aidsВИЧ-инфекция и иммуносупрессииHIV Infection and Immunosuppressive Disorders2077-9828Baltic Medical Education Center10.22328/2077-9828-2014-6-3-16-23aids-34Research ArticleАНАЛИТИЧЕСКИЙ ОБЗОРANALYTICAL REVIEWМОЛЕКУЛЯРНЫЕ МАРКЕРЫ ГЕПАТОЦЕЛЛЮЛЯРНОЙ КАРЦИНОМЫ. ПЕРСПЕКТИВЫ РАННЕЙ ДИАГНОСТИКИMOLECULAR MARKERS OF HEPATOCELLULAR CARCINOMA. PERSPECTIVES OF EARLY DIAGNOSTICSСергеевМихаил НиколаевичSergeevM. N.4353112@mail.ruШевалдинАнатолий ГеннадьевичShevaldinA. G.noemail@neicon.ruРахмановаАза ГасановнаRakhmanovaA. G.noemail@neicon.ruСлепцоваСнежана СпиридоновнаSleptsovaS. S.sssleptsova@yandex.ruЛяшенкоЕвгений АлександровичLyashenkoE. A.evgeny.lyashenko@gmail.comШаройкоВладимир ВладимировичSharoykoV. V.sharoyko@gmail.comГородская поликлиника № 74РоссияSaint-Petersburg Municipal out-patients' clinic № 74Russian FederationГородская поликлиника № 74; Санкт-Петербургский центр по профилактике и борьбе со СПИД и инфекционными заболеваниямиРоссияSaint-Petersburg Municipal out-patients' clinic № 74Russian FederationПервый Санкт-Петербургский государственный медицинский университет им. академика И.П.ПавловаРоссияFirst Pavlov State Medical University of Saint-Petersburg; Saint-Petersburg Center for Control of AIDS and Infectious DiseasesRussian FederationСеверо-Восточный Федеральный университет им. М.К. АммосоваРоссияAmmosovM.K. North-Eastern Federal UniversityRussian FederationПервый Санкт-Петербургский государственный медицинский университет им. академика И.П.ПавловаРоссияFirst Pavlov State Medical University of Saint-PetersburgRussian FederationСанкт-Петербургский государственный университетРоссияSaint-Petersburg State University, Institute of ChemistryRussian Federation201430092014631623Copyright © Сергеев М.Н., Шевалдин А.Г., Рахманова А.Г., Слепцова С.С., Ляшенко Е.А., Шаройко В.В., 20142014Сергеев М.Н., Шевалдин А.Г., Рахманова А.Г., Слепцова С.С., Ляшенко Е.А., Шаройко В.В.Sergeev M.N., Shevaldin A.G., Rakhmanova A.G., Sleptsova S.S., Lyashenko E.A., Sharoyko V.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://hiv.bmoc-spb.ru/jour/article/view/34

Гепатоцеллюлярная карцинома является одной из наиболее распространенных злокачественных опухолей, характеризующаяся неблагоприятным жизненным прогнозом при отсутствии своевременного и адекватного лечения. Таким образом, ранняя диагностика гепатоцеллюлярной карциномы имеет решающее значение для улучшения качества и увеличения продолжительности жизни. Измерение концентрации Ot-фетопротеина и ультразвуковое исследование печени используются для ранней диагностики рака печени. Однако, чувствительность и специфичность измерения О-фетопротеина в скрининге рака печени не всегда являются удовлетворительными. Достижения биохимии, молекулярной генетики и системной биологии в интегративном анализе опухолей и их окружения привели к идентификации новых молекулярных маркеров гепатоцеллюлярной карциномы, которые могут быть перспективными инструментами для улучшения имеющихся алгоритмов диагностики и лечения гепатоцеллюлярной карциномы.

Hepatocellular carcinoma is one of the most common malignant tumors with a high rate mortality of patients without adequate therapy. Thus, early diagnosis of hepatocellular carcinoma is crucial for improving the quality of life and the survival rate for patients. Measuring the concentration of O-fetoprotein and liver ultrasound are commonly used in the early diagnosis of liver cancer. However, the sensitivity and specificity of measuring O-fetoprotein in liver cancer screening is not always satisfactory. Achievements of biochemistry, molecular genetics and systems biology in the integrative analysis of tumors and their environment led to the identification of new molecular markers of hepatocellular carcinoma, which may be promising tools to improve the existing algorithms of diagnosis and treatment of hepatocellular carcinoma.

