绿茶：一种潜在的肝癌化学预防措施？

StephenW

Editorial
Green tea consumption: A potential chemopreventive measure for hepatocellular carcinoma?
Hepatology 14 November 2017


Abbreviations

AFP alfa-fetoprotein
CI confidence interval
γ-OHPdG gamma-hydroxy-1,N2-propanodeoxyguanosine
HCC hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major global health problem.[1] HCC is the sixth-most common incident cancer and the fourth-leading cause of cancer death in 2015.[2] HCC is more common in men; 1 in 45 men and 1 in 113 women develop liver cancer before age 79 years in the world.[2] HCC is a highly lethal cancer given that a majority of patents with HCC are diagnosed in noncurative stages.[3] Although patients with early-stage HCC are eligible for potentially curative treatment, up to 70% of patients who receive curative resection or local ablation eventually develop recurrent tumors within 5 years.[1] There are no effective chemopreventive strategies for these patients and those at risk for HCC development.

In order to decrease the burden of HCC mortality, it is crucial to identify high-risk groups of patients and provide interventions to decrease the risk of tumor development and recurrence after curative treatment. Prognostic biomarkers should provide information to identify such high-risk patients. Serum alfa-fetoprotein (AFP) is a well-established diagnostic and prognostic biomarker for HCC.[4] Although highly elevated serum AFP predicts a poor clinical outcome, therapeutic implications of an elevated AFP in HCC patients remain unclear. Similarly, several other proteomic or genomic biomarkers aid in diagnosis and correlate with prognosis; however, they remain underutilized because of lack of wide availability. For example, with recent technical advances in genomics and transcriptomics, researchers used genome-wide expression profiling of liver cancer and adjacent benign tissues and showed that the gene expression pattern of tissue adjacent to the tumor predicts clinical outcome in HCC patients after surgical resection.[5] Although this gene expression signature provides prognostic information, it does not provide biological information amenable to interventions that may improve clinical outcomes. More recently, sorafenib was tested as an adjuvant treatment, but failed to prolong recurrent free survival following curative surgical resection or local ablation in a large, phase 3, double-blind, placebo-controlled trial.[6] Identification of mechanism-based prognostic biomarkers that can be intervened to improve the clinical outcomes is a critical unmet need in HCC research.

In the current issue of Hepatology, Fu et al. have published their research examining the utility of an exocyclic deoxyguanosine DNA adduct, gamma-hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG), in three mouse models of hepatocarcinogenesis and its utility as a prognostic biomarker with further validation in human HCC samples.[7] γ-OHPdG is one of the most common lipid peroxidation–derived DNA adducts that can modify DNA bases, including p53 genes, and it frequently causes G to T and G to A mutations. It is a well-established mutagen in smoking-induced lung cancer. However, the role of γ-OHPdG in HCC has not been investigated in the past. The investigators showed that γ-OHPdG levels increase with age in nucleotide excision repair-deficient mice (Xpa–/–) and the whole-liver levels correlated with HCC development. With whole-exome sequencing of tumors and adjacent benign tissues, they determined that GC>TA mutation is the dominant alteration in Xpa–/– mice, implying that γ-OHPdG may play a role in HCC-specific mutagenesis. Next, investigators showed that suppression of γ-OHPdG formation in the mouse liver led to inhibition of hepatocarcinogenesis. Three antioxidants (Theaphenon E, α-lipoic acid, and α-tocopherol) were tested. Theaphenon E, which is a potent antioxidative green tea extract, was shown to lower the level of γ-OHPdG the most. Furthermore, Theaphenon E prevented tumor formation and decreased tumor number and size in diethylnitrosamine-injected mice (Fig. 1). Last, the investigators examined the levels of γ-OHPdG in HCC patients who had undergone a liver resection and stratified them by γ-OHPdG expression level. Higher levels of γ-OHPdG were strongly associated with shorter overall survival and recurrence-free survival, confirming the role of γ-OHPdG as a prognostic biomarker in human HCC.
Figure 1.
Figure 1.

Green tea for the chemoprevention of HCC. γ-OHPdG, a mutagenic lipid peroxidation-induced DNA adduct, correlates with HCC incidence in experimental murine models of HCC. Theaphenon E administration reduced the HCC tumor burden and γ-OHPdG levels, suggesting that the chemopreventive effect of green tea might be mediated by Theaphenon E by decreasing γ-OHPdG in liver DNA and consequent DNA mutations.

