Advances in Clinical Medicine
Vol.
11
No.
06
(
2021
), Article ID:
43253
,
6
pages
10.12677/ACM.2021.116394
肝细胞肝癌代谢异常相关问题的研究现状及 展望
祁峰*,龚建平#
重庆医科大学附属第二医院肝胆外科,重庆
![](http://html.hanspub.org/file/36-1572315x1_hanspub.png)
收稿日期:2021年5月17日;录用日期:2021年6月3日;发布日期:2021年6月21日
![](http://html.hanspub.org/file/36-1572315x2_hanspub.png)
摘要
肝细胞肝癌(下简称“肝癌”)作为目前全球第四大死因,诊断与治疗都尚未达到一个理想的水平。肝脏作为人体最大也是最重要的代谢器官之一,在人体糖质、脂肪酸、维生素等人体常见元素的代谢中起到重要的作用。同时,代谢异常相关疾病发病率逐渐上升,其中不少疾病已经成为肝脏相关疾病的高危因素、起因等。代谢相关疾病与肝癌的相关研究已多见报道。本文从脂肪酸代谢、糖质代谢以及维生素代谢三个角度,对肝癌与代谢异常相关问题做简要的阐述。
关键词
肝细胞肝癌,脂肪酸代谢,糖质代谢,维生素代谢,代谢综合征
Research Status and Prospect of Metabolic Abnormalities in Hepatocellular Carcinoma
Feng Qi*, Jianping Gong#
Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing
Received: May 17th, 2021; accepted: Jun. 3rd, 2021; published: Jun. 21st, 2021
ABSTRACT
As the fourth leading cause of death in the world, liver cancer, of which hepatocellular carcinoma (HCC) is the dominant variety, has not yet reached an ideal level of diagnosis and treatment. As one of the largest and most important metabolic organs of the human body, the liver plays an important role in the metabolism of glucose, lipids, proteins, vitamins and hormones. At the same time, the incidence of metabolic abnormalities-related diseases is gradually increasing. Many of them have become high-risk factors and causes of liver diseases. Researches on metabolism-related diseases and liver cancer have been reported frequently. This article will briefly explain the problems related to liver cancer and abnormal metabolism from the perspectives of lipid metabolism, glucose metabolism and vitamin metabolism.
Keywords:Hepatocellular Carcinoma, Lipid Metabolism, Glucose Metabolism Disorders, Vitamin Metabolism, Metabolic Syndrome
Copyright © 2021 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
肝细胞肝癌(以下简称“肝癌”)目前是全球第四大死因,其中占主导地位的是肝细胞肝癌 [1]。早期的肝癌可以采取较为理想的根治性治疗手段,比如外科手术切除、射频、经导管动脉化疗栓塞(TACE)、高强度聚焦超声(HIFU)和肝移植等 [2]。然而早期肝癌缺乏明显的症状体征,亦缺少典型的实验室和影像学检查,故超过80%的患者在确诊时都难以获得根治性的治疗 [3]。探索肝癌的发病原理、诊断、治疗以及预后显得十分重要,近年来肝癌相关问题已成为外科学、肿瘤学等领域研究的热点。