гепатоцеллюлярная карциномамаркерыальфа-фетопротеинциррозвирусный гепатитhepatocellular carcinoma marker alpha-fetoproteincirrhosisviral hepatitisReferencesBosch F.X., RibesJ., Cleries R., Diaz M. Epidemiology of hepatocellular carcinoma // Clin. Liver. Dis.- 2005.- Vol. 9.- P. 191-211.Bosch F.X., RibesJ., Cleries R., Diaz M. Epidemiology of hepatocellular carcinoma // Clin. Liver. Dis.- 2005.- Vol. 9.- P. 191-211.JemalA., Bray F., Center M.M., Ferlay J., Ward E., FormanD. Global cancer statistics, CA Cancer // J.Clin.- 2011.- Vol.61.- P. 69-90.JemalA., Bray F., Center M.M., Ferlay J., Ward E., FormanD. Global cancer statistics, CA Cancer // J.Clin.- 2011.- Vol.61.- P. 69-90.Cole P., Morrison A.S. Basic issues in population screening for cancer // J. Natl. Cancer. Inst.- 1980.- Vol. 64.- P. 1263-1272.Cole P., Morrison A.S. Basic issues in population screening for cancer // J. Natl. Cancer. Inst.- 1980.- Vol. 64.- P. 1263-1272.Marrero J.A., Hussain H.K., Nghiem H.V., Umar R., Fontana R.J., Lok A.S. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass // Liver Transpl.- 2005.- Vol. 11.- P. 281-289.Marrero J.A., Hussain H.K., Nghiem H.V., Umar R., Fontana R.J., Lok A.S. Improving the prediction of hepatocellular carcinoma in cirrhotic patients with an arterially-enhancing liver mass // Liver Transpl.- 2005.- Vol. 11.- P. 281-289.LlovetJ.M., Burroughs A., BruixJ. Hepatocellular carcinoma // Lancet.- 2003.- Vol. 362.- P. 1907-1917.LlovetJ.M., Burroughs A., BruixJ. Hepatocellular carcinoma // Lancet.- 2003.- Vol. 362.- P. 1907-1917.Flores A., Marrero J.A. Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics // Clin. Med. Insights. Oncol.- 2014.- May.- Vol. 19 (8).- P. 71-76.Flores A., Marrero J.A. Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics // Clin. Med. Insights. Oncol.- 2014.- May.- Vol. 19 (8).- P. 71-76.Parmelee D.C., Evenson M.A., Deutsch H.F. The presence of fatty acids in human alpha-fetoprotein // J. Biol. Chem.- 1978.- Vol. 253.- P. 2114-2119.Parmelee D.C., Evenson M.A., Deutsch H.F. The presence of fatty acids in human alpha-fetoprotein // J. Biol. Chem.- 1978.- Vol. 253.- P. 2114-2119.Iturralde M., Alava M.A., Gonzalez B., AnelA., Pineiro A. Effect of AFP and albumin on the uptake of polyunsaturated fatty acids byrat hepatoma cells and fetal rat hepatocytes // Biochim Biophys Acta.- 1991.- Vol. 1086.- P. 81-88.Iturralde M., Alava M.A., Gonzalez B., AnelA., Pineiro A. Effect of AFP and albumin on the uptake of polyunsaturated fatty acids byrat hepatoma cells and fetal rat hepatocytes // Biochim Biophys Acta.- 1991.- Vol. 1086.- P. 81-88.Шмагель К.В., Черешнев В.А. Альфа-фетопротеин: строение, функции и роль в эмбриогенезе // Акушерство и гинекология.- 2002.- № 5.- С. 6-8.Шмагель К.В., Черешнев В.А. Альфа-фетопротеин: строение, функции и роль в эмбриогенезе // Акушерство и гинекология.- 2002.- № 5.- С. 6-8.Johnson P.J. Tumor markers in primary malignancies of the liver. In: Diamandis E.P., Fritsch H.A, Lilja H., Chan D.W., Schwartz M.K., editors // Tumor Markers - Physiology, pathobiology, technology and clinical applications. - Washington: AACC Press, 2002.- Chapter 22.