Sonic Hedgehog信号通路在肝细胞癌中的表达及意义

背景与目的：有研究表明Sonic Hedgehog（SHH）信号通路参与多种肿瘤的发生和发展,本研究通过检测SHH信号通路中蛋白Shh、Gli2在肝细胞癌（hepatocellular carcinoma,HCC）中的表达情况,探讨其与HCC各临床病理特征的关系和意义。方法：采用免疫组织化学法检测30例肝癌组织及10例正常肝组织中蛋白Shh、Gli2的表达;RT-PCR法检测10例HCC组织及相应癌旁组织中和肝癌细胞系HepG2、Huh7中Shh和Gli2mRNA的表达。结果：免疫组织化学法检测结果显示Shh、Gli2在HCC组织中阳性率分别为63.3%（19/30）和66.7%（20/30）;Gli2的表达与HCC病理分级和肝门静脉侵犯相关（P=0.017,P=0.024）。Shh、Gli2在正常肝组织中无表达。RT-PCR检测结果显示HCC组织和HepG2、Huh7细胞系中都存在Shh、Gli2 mRNA的表达。HCC组织中Shh、Gli2基因表达高于癌旁组织（P〈0.05）;Shh、Gli2 mRNA在Huh7中的表达强度高于HepG2,但两者间差异无统计学意义（P〉0.05）。结论：Shh和Gli2在HCC细胞系和组织中的高表达,可能参与了肝癌的发生和发展,为肝癌的防治研究提供了新的实验依据。     

口腔鳞状细胞癌中Hh通路关键分子

[目的]探讨Hh通路关键分子Shh、Ptch、Gli-1在口腔鳞状细胞癌中的表达及意义.[方法]采用免疫组织化学方法分别检测40例口腔鳞状细胞癌组织和30例口腔黏膜正常组织中Shh、Ptch、Gli-1的表达.[结果]Shh、Ptch、Gli-1在30例正常口腔黏膜中均无表达,在口腔鳞状细胞癌中,Shh、Ptch、Gli-1阳性率分别为62.5％、60.0％和65.0％.Shh、Gli-1的阳性表达与肿瘤大小、淋巴结转移、临床分期相关(P＜0.05),Ptch表达与淋巴结转移相关(P＜0.05).Spearman等级相关分析显示Shh、Ptch和Gli-1的表达间均存在正相关(rs=0.527、0.406、0.578,P＜0.01).[结论]Shh、Ptch、Gli-1蛋白在口腔鳞状细胞癌组织中均过表达,三者可能通过配体依赖途径被激活并参与口腔鳞癌的发生发展、转移.     

DNA修复基因ERCC1在原发性肝细胞癌组织中的表达及临床意义

  目的  探讨切除修复交叉互补基因1(ERCC1)在原发性肝细胞癌(Hepatocellular carcinoma, HCC)组织中的表达情况及临床意义。   方法  应用免疫组织化学方法检测226例HCC癌组织、65例HCC癌旁组织和17例非癌肝组织中ERCC1的表达情况, 并分析其与HCC临床病理因素和预后的关系。   结果  肝癌组织中ERCC1阳性率为44.2%(100/226), 显著高于癌旁组织及非癌正常肝组织中的阳性率(分别为16.9%和5.9%, P < 0.05)。有门静脉癌栓组的ERCC1阳性率为66.7%, 无癌栓组为42.3%, 差异具有统计学意义(P < 0.05);但ERCC1阳性表达与性别等其他临床病理特征均无关(P均 > 0.05)。接受根治术的184例患者中, ERCC1阳性率随着中位复发转移时间(TTR/M)的延长而显著降低(χ2=9.630, P=0.047);ERCCI阳性组TTR/M为10.3个月, 而阴性表达组为20.3个月, 差异具有统计学意义(P < 0.05)。多因素生存分析显示, 术前谷草转氨酶 > 2.5倍正常值、病灶最大径 > 5 cm和ERCCl阳性表达是HCC患者术后复发转移风险增加的独立危险因素。   结论  肝癌组织中ERCCl阳性率显著高于癌旁肝组织及非癌肝组织, 其阳性表达与门静脉癌栓形成及术后复发、转移风险增高显著相关。      