The current study findings provide biological evidence of the chemopreventive effect of Theaphenon E for HCC. A population-based case-control study from China on 204 HCC cases and 415 healthy controls showed that green tea consumption was inversely associated with the risk of HCC. Individuals who drank green tea longer than 30 years were at lowest risk compared with nondrinkers (adjusted odds ratio, 0.44; 95% confidence interval [CI], 0.19-0.96).[8] A recent meta-analysis of nine prospective cohort studies (465,274 subjects and 3,694 cases) again confirmed the association between green tea consumption and reduced risk for liver cancer (relative risk, 0.88; 95% CI, 0.19-0.96).[9] Whereas the vast majority of epidemiological evidence supporting the protective effect of green tea is from Asia, a recent European study confirmed a preventative effect of tea on HCC: Tea intake was associated with a 59% reduction in the risk of HCC development among 486,799 subjects after a median follow-up of 11 years.[10] However type of tea was not available in that European study.

An important limitation of the current study is the small number of human HCC tissues analyzed. It remains unclear whether γ-OHPdG levels are independently associated with clinical outcomes after adjusting for known prognostic factors, such as tumor size, number of lesions, AFP, vascular invasion, and metastasis. For the same reason, it has not been investigated whether γ-OHPdG is implicated in hepatocarcinogenesis in an etiology-specific manner. Nonetheless, the investigators reported a mechanistically relevant prognostic biomarker that can help select a subgroup of HCC patients who may benefit from Theaphenon E/green tea consumption.

Should we recommend green tea consumption in patients who are at increased risk for HCC development or recurrence? The current study provides a biological mechanism for the protective effect of green tea on HCC, which has been demonstrated in previous epidemiological studies. Therefore, we may encourage high-risk patients to drink green tea. In order to clearly measure the biological impact of Theaphenon E/green tea, the associations between green tea consumption, the level of γ-OHPdG in tumor and adjacent benign tissues DNA, and HCC development and recurrence should be externally validated, especially in Western countries where it has been under studied. Last, it is worth mentioning that green tea catechins exert chemopreventive properties by modulating signal transduction and metabolic pathways, hence inhibiting metabolic syndrome-related carcinogenesis in addition to antioxidant and anti-inflammatory activities.[11] This might provide a different level of preventive effect in nonalcoholic steatohepatitis, which is emerging as a major etiology of HCC. The etiology-specific mutagenic role of γ-OHPdG in hepatocarcinogenesis should be further investigated in the future, and this will help toward identifying patients who may get the most benefit from an antioxidant effect of green tea in the era of precision and individualized medicine.

    Ju Dong Yang, M.D., M.Sc.

    Harmeet Malhi, M.B.B.S.

    Division of Gastroenterology and Hepatology

    Mayo Clinic College of Medicine

    Rochester, MN

StephenW

社论
绿茶消费：一种潜在的肝癌化学预防措施？
肝病学2017年11月14日


法新社阿法甲胎蛋白
CI置信区间
γ-OHPdGγ-羟基-1，N 2 - 丙醛脱氧鸟苷
HCC肝细胞癌

肝细胞癌（HCC）是一个主要的全球健康问题[1] HCC是2015年第六大常见癌症事件和第四大癌症死亡原因。[2]肝癌更常见于男性; 1名45岁男性和1名113名女性在世界上79岁以前发生肝癌[2]。 HCC是一种高度致命的癌症，因为HCC的大部分专利都是在非治愈阶段被诊断出来的[3]。虽然早期HCC患者有资格进行潜在的治愈性治疗，但是接受根治性切除或局部消融治疗的患者中，高达70％的患者在5年内最终会出现复发性肿瘤[1]。对于这些患者和处于HCC发展风险的患者，没有有效的化学预防策略。

为了减轻HCC死亡的负担，确定高危人群并提供干预措施以降低治愈后肿瘤发展和复发的风险至关重要。预后生物标志物应该提供信息来识别这样的高危患者。血清甲胎蛋白（AFP）是HCC确定的诊断和预后生物标志物[4]。虽然血清AFP的高度升高预示着较差的临床结果，但HCC患者中AFP升高的治疗意义尚不清楚。同样，其他几种蛋白质组学或基因组生物标志物有助于诊断并与预后相关联;然而，由于缺乏广泛的可用性，它们仍然没有得到充分利用。例如，随着基因组学和转录组学的最新技术进展，研究人员利用全基因组表达谱分析肝癌和相邻的良性组织，并显示与肿瘤相邻的组织的基因表达模式预测HCC患者在手术切除后的临床结果[ 5]虽然这种基因表达签名提供了预后信息，但它不提供可以改善临床结果的干预措施的生物学信息。最近，索拉非尼被作为辅助治疗进行检测，但是在一项大型的3期双盲安慰剂对照试验中，根治性手术切除或局部消融术后未能延长其复发生存期[6]。可以干预以改善临床结果的基于机制的预后生物标志物的鉴定是HCC研究中关键的未满足的需求。