肝炎病毒感染,包括但不仅限于乙型肝炎病毒(Hepatitis B Virus, HBV)和丙型肝炎病毒(Hepatitis B Virus, HCV),被大量研究证实是肝细胞肝癌的主要危险因素,感染HBV和HCV而引起的原发性肝癌占全部病例的75%以上 [4]。但随着居民生活水平的日益提高,以2型糖尿病、高血压、肥胖和高血脂等疾病为代表的代谢相关疾病患病率呈明显的升高趋势,其中颇具代表性的疾病之一——非酒精性脂肪性肝病(Non-alcoholic fatty liver disease, NAFLD)也被证实在一定条件下会引发慢性肝病 [5] [6]。同时,肝脏作为人体的消化器官、内分泌器官,主导或参与超过五百种与机体密切相关的生物学功能 [7],这其中就包括代谢糖质、脂肪酸以及维生素等物质,分解体内产生的或人体摄入的有毒有害物质,为体内一些物质的分泌提供场所、原材料等,例如胆汁酸、白蛋白等等 [8]。因而从代谢角度研究肝癌的发病机制、诊断、治疗以及预后已经成为当今肝癌研究领域一个新的方向。探究代谢因素在肝癌发病机制中的作用、寻找代谢相关基因、蛋白等在肝癌治疗及预后中的意义就显得至关重要。本文从代谢异常与肝癌的关系这个角度,结合近期的研究成果进行简要的阐述。
2. 脂肪酸代谢与肝癌
代谢作为机体维持正常运转最基本的功能之一,往往也时刻反映着机体的工作状态,脂肪酸代谢异常,尤其是脂肪酸异常聚积增多,已经被证实是各种肿瘤细胞常见的特性之一。一般来说,人体对摄入的脂肪酸类物质加以利用,是细胞内功能性脂质的主要来源。而在肿瘤细胞中,往往会异常激活脂质的重头合成途径,使得肿瘤细胞可以使用体内的代谢产物作为原料重新合成脂肪酸。这就会导致细胞内脂质代谢原有的稳态被破坏,进而影响细胞的功能、分化 [9] [10]。很早就有报道,在肿瘤细胞中,很多主导或者参与脂肪酸类物质合成的酶都会被异常激活,有些甚至高度激活,这其中不乏关键途径的调控酶 [11] [12]。脂肪酸既是三大营养物质之一,同时又是构建有机体细胞膜磷脂双分子层的主要原材料,在很多蛋白质中它又是一个不可或缺的修饰底物,参与多种生物途径。正是因为如此,通过各种途径生产、累积和储存一定量的脂肪酸,对于增殖速度很快的肿瘤细胞就显得非常重要。已有研究证实,在一些特定的外界因素刺激下,肝细胞中与正常脂质生成途径不同的胞内脂质异常新生途径会被激活,从而导致细胞中脂肪酸类物质增多,促进肝脏纤维化形成,甚至有可能发展为肝癌 [13] [14]。杨艳等人的研究发现,LASS2可能通过与NDUFS2/OXPHOS互作介导mtROS的生成,调控AMPK/Raptor/自噬(脂噬)级联信号通路,对FFAs诱导的肝细胞脂肪变性起保护作用,这也可能是LASS2调控肝脂质代谢的可能机制之一 [15]。莎仁高娃等人的研究表明,SREBP1可能会受到CC3/TIP30信号通路变化,尤其是下调的影响,进而影响到脂肪酸代谢,表现为促进肝癌细胞的生长。故在一定程度上SREBP1以及CC3/TIP30蛋白可以用于评价肝癌患者的预后情况 [16]。
目前已确认,肥胖是可以引起肝癌的独立危险因素 [17] [18]。有近一半的肥胖患者都伴随着肝脏的脂肪堆积,也就是常说的脂肪肝。细胞内过高的脂肪含量会提高肿瘤坏死因子TNF-α的表达水平,而过高的TNF-α又会过度促进脂肪细胞的发育,进一步增加了机体内脂肪酸的含量,最终陷入恶性循环,脂肪肝进一步加重,引发肝脏一系列病理改变,甚至最后发生恶性病变 [19]。非酒精性脂肪性肝病(Nonalcoholic fatty liver disease, NAFLD)亦是肝脏脂肪酸代谢异常的结果,是代谢综合征在肝脏的特征性表现之一 [20]。非酒精性脂肪肝的发病机理十分复杂, 目前研究成果都停留在假说阶段,目前被国内外学者广泛接受的是“二次打击”学说,它被认为在一定程度上解释了NAFLD的发病机制。其中,首次打击主要是指肝细胞中脂肪酸代谢异常导致细胞内脂肪酸异常堆积,仅仅形成单一脂肪肝的过程;二次打击程度较首次更重,包括了肝细胞的氧化应激反应、促炎因子等细胞因子的释放,最终形成脂肪性肝炎的过程 [21]。
综上,肝细胞内脂质异常代谢,包括异常合成、异常积聚等,都与其恶性转化及生长密切相关。但是,在肝细胞肝癌中,脂肪酸代谢调节的相关通路、关键酶以及调控蛋白等尚未研究明了。因此,更进一步的探索肝癌细胞脂肪酸代谢相关问题,对于寻找特异性灵敏度更高的诊断方法、更加理想的治疗策略以及更有效的预估预后,都有很重要的指导意义。
3. 糖质代谢与肝癌