Hh信号通路在口腔鳞状细胞癌中的激活及意义

目的： 研究口腔鳞状细胞癌中Shh、Ptch、Gli-1在基因及蛋白水平的表达,并探讨其阳性表达与口腔鳞状细胞癌生物学特性之间的关系。方法：采用免疫组织化学方法分别检测40例口腔鳞癌和30例正常口腔黏膜中Shh、Ptch、Gli-1蛋白的表达;RT-PCR法检测10例口腔鳞癌组织及5例正常口腔黏膜组织中Shh、Gli-1和Ptch mRNA的表达。结果：免疫组织化学结果显示,Shh、Ptch和Gli-1蛋白在口腔鳞癌中阳性表达率分别为62.5%、60.0％和65.0％,在正常口腔黏膜中3种蛋白均不表达。非参数统计分析示,Shh及Gli-1的阳性表达与肿瘤的大小、淋巴结转移及临床分期相关 (P<0.05),Ptch蛋白的表达与淋巴结转移呈显著正相关 (P<0.05)。RT-PCR结果显示,Shh、Ptch、Gli-1 mRNA在口腔鳞癌组织中的阳性表达分别为60%、50%、70%,明显高于正常口腔黏膜,差异有统计学意义 (P<0.05)。结论：Hh信号通路在口腔鳞状细胞癌组织中被激活并与口腔鳞癌的发生、发展、转移关系密切。     

肝细胞癌组织中MMP-2和VEGF表达

[目的]研究肝细胞癌(HCC)组织中基质金属蛋白酶2(MMP-2)和血管内皮生长因子(VEGF)蛋白的表达及其临床意义.[方法]通过免疫组化的方法检测了51例HCC组织和46例癌旁肝组织中MMP-2和VEGF蛋白的表达,及其与HCC门静脉癌栓形成和手术后2年内复发等的关系.[结果]VEGF在51例HCC的阳性率为62.7%,明显高于46例癌旁组织的17.4%(P＜0.001);MMP-2和VEGF在有门静脉癌栓组的阳性率分别为100%和85.7%,均分别明显高于无癌栓组的67.6%和54.1%(P＜0.05);VEGF在2年内复发组的阳性率为81.8%,明显高于无复发组的48.3%(P＜0.05).[结论]HCC组织中MMP-2和VEGF蛋白的表达可能促进门静脉癌栓的形成和术后复发.     

肝细胞癌组织PTEN和Cyclin D1及C-myc表达的临床病理意义

目的:研究PTEN、Cyclin D1及C-myc蛋白在肝癌组织中的表达及其临床病理意义.方法:采用EnVisionTM plus免疫组织化学方法研究PTEN、Cyclin D1及C-myc蛋白在52例原发性肝细胞癌(HCC)及癌旁肝组织中的表达情况.结果: 52例HCC中PTEN、Cyclin D1和C-myc 蛋白染色阳性率分别为42.31%、48.08%和53.84%,癌旁肝组织的阳性率分别为92.31%、25.00%和32.69%,Cyclin D1及C-myc在HCC中的表达明显高于癌旁肝组织(χ2=5.971,P=0.015;χ2=4.740,P=0.029),而PTEN在HCC中的表达明显低于癌旁组织(χ2=29.539, P=0.000). 在HCC中PTEN的阳性表达与Cyclin D1、C-myc的阳性表达呈负相关(r=-0.363 1,P=0.019 7;r=-0.369 7,P=0.017 2);PTEN、Cyclin D1和C-myc在人肝癌组织中的检出率与肝外转移、术后复发及肿瘤分化程度明显有关(P<0.05),Cyclin D1、PTEN的检出率与门静脉癌栓也明显有关(P<0.05).结论:PTEN蛋白低表达、Cyclin D1及C-myc 蛋白的过表达可促使肝癌细胞增殖,使肝癌细胞具有更强的侵袭力,与肝癌的发生发展密切相关.     