在当前的肝病学问题中，傅等人已经发表了他们的研究，在三种小鼠肝癌模型中检测了环外脱氧鸟苷DNA加合物γ-羟基-1，N2-丙醛氧基鸟苷（γ-OHPdG）的用途，并将其用作预后生物标志物，并在人类HCC样品中进一步验证。 [7] γ-OHPdG是可以修饰DNA碱基（包括p53基因）的最常见的脂质过氧化衍生的DNA加合物之一，并且经常引起G到T和G到A的突变。在吸烟引起的肺癌中，它是一种行之有效的诱变剂。然而，γ-OHPdG在HCC中的作用还没有被研究过。研究人员发现核苷酸切除修复缺陷小鼠（Xpa - / - ）中γ-OHPdG水平随着年龄增加而增加，全肝水平与HCC发展相关。通过对肿瘤及其邻近良性组织的全外显子测序，他们确定GC> TA突变是Xpa - / - 小鼠中的显性改变，这意味着γ-OHPdG可能在HCC特异性诱变中起作用。接下来，研究者表明抑制小鼠肝脏中γ-OHPdG的形成导致抑制肝癌发生。测试了三种抗氧化剂（Theaphenon E，α-硫辛酸和α-生育酚）。 Theaphenon E是一种有效的抗氧化绿茶提取物，可显着降低γ-OHPdG水平。此外，Theaphenon E预防二乙基亚硝胺注射小鼠肿瘤形成并减少肿瘤数目和大小（图1）。最后，研究人员检查了经肝切除的HCC患者中γ-OHPdG的水平，并通过γ-OHPdG表达水平将其分层。更高水平的γ-OHPdG与更短的总生存期和无复发生存率密切相关，证实了γ-OHPdG作为人类HCC预后生物标志物的作用。
图1。
图1。

绿茶化学预防HCC。 γ-OHPdG（一种诱变的脂质过氧化诱导的DNA加合物）与HCC实验鼠模型中的HCC发病率相关。叶酸E给药可降低HCC肿瘤负荷和γ-OHPdG水平，提示绿茶的化学预防作用可能是由Theaphenon E通过降低肝脏DNA中的γ-OHPdG和随后的DNA突变而介导的。
目前的研究结果提供了Theaphenon E对HCC的化学预防作用的生物学证据。来自中国的204例HCC病例和415例健康对照的基于人群的病例对照研究显示，绿茶消费量与HCC风险呈负相关。喝绿茶30年以上的人与非饮酒者相比风险最低（校正比值比为0.44; 95％置信区间[CI]为0.19-0.96）[8]。最近对9项前瞻性队列研究（465,274例受试者和3,694例受试者）的荟萃分析再次证实了绿茶消费与降低肝癌风险之间的相关性（相对风险0.88; 95％CI，0.19-0.96）。鉴于绝大多数支持绿茶保护效果的流行病学证据来自亚洲，欧洲最近的一项研究证实了茶对肝癌的预防作用：饮茶后486,799名受试者中HCC发展风险降低了59％中位随访11年[10]。然而，这种欧洲研究中没有提供茶的种类。

目前研究的一个重要限制是分析的人肝癌组织数量很少。在调整已知的预后因素（如肿瘤大小，病变数量，AFP，血管侵入和转移）之后，γ-OHPdG水平是否与临床结果独立相关尚不清楚。出于同样的原因，尚未研究γ-OHPdG是否以病因特异性方式参与肝癌发生。尽管如此，研究人员报告了一种机械相关的预后生物标记物，可以帮助选择可能受益于Theaphenon E /绿茶消费的亚组HCC患者。

我们应该建议患有HCC发展或复发风险增加的患者食用绿茶吗？目前的研究为绿茶对HCC的保护作用提供了一个生物学机制，这在以前的流行病学研究中已经得到证实。因此，我们可能鼓励高危患者喝绿茶。为了明确测量Theaphenon E /绿茶的生物学影响，绿茶消费量，肿瘤中γ-OHPdG水平与癌旁良性组织DNA水平以及HCC的发生和复发之间的关系应该在外部验证，特别是在西方国家它在哪里被研究。最后，值得一提的是，绿茶儿茶素通过调节信号转导和代谢途径发挥化学预防特性，从而抑制与抗氧化剂和抗炎活性相关的代谢综合征相关癌变[11]。这可能对非酒精性脂肪性肝炎提供不同程度的预防作用，这是肝癌的主要病因。 γ-OHPdG在肝癌发生中的病因学特异性诱变作用在今后应进一步研究，这将有助于鉴别在精确性和个体化医学时代从绿茶的抗氧化作用中获得最大益处的患者。

    朱东阳博士，硕士研究生

    Harmeet Malhi，M.B.B.S

    消化科和肝病科

    梅奥诊所医学院

    明尼苏达州罗切斯特

9病成医

楼主别来无恙？你还一直活跃在这里，不容易，更不简单，谢谢！

tacolynn

老公常年喝绿茶，不喝酒，喝绿茶是不是能预防肝癌，只能自己给自己做实验了。

小牡丹

绿茶是好，农药残留不好，甚至是人体化工厂杀手