通常来说,正常的机体细胞通过线粒体氧化糖类,释放能量,供给细胞以及机体正常的生长活动需要。在二十世纪初期,Otto Warburg发现即便是在氧气充足的环境中,将肿瘤细胞与机体正常组织细胞相对比,肿瘤细胞会消耗更多的葡萄糖等糖质,而且会产生更多的乳酸 [22]。进一步的研究发现,肿瘤细胞所特有的这个过程既可以在无氧环境中完成,也可以在没有线粒体的参与下完成。这个发现就是著名的Warburg效应,指正常分化的细胞主要依靠线粒体的氧化磷酸化为细胞供能,而大多数肿瘤细胞则依赖有氧糖酵解,这种方式可以在短时间内产生足够多的能量供肿瘤增殖使用。李晓等人的研究表明,长链非编码RNA Ftx可以正向调控糖质代谢中的关键分子GLUT、LDH等,负向调控CS、OGDH等,来干预肝癌细胞糖摄取、乳酸生成等过程,进而影响了肝癌细胞的增殖、侵袭转移的行为 [23]。罗菲等人发现亚砷酸钠能够诱导肝细胞上调长链非编码RNA AMALAT1,通过减少HIFs的降解来实现其表达量的升高,进而促进糖酵解过程,诱导Warburg效应的发生,最终在这种影响下,一部分肝细胞恶变转化为肝癌 [24]。魏士博等发现,肝癌细胞中长链非编码RNA HOTAIR表达水平较正常肝细胞明显升高,且表达量高低与肿瘤大小相关。此外HOTAIR也能通过调节mTOR活性,与糖质代谢重要分子GLUT1耦合,从另一个角度促进了肝癌细胞中的糖酵解过程,一定程度上促进了肝癌发生发展 [25]。
糖尿病作为一种国人常见的以高血糖为特征的代谢性疾病,已被证实与多种恶性肿瘤有密不可分的关系,例如胰腺癌、肝癌、胃癌等,且已经成为重要的危险因素之一。对于HBV感染合并2型糖尿病的患者,胰岛素抵抗已被证实是诱发肝癌的起因之一 [26]。严英才等人的研究发现,RRAD作为糖尿病关键基因Ras家族的成员之一,作用于ACTG1来影响肝细胞肝癌的分子生物学功能。具体表现为RRAD表达水平与肿瘤体积和TNM分期有关,RRAD和ACTG1与患者的预后密切相关 [27]。同时,越来越多的临床表明,乳腺癌、肠癌等多种癌症的患者服用一定量的二甲双胍,可以一定程度上抑制肿瘤组织的增殖,亦或是诱导肿瘤细胞的凋亡,甚至还有抑制肿瘤细胞的侵袭和转移的功能,此外还有研究显示,二甲双胍和传统化学治疗药物联合用药会产生协同抗肿瘤的作用,联合二甲双胍抗肿瘤能够有效减少化学治疗药物的用药频率和用量,已实现减少毒副作用的目的 [28] - [33]。
综上,虽然已经有许多研究证实,以糖尿病为代表的糖质代谢异常与肝癌的发生发展有密不可分的联系,但其中的关键分子调控机制仍然不明。进一步深入研究肝脏癌变过程中的糖质代谢问题,也具有非常重要的指导价值。
4. 维生素代谢与肝癌
维生素是人和动物为维持正常的生理功能而必须从食物中获得的一类微量有机物质,在人体生长、代谢、发育过程中发挥着重要的作用。常见的维生素分为水溶性维生素和脂溶性维生素两种。水溶性维生素常见的有维生素B系(B1、B6、B12)、叶酸、维生素C等。脂溶性维生素常见的有维生素A、维生素K等。已经有研究表明,机体的维生素水平与包括但不仅限于肝癌等恶性肿瘤有密切的关系,包括促进或抑制肿瘤的发生 [34] [35]。最新研究显示维生素A的紊乱可以导致肝癌、肺癌、乳腺癌的发生 [36]。Yan等人的研究发现,维生素A代谢产物视黄酸受到其受体的调控参与多效反应,通过NF-κB和PI3K/Akt通路调节肝癌细胞的增殖与侵袭转移 [37]。有研究表明维生素K2和维生素K3可分别通过诱导凋亡并激活MEK/ERK信号转导通路,调控自噬及激活细胞色素P450抑制肝癌细胞的增殖 [38] [39] [40]。此外,对于维生素D、维生素E和维生素C,也有研究表明它们在肝癌的发生发展或是预防诊断方面起到了重要的作用 [41] [42] [43] [44] [45]。
综观上述研究,维生素代谢与肝癌息息相关,但尚未得到足够的重视,尚未见高质量的研究报告。进一步研究维生素代谢与肝癌的关系,将会是十分有意义的工作,具有极强的指导意义。
5. 总结与展望
脂肪酸代谢、糖质代谢、维生素代谢、蛋白质代谢和激素代谢是肝脏最主要的代谢功能,其中脂肪酸代谢、糖质代谢和维生素代谢与肝癌的研究已多见报道,表明了肝癌的发生发展过程中这三者起到了至关重要的作用。有的可以作为新的治疗靶点,为新的治疗药物的研究提供思路;有的可以作为患者诊断或者预后的评价标准,为患者综合治疗提供指导。但蛋白质代谢与激素代谢的相关研究尚未见有价值的报道,在一定程度上可以作为今后研究的方向。与此同时,代谢相关问题又与肝脏炎症反应、免疫水平,肿瘤细胞的来源、分化程度、机体的营养状况等问题有着千丝万缕的联系,期间的相互作用相互影响仍值得深入研究,也是未来的研究重点。
文章引用
祁 峰,龚建平. 肝细胞肝癌代谢异常相关问题的研究现状及展望
Research Status and Prospect of Metabolic Abnormalities in Hepatocellular Carcinoma[J]. 临床医学进展, 2021, 11(06): 2724-2729. https://doi.org/10.12677/ACM.2021.116394
