACS analysis, electron microscopy, caspase-3, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) analysis were performed. Decreased cell viability and G1 phase arrest were detected in papillary thyroid cell line treated with rosuvastatin. Positive immunoreactivity of Ki-67 and dose-dependent increase in S phase on Nthy-ori 3-1 cells were also detected. B-CPAP cells showed intense vacuolisation and autophagosomes with low concentrations and 48 h incubations, while Nthy-ori 3-1 cells showed these changes at higher concentrations. A decrease in the percentage of cells showing autophagy was determined with increasing concentrations of rosuvastatin in B-CPAP cells. Rosuvastatin treatment also caused a dose- and time-dependent increase in caspase-3 activity and apoptotic index by TUNEL assay in B-CPAP cells compared with the Nthy-ori 3-1 cells. Apoptotic cells with nuclear condensation and fragmentation were observed in B-CPAP cell line. Rosuvastatin induced autophagic changes in B-CPAP papillary thyroid cancer cells in lower doses and caused a shift from autophagy to apoptosis. Rosuvastatin may be an alternative treatment for refractory papillary thyroid cancer. Further in vivo studies are necessary to clarify the effects of rosuvastatin in papillary thyroid carcinoma and the clinical implications of rosuvastatin treatment.     

腺病毒介导的HCY2基因对血管平滑肌细胞凋亡的诱导作用

目的　观察高同型半胱氨酸诱导基因HCY2对于平滑肌细胞的作用。方法　以复制缺陷型腺病毒作为载体 ,将HCY2基因转移到平滑肌细胞中。提取平滑肌细胞的DNA ,进行凝胶电泳及ELISA ,行DNA片段化分析。用流式细胞术观察平滑肌细胞的亚二倍体。结果　转染HCY2后平滑肌细胞的DNA断裂成相差 2 0 0bp左右的片段 ,流式细胞术测定时发现 ,位于亚二倍体区的平滑肌细胞明显增多。结论　HCY2基因能引起平滑肌细胞的凋亡。     

Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer

AIM:To investigate the expression of insulin-like growth factor-1(IGF-1)/insulin-like growth factor-1 receptor(IGF-1R)in colorectal cancer(CRC)tissues and to analyze their correlation with lymphangiogenesis and lymphatic metastasis.METHODS:Immunohistochemistry was used to evaluate IGF-1 and IGF-1R expression and lymphatic vessel density(LVD)in 40 CRC specimens.The correlation between IGF-1/IGF-1R and LVD was investigated.Effects of IGF-1 on migration and invasion of CRC cells were examined using transwell chamber assays.A LoVo cell xenograft model was established to further detect the role of IGF-1 in CRC lymphangiogenesis in vivo. RESULTS:Elevated IGF-1 and IGF-1R expression in CRC tissues was correlated with lymph node metastasis(r=0.715 and 0.569,respectively,P<0.05)and tumor TNM stage(r=0.731 and 0.609,P<0.05).A higher LVD was also found in CRC tissues and was correlated with lymphatic metastasis(r=0.405,P<0.05).A positive correlation was found between LVD and IGF-1R expression(r=0.437,P<0.05).Transwell assays revealed that IGF-1 increased the migration and invasion of CRC cells.In vivo mouse studies showed that IGF-1 also increased LVD in LoVo cell xenografts.CONCLUSION:IGF-1/IGF-1R signaling induces tumorassociated lymphangiogenesis and contributes to lymphatic metastasis of CRC.     

一氧化氮供体硝普钠对人甲状腺细胞碘有机化的影响

运用细胞原代培养技术、愈创木酚法及同位素法,观察不同浓度硝普钠(SNP)对甲状腺细胞甲状腺过氧化物酶(TPO)及碘有机化的影响。0、10-6、10-5、10-4和10-3mol/LSNP呈剂量依赖性抑制碘有机化[分别为(2708±250,2471±186,2319±159,1464±143,596±161)cpm/孔]。SNP(10-6~10-4mol/L)短时间(0.5h)孵育可增强甲状腺细胞TPO活性(0.027±0.004,0.033±0.002,0.050±0.003,0.040±0.003)U×10-5,10-3mol/LSNP对TPO活性没有影响(0.025±0.005)U×10-5。不同浓度的SNP长时间(72h)孵育未显示对甲状腺细胞TPO活性有影响(P>0.05)。碘有机化与TPO活性不相关。以上结果提示,NO抑制甲状腺细胞碘有机化,此作用可能与TPO无关。