肝细胞癌组织MTA1和MMP-2表达及其相关性研究

目的:研究肝细胞癌(HCC)组织中转移相关基因1(MTA1)及基质金属蛋白酶-2(MMP-2)蛋白的表达及其临床意义,并探讨其与HCC生长及浸润转移的关系.方法:采用免疫组化法检测60例HCC组织及癌旁肝组织中MTA1和MMP-2的表达.结果:MTA1及MMP-2在癌组织中的阳性率分别为65.00%和60.00%,而在癌旁组织中的阳性率分别为35.00%和26.67%,癌组织与癌旁组织比较差异有统计学意义,P<0.05.MTA1在人HCC组织中的表达与临床分期、术后复发、肝外转移及门静脉癌栓相关.MMP-2在人HCC组织中的表达与临床分期、门静脉癌栓、肝外转移及术后复发相关.在癌组织中MTA1与MMP-2的表达呈正相关.结论:HCC中MTA1及MMP-2的高表达与HCC生长及浸润转移有关,在HCC的发生、发展及术后复发过程中起重要作用.     

肝癌组织GPC-3 mRNA和IGF-Ⅱ mRNA表达及其临床意义的研究

目的:探讨人肝细胞癌(HOC)组织GPC-3 mRNA和胰岛素样生长因子-Ⅱ(insulin like growth factor-Ⅱ,IGF-Ⅱ)mRNA的表达夏其与肿瘤发生发展的关系.方法:RT-PCR法检测70例HCC组织、癌旁肝组织和18例正常肝组织中GPC-3 mRNA和IGF-ⅡmRNA的表达.结果:HOE组织GPC-3阳性率(82.85%)及其mRNA表达水平(0.596±0.205)均明显高于癌旁组织(34.28%,0.428±0.137),P<0.01;HOC组织IGF-Ⅱ阳性率(92.86%)及其mRNA表达水平(0.750±0.309)也均明显高于癌旁组织(81.43%,0.648±0.237),P<0.05,GPC-3 mRNA和IGF-Ⅱ mRNA在HOC组织中的表达水平均与肿瘤直径、肿瘤分化程度和肝外转移等明显相关,而与临床分期、门静脉癌栓、肿瘤个数、血清AFP水平及术后复发等无明显关系.GPC-3 mRNA和IGF-Ⅱ mRNA在HOC组织中的表达呈正相关,r=0.281,P=0.038;而两者在癌旁肝组织的表达不相关.结论:HCC组织中GPC-3及IGF-Ⅱ高表达,可促使HCC细胞增殖,与HCC的发生发展密切相关.     

联合检测Shh Gli1 Snail及E-cadher in在胃癌中的表达及其意义

目的:探讨Shh、Gli1、Snail及E-cadherin在胃癌中的表达及意义.方法:采用免疫组化方法检测54例胃癌组织、癌旁组织及30例正常人胃黏膜组织中Shh、Gli1、Snail及E-cadherin的表达情况,并与临床病理资料做对照分析.结果:胃癌组织中Shh、Gli1、Snail及E-cadherin阳性表达率分别为68.52%、61.11%、77.78%、25.93%;癌旁组织27.78%、24.07%、40.74%、70.37%:正常胃粘膜组织36.67%、26.67%、30.00%、96.67%.四种蛋白在胃癌组织和癌旁组织中的表达差异均具有统计学意义(P＜0.05).Shh、Gli1及Snail在癌旁组织及正常胃黏膜组织中的表达差异均无统计学意义(P＜0.05),E-eadherin有统计学意义(P＜0.05);四种蛋白的表达均与胃癌的分化程度、淋巴结转移相关(P＜0.05),其中Shh、Gli1及Snail与胃癌浸润深度有关(P＜0.05),而E-cadherin 无关(P＞0.05);四种蛋白的表达与性别、年龄、位置及远处转移均无相关性(P＞0.05);Shh、Gli1和Snail三者之间在胃癌中的表达呈正相关(P＜0.05),而这三个蛋白表达与E-cadherin呈负相关(P＜0.05).结论:Hedgehog信号通路与上皮间质转换(epithelial-mesenchymal transition,EMT)分子在胃癌组织中皆异常表达,提示异常激活的Hedgehog信号通路可能引起EMT分子的异常表达.这在胃癌的发生发展中可能起到一定的作用.     