参考文献
- 1. Mcglynn, K., Petrick, J. and El-Serag, H. (2021) Epidemiology of Hepatocellular Carcinoma. Hepatology (Baltimore, MD), 73, 4-13. https://doi.org/10.1002/hep.31288
- 2. Yang, J., Hainaut, P., Gores, G., et al. (2019) A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management. Nature Reviews Gastroenterology & Hepatology, 16, 589-604. https://doi.org/10.1038/s41575-019-0186-y
- 3. Yin, Z. and Li, X. (2020) Immunotherapy for Hepatocellular Carcinoma. Cancer Letters, 470, 8-17. https://doi.org/10.1016/j.canlet.2019.12.002
- 4. Bosetti, C., Turati, F. and La Vecchia, C. (2014) Hepatocellular Carcinoma Epidemiology. Best Practice & Research Clinical Gastroenterology, 28, 753-770. https://doi.org/10.1016/j.bpg.2014.08.007
- 5. Rinella, M. (2015) Nonalcoholic Fatty Liver Disease: A Systematic Review. JAMA, 313, 2263-2273. https://doi.org/10.1001/jama.2015.5370
- 6. Dyson, J., Jaques, B., Chattopadyhay, D., et al. (2014) Hepatocellular Cancer: The Impact of Obesity, Type 2 Diabetes and a Multidisciplinary Team. Journal of Hepatology, 60, 110-117. https://doi.org/10.1016/j.jhep.2013.08.011
- 7. Naruse, K., Tang, W. and Makuuch, M. (2007) Artificial and Bioartificial Liver Support: A Review of Perfusion Treatment for Hepatic Failure Patients. World Journal of Gastroenterology, 13, 1516-1521. https://doi.org/10.3748/wjg.v13.i10.1516
- 8. Green, C., Pramfalk, C., Morten, K., et al. (2015) From Whole Body to Cellular Models of Hepatic Triglyceride Metabolism: Man Has Got to Know His Limitations. American Journal of Physiology Endocrinology and Metabolism, 308, E1-E20. https://doi.org/10.1152/ajpendo.00192.2014
- 9. Kato, A., Ando, K., Tamura, G., et al. (1971) Effects of Some Fatty Acid Esters on the Viability and Transplantability of Ehrlich Ascites Tumor Cells. Cancer Research, 31, 501-504.
- 10. Mcgee, R. and Spector, A. (1974) Short-Term Effects of Free Fatty Acids on the Regulation of Fatty Acid Biosynthesis in Ehrlich Ascites Tumor Cells. Cancer Research, 34, 3355-3362.