- P. 269-279.Johnson P.J. Tumor markers in primary malignancies of the liver. In: Diamandis E.P., Fritsch H.A, Lilja H., Chan D.W., Schwartz M.K., editors // Tumor Markers - Physiology, pathobiology, technology and clinical applications. - Washington: AACC Press, 2002.- Chapter 22.- P. 269-279.Абелев Г.И., Перова С.Д., Храмкова Н.И., Постникова З.А., Ирлин И.С. Эмбриональный сывороточный a-глобулин и его синтез перевиваемыми гепатомами мышей // Биохимия.- 1963.- Vol. 28.- № 4.- С. 625 - 634.Абелев Г.И., Перова С.Д., Храмкова Н.И., Постникова З.А., Ирлин И.С. Эмбриональный сывороточный a-глобулин и его синтез перевиваемыми гепатомами мышей // Биохимия.- 1963.- Vol. 28.- № 4.- С. 625 - 634.Abelev G.I., Perova S.D., Khramkova N.I., Postnikova Z.A., Irlin I.S. Production of embryonic alpha-globulin by the transplantable mouse hepatomas // Transplantation.- 1963.- Vol. 1.- P. 174 - 180.Abelev G.I., Perova S.D., Khramkova N.I., Postnikova Z.A., Irlin I.S. Production of embryonic alpha-globulin by the transplantable mouse hepatomas // Transplantation.- 1963.- Vol. 1.- P. 174 - 180.Tatarinov Yu.S. Detection of embryospecific alpha-globulin in serum of patients with primary liver cancer // In I-st All-Union Biochem Cong Abstr Book.- Moscow-Leningrad, 1963.- Vol. 2.- P. 274.Tatarinov Yu.S. Detection of embryospecific alpha-globulin in serum of patients with primary liver cancer // In I-st All-Union Biochem Cong Abstr Book.- Moscow-Leningrad, 1963.- Vol. 2.- P. 274.Volk M.L., Hernandez J.C., Su G.L., Lok A.S., Marrero J.A. Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3 // Cancer Biomark.- 2007.- Vol. 3 (1).- P. 79-87.Volk M.L., Hernandez J.C., Su G.L., Lok A.S., Marrero J.A. Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3 // Cancer Biomark.- 2007.- Vol. 3 (1).- P. 79-87.Daniele B., Bencivenga A., Megna A.S., Tinessa V. Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma // Gastroenterology.- 2004.- Nov.- Vol. 127.- 5 Suppl 1.- S. 108-112.Daniele B., Bencivenga A., Megna A.S., Tinessa V. Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma // Gastroenterology.- 2004.- Nov.- Vol. 127.- 5 Suppl 1.- S. 108-112.Gomaa A.I, Khan S.A., Leen E.L., Waked I., Taylor-Robinson S.D. Diagnosis of hepatocellular carcinoma // World J. Gastroenterol.- 2009.- 21 Mar.- Vol. 15 (11).- P. 1301 - 1314.Gomaa A.I, Khan S.A., Leen E.L., Waked I., Taylor-Robinson S.D. Diagnosis of hepatocellular carcinoma // World J. Gastroenterol.- 2009.- 21 Mar.- Vol. 15 (11).- P. 1301 - 1314.Singhal A., Jayaraman M., Dhanasekaran D.N., Kohli V. Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence // Crit Rev Oncol Hematol.- 2012.- Vol. 82.- P. 116-140.Singhal A., Jayaraman M., Dhanasekaran D.N., Kohli V. Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence // Crit Rev Oncol Hematol.- 2012.- Vol. 82.- P. 116-140.Naraki T., Kohno N., Saito H., Fujimoto Y., Ohhira M., Morita T., Kohgo Y. Gamma-carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin // Biochim. Biophys. Acta.- 2002.- Vol. 1586.- P. 287-298.Naraki T., Kohno N., Saito H., Fujimoto Y., Ohhira M., Morita T., Kohgo Y. Gamma-carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin // Biochim. Biophys. Acta.