TGFβ1与Smad4基因在肝细胞癌中的表达及意义

目的 探讨TGFβ-Smad信号通路中TGFβ1与Co- Smad(Smad 4)与肝细胞癌的发生、发展的关系.方法 采用免疫组化ABC法及原位杂交法(ISH),检测41例肝细胞癌组织与癌旁组织中TGFβ1、Smad 4蛋白、Smad 4 mRNA的表达,以5例外伤性肝破裂手术切除标本作为正常对照.比较HCC组与时照组及HCC癌旁中TGFβ1与Smad 4蛋白、Smad4 mRNA表达的差异,并进行图像分析.结果 正常对照组中TGFβ1呈阴性表达,Smad 4蛋白、Smad 4 mRNA均呈阳性表达;HCC组织中TGFβ1阳性表达率为78.0%(32/41),癌旁组织中为95.1%(39/41),两者比较差异显著(P<0.05);Smad 4蛋白在HCC组织中阳性表达率为48.8%(20/41),在癌旁组织中为78.0%(32/41),两者比较有显著性差异(P<0.01);Smad 4 m RNA在HCC组织中阳性表达率为51.2%(21/41),在癌旁组织中为73.1%(30/41),两者比较有显著性差异(P<0.05);与正常肝组织比较,HCC组织中Smad 4蛋白和Smad 4 mRNA阳性表达率均显著降低(P<0.05);Ⅰ、Ⅱ级HCC组织与Ⅲ、Ⅳ级HCC组织Smad 4 m RNA阳性表达存在显著差异(P<0.05),Ⅲ、Ⅳ级阳性表达率较Ⅰ、Ⅱ级降低;Smad 4蛋白的阳性面积百分比、光密度及Smad 4 m RNA的阳性面积百分比癌旁组织均显著高于HCC组织(P均<0.05).HCC组织中Smad 4蛋白、Smad 4 m RNA表达与TGF-β1表达比较均存在显著差异(P<0.05),但均无显著相关性(P>0.05).结论 TGFβ1过表达、Smad4表达缺失可能在肝细胞癌的发生、发展中发挥重要作用.     

Religiosity and Physical and Emotional Functioning Among African American and White Colorectal and Lung Cancer Patients

The literature suggests that religiosity helps cope with illness. The present study examined the role of religiosity in functioning among African Americans and Whites with a cancer diagnosis. Patients were recruited from an existing study and mailed a religiosity survey. Participants (N = 269; 36% African American, 56% women) completed the mail survey, and interview data from the larger cohort was utilized in the analysis. Multivariate analyses indicated that in the overall sample religious behaviors were marginally and positively associated with mental health and negatively with depressive symptoms. Among women, religious behaviors were positively associated with mental health and negatively with depressive symptoms. Religiosity was not a predictor of study outcomes for men. Among African Americans, religious behaviors were positively associated with mental health and vitality. Among Whites, religious behaviors were negatively associated with depressive symptoms. These findings suggest a mixed role of religious involvement in cancer outcomes. The current findings may have applied potential in the areas of emotional functioning and depression.     