- 11. Chen, Y., Liu, B., Tang, D., et al. (1992) Fatty Acid Modulation of Tumor Cell-Platelet-Vessel Wall Interaction. Cancer Metastasis Reviews, 11, 389-409. https://doi.org/10.1007/BF01307189
- 12. Honn, K., Nelson, K., Renaud, C., et al. (1992) Fatty Acid Modulation of Tumor Cell Adhesion to Microvessel Endothelium and Experimental Metastasis. Prostaglandins, 44, 413-429. https://doi.org/10.1016/0090-6980(92)90137-I
- 13. Feldstein, A. (2010) Novel Insights into the Pathophysiology of Nonalcoholic Fatty Liver Disease. Seminars in Liver Disease, 30, 391-401. https://doi.org/10.1055/s-0030-1267539
- 14. Adams, L., Lymp, J., St. Sauver, J., et al. (2005) The Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study. Gastroenterology, 129, 113-121. https://doi.org/10.1053/j.gastro.2005.04.014
- 15. Yang, Y., Yang, X., Lin, Y., et al. (2020) LASS2 Regulates Hepatocyte Steatosis by Interacting with NDUFS2/OXPHOS Related Proteins. Biochemical and Biophysical Research Communications, 526, 871-879. https://doi.org/10.1016/j.bbrc.2020.02.166
- 16. Yin, F., Sharen, G., Yuan, F., et al. (2017) TIP30 Regulates Lipid Metabolism in Hepatocellular Carcinoma by Regulating SREBP1 through the Akt/mTOR Signaling Pathway. Oncogenesis, 6, e347. https://doi.org/10.1038/oncsis.2017.49
- 17. Calle, E., Rodriguez, C., Walker-Thurmond, K., et al. (2003) Overweight, Obesity, and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults. The New England Journal of Medicine, 348, 1625-1638. https://doi.org/10.1056/NEJMoa021423
- 18. Davila, J., Morgan, R., Shaib, Y., et al. (2005) Diabetes Increases the Risk of Hepatocellular Carcinoma in the United States: A Population Based Case Control Study. Gut, 54, 533-539. https://doi.org/10.1136/gut.2004.052167
- 19. Savage, D. and Semple, R. (2010) Recent Insights into Fatty Liver, Metabolic Dyslipidaemia and Their Links to Insulin Resistance. Current Opinion in Lipidology, 21, 329-336. https://doi.org/10.1097/MOL.0b013e32833b7782
- 20. Chalasani, N., Younossi, Z., Lavine, J., et al. (2012) The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology (Baltimore, MD), 55, 2005-2023. https://doi.org/10.1002/hep.25762
- 21. Day, C. and James, O. (1998) Steatohepatitis: A Tale of Two “Hits”? Gastroenterology, 114, 842-845. https://doi.org/10.1016/S0016-5085(98)70599-2
- 22. Warburg, O. (1956) On the Origin of Cancer Cells. Science (New York, NY), 123, 309-314. https://doi.org/10.1126/science.123.3191.309
- 23. Simon, T., King, L., Chong, D., et al. (2018) Diabetes, Metabolic Comorbidities, and Risk of Hepatocellular Carcinoma: Results from Two Prospective Cohort Studies. Hepatology (Baltimore, MD), 67, 1797-806. https://doi.org/10.1002/hep.29660
- 24. Luo, F., Liu, X., Ling, M., et al. (2016) The lncRNA MALAT1, Acting through HIF-1α Stabilization, Enhances Arsenite-Induced Glycolysis in Human Hepatic L-02 Cells. Biochimica et Biophysica Acta, 1862, 1685-1695. https://doi.org/10.1016/j.bbadis.2016.06.004
- 25. Wei, S., Fan, Q., Yang, L., et al. (2017) Promotion of Glycolysis by HOTAIR through GLUT1 Upregulation via mTOR Signaling. Oncology Reports, 38, 1902-1908. https://doi.org/10.3892/or.2017.5840
- 26. Huang, Y., Cai, X., Qiu, M., et al. (2014) Prediabetes and the Risk of Cancer: A Meta-Analysis. Diabetologia, 57, 2261-2269. https://doi.org/10.1007/s00125-014-3361-2
- 27. Yan, Y., Xu, H., Zhang, L., et al. (2019) RRAD Suppresses the Warburg Effect by Downregulating ACTG1 in Hepatocellular Carcinoma. OncoTargets and Therapy, 12, 1691-1703. https://doi.org/10.2147/OTT.S197844
- 28. Apetoh, L., Ghiringhelli, F., Tesniere, A., et al. (2007) Toll-Like Receptor 4-Dependent Contribution of the Immune System to Anticancer Chemotherapy and Radiotherapy. Nature Medicine, 13, 1050-1059. https://doi.org/10.1038/nm1622