- 2002.- Vol. 1586.- P. 287-298.Baek Y.H., Lee J.H., Jang J.S., Lee S.W., Han J.Y., Jeong J.S., Choi J.C., Kim H.Y., Han S.Y. Diagnostic role and correlation with staging systems of PIVKA-II compared with AFP // Hepatogastroenterology.- 2009.- Vol. 56.- P. 763-767.Baek Y.H., Lee J.H., Jang J.S., Lee S.W., Han J.Y., Jeong J.S., Choi J.C., Kim H.Y., Han S.Y. Diagnostic role and correlation with staging systems of PIVKA-II compared with AFP // Hepatogastroenterology.- 2009.- Vol. 56.- P. 763-767.Yamamoto K., ImamuraH., Matsuyama Y., HasegawaK., Beck Y., Sugawara Y., MakuuchiM., KokudoN. Significance of alpha-fetopmtein and des-gamma-carbroxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy // Ann Surg. Oncol.- 2009.- Vol. 16.- P. 2795-2804.Yamamoto K., ImamuraH., Matsuyama Y., HasegawaK., Beck Y., Sugawara Y., MakuuchiM., KokudoN. Significance of alpha-fetopmtein and des-gamma-carbroxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy // Ann Surg. Oncol.- 2009.- Vol. 16.- P. 2795-2804.Yamamoto K., Imamura H., Matsuyama Y., Kume Y., Ikeda H., Norman G.L., Shums Z., Aoki T., Hasegawa K., Beck Y., Sugawara Y., Kokudo N. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopatho-logical variables of HCC // J Gastroenterol.- 2010.- Vol. 45.- P. 1272-1282.Yamamoto K., Imamura H., Matsuyama Y., Kume Y., Ikeda H., Norman G.L., Shums Z., Aoki T., Hasegawa K., Beck Y., Sugawara Y., Kokudo N. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopatho-logical variables of HCC // J Gastroenterol.- 2010.- Vol. 45.- P. 1272-1282.FilmusJ., Capurro M. and RastJ. Glypicans // Genome Biol.- 2008.- Vol. 9.- P. 224.FilmusJ., Capurro M. and RastJ. Glypicans // Genome Biol.- 2008.- Vol. 9.- P. 224.Shirakawa H., Kuronuma T., Nishimura Y., Hasebe T., Nakano M., Gotohda N., Takahashi S., Nakagohri T., Konishi M., Kobayashi N., Kinoshita T., Nakatsura T. Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer // Int. J. Oncol.- 2009.- Vol. 34.- P. 649-656.Shirakawa H., Kuronuma T., Nishimura Y., Hasebe T., Nakano M., Gotohda N., Takahashi S., Nakagohri T., Konishi M., Kobayashi N., Kinoshita T., Nakatsura T. Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer // Int. J. Oncol.- 2009.- Vol. 34.- P. 649-656.Guido M., Roskams T., Pontisso P., Fassan M., Thung S.N., Giacomelli L., Sergio A., Farinati F., Cillo U., Rugge M. Squamous cell carcinoma antigen in human liver carcinogenesis // J. Clin. Pathol.- 2008.- Vol. 61.- P. 445-447.Guido M., Roskams T., Pontisso P., Fassan M., Thung S.N., Giacomelli L., Sergio A., Farinati F., Cillo U., Rugge M. Squamous cell carcinoma antigen in human liver carcinogenesis // J. Clin. Pathol.- 2008.- Vol. 61.- P. 445-447.Giannelli G., Marinosci F., Sgarra C., Lupo L., Dentico P., Antonaci S. Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma // Int. J. Cancer.- 2005.- Vol. 116.- P. 579-583.Giannelli G., Marinosci F., Sgarra C., Lupo L., Dentico P., Antonaci S. Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma // Int. J. Cancer.- 2005.- Vol. 116.