New and emerging radiosensitizers and radioprotectors

The combination of chemotherapy and radiation has led to clinical breakthroughs in several disease sites, and current work continues to define optimum combinations of proven chemotherapy as well as more recently available, noncytotoxic agents. Administration of systemic therapies allows modulation of radiation response to improve tumor control (radiosensitization) or to prevent normal tissue toxicity (radioprotection). Substantial progress has been made in identifying the targets of standard chemotherapeutic radiation sensitizers and protectors as well as in the introduction of a new generation of molecularly targeted therapies in combination with radiation. We have reviewed the most recent, predominantly early phase clinical trials combining systemic agents with radiation. Although the proof of an improved schedule ultimately needs to come from well-run Phase III trials, the search among schedules could be shortened by the use of surrogate endpoints such as presence of active drug metabolites in the tumor. This has been accomplished only in a few cases and needs to become a more standard part of radiation sensitizer and protector trials.     

Fruit and vegetables and cancer risk

The possibility that fruit and vegetables may help to reduce the risk of cancer has been studied for over 30 years, but no protective effects have been firmly established. For cancers of the upper gastrointestinal tract, epidemiological studies have generally observed that people with a relatively high intake of fruit and vegetables have a moderately reduced risk, but these observations must be interpreted cautiously because of potential confounding by smoking and alcohol. For lung cancer, recent large prospective analyses with detailed adjustment for smoking have not shown a convincing association between fruit and vegetable intake and reduced risk. For other common cancers, including colorectal, breast and prostate cancer, epidemiological studies suggest little or no association between total fruit and vegetable consumption and risk. It is still possible that there are benefits to be identified: there could be benefits in populations with low average intakes of fruit and vegetables, such that those eating moderate amounts have a lower cancer risk than those eating very low amounts, and there could also be effects of particular nutrients in certain fruits and vegetables, as fruit and vegetables have very varied composition. Nutritional principles indicate that healthy diets should include at least moderate amounts of fruit and vegetables, but the available data suggest that general increases in fruit and vegetable intake would not have much effect on cancer rates, at least in well-nourished populations. Current advice in relation to diet and cancer should include the recommendation to consume adequate amounts of fruit and vegetables, but should put most emphasis on the well-established adverse effects of obesity and high alcohol intakes.     

VEGF及KDR在大肠腺瘤和腺癌中的表达及意义

目的：探讨VEGF和KDR在大肠腺瘤和大肠腺癌中的表达及临床病理特征的关系。方法：大肠腺瘤和大肠腺癌组织标本各100例,采用免疫组织化学染色法检测VEGF和KDR在标本中的表达情况。结果：VEGF和KDR在大肠腺癌组中的阳性表达明显高于大肠腺瘤组（P〈0.05）;在正常大肠黏膜均未见VEGF和KDR表达的阳性染色;VEGF阳性表达组中KDR的阳性表达率为70%,显著高于VEGF阴性表达组中KDR的阳性表达率16%,两组比较有统计学意义（P〈0.01）。结论：大肠腺癌组织中KDR的表达与肿瘤大小、转移情况、浸润深度密切相关;VEGF和KDR在大肠腺瘤中的表达与患者的年龄、性别及分型均无相关性,而与增生程度相关（P〈0.05）。在大肠腺癌患者中VEGF及KDR表达更高,二者具有协同效应。     

肾上腺素能β受体与肿瘤生长及转移

大量研究表明肿瘤细胞可表达β受体，而一些神经递质、药物和社会心理因素可能通过β受体影响肿瘤的生长和转移，β受体激动剂、β受体阻滞剂以及抑郁等社会心理因素可加强或削弱这种作用。这为表达β受体肿瘤的治疗开辟了新的道路，提供了新的治疗靶点。     

Occupational and environmental radiation and cancer

Epidemiologic evidence on the relation between occupational and environmental radiation and cancer is reviewed. Studies of pioneering radiation workers, underground miners, and radium dial painters revealed excess cancer deaths and contributed to the setting of radiation protection standards and to theories of carcinogenesis. Occupational exposures today are generally much lower than in the past, thus any associated increases in cancer will be difficult to detect. Pooling investigations of these more recently exposed workers, however, has the potential to validate current estimates of risk used in radiation protection. New information on the effects of chronic radiation exposure also may come from studies in the former Soviet Union of Chernobyl clean-up workers and of workers at the Mayak nuclear facilities. Studies of environmental radiation exposures, other than radon, are largely inconclusive, due mainly to the difficulties in detecting the low risks associated with low dose exposures. Thyroid cancer, however, has been linked to environmental radiation from the Chernobyl accident and from nuclear weapons tests. Low-level radiation released during normal operations at nuclear plants has not been found to increase cancer rates in surrounding populations. Radon, a human carcinogen, is the most ubiquitous exposure to human populations; remediating high residential-radon levels is recommended, recognizing that the exposure can never be removed completely because it occurs naturally.     

Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance

This review describes a new vision for future directions in the study of metastatic cancer biology and pathology. It is based upon clinical and experimental observations on the constituent cell lineages within a neoplasm and on tumour-host interactions. The vision incorporates information from studies in population biology, developmental biology and experimental pathology as well as investigations upon human malignant disease. The assembled information reveals that invasion and metastasis are supra-cellular manifestations of "emergent behavior" among combinations of normal and malignant cell lineages in vivo. Emergent behavior is a combinatorial interactive process in which a population displays new traits which cannot be achieved by individuals acting separately and which subside when the specific population mix disaggregates. Disruption of such pathological interactions in the field of a developing primary or secondary tumour is, therefore, required to disable the malignant population and arrest progression without tissue destruction. These conclusions originate, in part, from principles which govern the sociobiology and group behavior of bees, ants, fish, birds and human societies. In all these social organisms, external factors can disrupt signaling mechanisms and induce expanding self-perpetuating rogue behavior, leading to social disintegration. These principles also apply to cellular societies composing higher animals, which likewise need intrinsic rules to maintain social order and avoid anarchy, and recognition of this is essential for advancing future research on the mechanisms involved in carcinogenesis and metastasis. Summarised evidence is presented here to support the conclusion that miscommunications between cells and tissues in the region of the developing tumour and its metastases are the main direct perpetrators of malignant disease. Genetic lesions (mutations, deletions, translocations, reduplications, etc.), commonly seen in cancers, can significantly disrupt important molecular pathways in the networks of communications needed to sustain orderly tissue/organ structure and function. However, genetic lesions can also, themselves, be induced by abnormal cell interactions initiated by extrinsic carcinogenic agents such as chemicals, viruses, hormones and radiation. The evidence shows that, irrespective of the initiating cause, it is this miscommunication in the region of a developing tumour and its metastases that is ultimately responsible for the emergence and progression of the disease. The article describes how this information collectively, provides a framework for designing specific novel therapeutic approaches targeting the cell and tissue interactions driving tumour metastasis and its manifold effects on the whole body.     

Vitamin D and melanoma and non-melanoma skin cancer risk and prognosis: A comprehensive review and meta-analysis

Vitamin D is formed mainly in the skin upon exposure to sunlight and can as well be taken orally with food or through supplements. While sun exposure is a known risk factor for skin cancer development, vitamin D exerts anti-proliferative and pro-apoptotic effects on melanocytes and keratinocytes in vitro. To clarify the role of vitamin D in skin carcinogenesis, we performed a review of the literature and meta-analysis to evaluate the association of vitamin D serum levels and dietary intake with cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) risk and melanoma prognostic factors. Twenty papers were included for an overall 1420 CM and 2317 NMSC. The summary relative risks (SRRs) from random effects models for the association of highest versus lowest vitamin D serum levels was 1.46 (95% confidence interval (CI) 0.60–3.53) and 1.64 (95% CI 1.02–2.65) for CM and NMSC, respectively. The SRR for the highest versus lowest quintile of vitamin D intake was 0.86 (95% CI 0.63–1.13) for CM and 1.03 (95% CI 0.95–1.13) for NMSC. Data were suggestive of an inverse association between vitamin D blood levels and CM thickness at diagnosis. Further research is needed to investigate the effect of vitamin D on skin cancer risk in populations with different exposure to sunlight and dietary habits, and to evaluate whether vitamin D supplementation is effective in improving CM survival.