- 29. Chowdhury, T.A. (2010) Diabetes and Cancer. QJM: Monthly Journal of the Association of Physicians, 103, 905-915. https://doi.org/10.1093/qjmed/hcq149
- 30. Jemal, A., Bray, F., Center, M., et al. (2011) Global Cancer Statistics. CA: A Cancer Journal for Clinicians, 61, 69-90. https://doi.org/10.3322/caac.20107
- 31. Giovannucci, E., Harlan, D., Archer, M., et al. (2010) Diabetes and Cancer: A Consensus Report. Diabetes Care, 33, 1674-1685. https://doi.org/10.2337/dc10-0666
- 32. Maiuri, M., Tasdemir, E., Criollo, A., et al. (2009) Control of Autophagy by Oncogenes and Tumor Suppressor Genes. Cell Death and Differentiation, 16, 87-93. https://doi.org/10.1038/cdd.2008.131
- 33. Vigneri, P., Frasca, F., Sciacca, L., et al. (2009) Diabetes and Cancer. Endocrine-Related Cancer, 16, 1103-1123. https://doi.org/10.1677/ERC-09-0087
- 34. Mccullough, M., Patel, A., Kushi, L., et al. (2011) Following Cancer Prevention Guidelines Reduces Risk of Cancer, Cardiovascular Disease, and All-Cause Mortality. Cancer Epidemiology, Biomarkers & Prevention, 20, 1089-1097. https://doi.org/10.1158/1055-9965.EPI-10-1173
- 35. Willett, W. (2008) Nutrition and Cancer: The Search Continues. Nutrition and Cancer, 60, 557-559. https://doi.org/10.1080/01635580802380370
- 36. Di Masi, A., Leboffe, L., De Marinis, E., et al. (2015) Retinoic Acid Receptors: From Molecular Mechanisms to Cancer Therapy. Molecular Aspects of Medicine, 41, 1-115. https://doi.org/10.1016/j.mam.2014.12.003
- 37. Yan, T., Wu, H., Zhang, H., et al. (2010) Oncogenic Potential of Retinoic Acid Receptor-Gamma in Hepatocellular Carcinoma. Cancer Research, 70, 2285-2295. https://doi.org/10.1158/0008-5472.CAN-09-2968
- 38. Matsumoto, K., Okano, J., Nagahara, T., et al. (2006) Apoptosis of Liver Cancer Cells by Vitamin K2 and Enhancement by MEK Inhibition. International Journal of Oncology, 29, 1501-1508. https://doi.org/10.3892/ijo.29.6.1501
- 39. Yang, C. and Han, L. (2010) Knockdown of Beclin 1 Inhibits Vitamin K3-Induced Autophagy, But Promotes Apoptosis of Human Hepatoma SMMC-7721 Cells. Molecular Medicine Reports, 3, 801-807. https://doi.org/10.3892/mmr.2010.347
- 40. Chun, Y., Lee, B., Yang, S., et al. (2001) Induction of Cytochrome P450 1A1 Gene Expression by a Vitamin K3 Analog in Mouse Hepatoma Hepa-1c1c7 Cells. Molecules and Cells, 12, 190-196.
- 41. Wang, J., Abnet, C., Chen, W., et al. (2013) Association between Serum 25(OH) Vitamin D, Incident Liver Cancer and Chronic Liver Disease Mortality in the Linxian Nutrition Intervention Trials: A Nested Case-Control Study. British Journal of Cancer, 109, 1997-2004. https://doi.org/10.1038/bjc.2013.546
- 42. Wibaux, C., Legroux-Gerot, I., Dharancy, S., et al. (2011) Assessing Bone Status in Patients Awaiting Liver Transplantation. Joint Bone Spine, 78, 387-391. https://doi.org/10.1016/j.jbspin.2011.03.001
- 43. Calvisi, D., Ladu, S., Hironaka, K., et al. (2004) Vitamin E Down-Modulates iNOS and NADPH Oxidase in c-Myc/TGF-Alpha Transgenic Mouse Model of Liver Cancer. Journal of Hepatology, 41, 815-822. https://doi.org/10.1016/j.jhep.2004.07.030
- 44. Factor, V., Laskowska, D., Jensen, M., et al. (2000) Vitamin E Reduces Chromosomal Damage and Inhibits Hepatic Tumor Formation in a Transgenic Mouse Model. Proceedings of the National Academy of Sciences of the United States of America, 97, 2196-2201. https://doi.org/10.1073/pnas.040428797
- 45. Zhang, W., Shu, X., Li, H., et al. (2012) Vitamin Intake and Liver Cancer Risk: A Report from Two Cohort Studies in China. Journal of the National Cancer Institute, 104, 1174-1182. https://doi.org/10.1093/jnci/djs277
NOTES
*第一作者。
#通讯作者。