- P. 579-583.Beneduce L., CastaldiF., Marino M., Quarta S., Ruvoletto M., Benvegnu L., Calabrese F., Gatta A., Pontisso P., Fassina G. Squamous cell carcinoma antigen-immunoglobulin M complexes as novel biomarkers for hepatocellular carcinoma // Cancer.- 2005.- Vol. 103.- P. 2558-2565.Beneduce L., CastaldiF., Marino M., Quarta S., Ruvoletto M., Benvegnu L., Calabrese F., Gatta A., Pontisso P., Fassina G. Squamous cell carcinoma antigen-immunoglobulin M complexes as novel biomarkers for hepatocellular carcinoma // Cancer.- 2005.- Vol. 103.- P. 2558-2565.Pontisso P., Quarta S., Caberlotto C., Beneduce L., Marino M., Bernardinello E., Tono N., Fassina G., Cavalletto L., Gatta A., Chemello L. Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma // Int. J. Cancer.- 2006.- Vol. 119.- P. 735-740.Pontisso P., Quarta S., Caberlotto C., Beneduce L., Marino M., Bernardinello E., Tono N., Fassina G., Cavalletto L., Gatta A., Chemello L. Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma // Int. J. Cancer.- 2006.- Vol. 119.- P. 735-740.Shi Y., Chen J., Li L., Sun Z., Zen L., Xu S., Zhang Y., Zhang L. A study of diagnostic value of golgi protein GP73 and its genetic assay in primary hepatic carcinoma // Technol. Cancer. Res. Treat.- 2011.- Vol. 10.- P. 287-294.Shi Y., Chen J., Li L., Sun Z., Zen L., Xu S., Zhang Y., Zhang L. A study of diagnostic value of golgi protein GP73 and its genetic assay in primary hepatic carcinoma // Technol. Cancer. Res. Treat.- 2011.- Vol. 10.- P. 287-294.RienerM.O., StennerF., LiewenH., SollC., Breitenstein S., Pestalozzi BC, Samaras P, Probst-Hensch N., Hellerbrand C., MiillhauptB., ClavienP.A., Bahra M., NeuhausP., Wild P., Fritzsche F., MochH., JochumW., KristiansenG. Golgi phosphoprotein 2 (GOLPH2) expres-sionin liver tumors and its value as a serum marker in hepatocellular carcinomas // Hepatology.- 2009.- P. 49.- P. 1602-1609.RienerM.O., StennerF., LiewenH., SollC., Breitenstein S., Pestalozzi BC, Samaras P, Probst-Hensch N., Hellerbrand C., MiillhauptB., ClavienP.A., Bahra M., NeuhausP., Wild P., Fritzsche F., MochH., JochumW., KristiansenG. Golgi phosphoprotein 2 (GOLPH2) expres-sionin liver tumors and its value as a serum marker in hepatocellular carcinomas // Hepatology.- 2009.- P. 49.- P. 1602-1609.Zhou Y., YinX., Ying J., ZhangB. Golgi protein 73 versus alpha-fetoprotein as a biomarker for hepatocellular carcinoma: a diagnostic meta-analysis // B-C Cancer.- 2012.- Vol. 12.- P. 17.Zhou Y., YinX., Ying J., ZhangB. Golgi protein 73 versus alpha-fetoprotein as a biomarker for hepatocellular carcinoma: a diagnostic meta-analysis // B-C Cancer.- 2012.- Vol. 12.- P. 17.Drake R.R., Schwegler E.E., Malik G., Diaz J., Block T., Mehta A., Semmes O.J. Lectin capture strategies combined with mass spectrometry for the discovery of serum glycoprotein biomarkers // Mol. Cell. Proteomics.- 2006.- Vol. 5.- P. 1957-1967.Drake R.R., Schwegler E.E., Malik G., Diaz J., Block T., Mehta A., Semmes O.J. Lectin capture strategies combined with mass spectrometry for the discovery of serum glycoprotein biomarkers // Mol. Cell. Proteomics.- 2006.- Vol. 5.- P. 1957-1967.Joo M, ChiJ.G., Lee H. Expressions of HSP70 and HSP27 in hepatocellular carcinoma // J. Korean. Med. Sci.- 2005.- Vol. 20.- P. 829-834.Joo M, ChiJ.G., Lee H. Expressions of HSP70 and HSP27 in hepatocellular carcinoma // J. Korean. Med. Sci.- 2005.- Vol. 20.- P. 829-834.Shin E., Ryu H.S., Kim S.H., Jung H., Jang J.J., Lee K. The clinico-pathological significance of heat shock protein 70 and glutamine synthetase expression in hepatocellular carcinoma // J. Hepatobiliary. Pancreat. Sci.- 2011.- Vol. 18.- P. 544-550.Shin E., Ryu H.S., Kim S.H., Jung H., Jang J.J., Lee K. The clinico-pathological significance of heat shock protein 70 and glutamine synthetase expression in hepatocellular carcinoma // J. Hepatobiliary. Pancreat. Sci.- 2011.- Vol. 18.- P. 544-550.TremosiniS., Forner A., BoixL., Vilana R., BianchiL., ReigM., Rimola J, Rodriguez-Lope C., Ayuso C., Sole M., BruixJ. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma // Gut.- 2012.- Vol. 61.- P. 1481 - 1487.TremosiniS., Forner A., BoixL., Vilana R., BianchiL., ReigM., Rimola J, Rodriguez-Lope C., Ayuso C., Sole M., BruixJ. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma // Gut.- 2012.- Vol. 61.- P. 1481 - 1487.LukJ.M., LamC.T., Siu A.F., LamB.Y., NgI.O., Hu M.Y., Che C.M., FanS.T. Proteomic profiling of hepatocellular carcinoma in Chinese cohort reveals heat-shock proteins (Hsp27, Hsp70, GRP78) up-regulation and their associated prognostic values // Proteomics.- 2006.- Vol. 6.- P. 1049-1057.LukJ.M., LamC.T., Siu A.F., LamB.Y., NgI.O., Hu M.Y., Che C.M., FanS.T. Proteomic profiling of hepatocellular carcinoma in Chinese cohort reveals heat-shock proteins (Hsp27, Hsp70, GRP78) up-regulation and their associated prognostic values // Proteomics.- 2006.- Vol. 6.- P. 1049-1057.Giardina M.G., Matarazzo M., Varriale A., Morante R., Napoli A., Martino R. Serum alpha-L-fucosidase. A useful marker in the diagnosis of hepatocellular carcinoma // Cancer.- 1992.- Vol. 70.- P. 1044-1104.Giardina M.G., Matarazzo M., Varriale A., Morante R., Napoli A., Martino R. Serum alpha-L-fucosidase. A useful marker in the diagnosis of hepatocellular carcinoma // Cancer.- 1992.- Vol. 70.- P. 1044-1104.Lee D., Chung Y.H., Kim J.A., Lee Y.S., Lee D., JangM.K., Kim K.M., Lim Y.S., Lee H.C., Lee Y.S. Transforming growth factor beta 1 overexpres-sion is closely related to invasiveness of hepatocellular carcinoma // Oncology.- 2012.- Vol. 82.- P. 11 - 18.Lee D., Chung Y.H., Kim J.A., Lee Y.S., Lee D., JangM.K., Kim K.M., Lim Y.S., Lee H.C., Lee Y.S. Transforming growth factor beta 1 overexpres-sion is closely related to invasiveness of hepatocellular carcinoma // Oncology.- 2012.- Vol. 82.- P. 11 - 18.DongZ.Z., YaoD.F., YaoM, QiuL.W., ZongL., Wu W., WuX.H, YaoD.B., MengX.Y. Clinical impact of plasma TGF-beta1 and circulating TGF-beta1 mRNA in diagnosis of hepatocellular carcinoma // Hepatobiliary. Pancreat. Dis. Int.- 2008.- Vol. 7.- P. 288-295.DongZ.Z., YaoD.F., YaoM, QiuL.W., ZongL., Wu W., WuX.H, YaoD.B., MengX.Y. Clinical impact of plasma TGF-beta1 and circulating TGF-beta1 mRNA in diagnosis of hepatocellular carcinoma // Hepatobiliary. Pancreat. Dis. Int.- 2008.- Vol. 7.- P. 288-295.Laktionov P.P., Tamkovich S.N., Rykova E.Y., Bryzgunova O.E., Starikov A.V., Kuznetsova N.P., Sumarokov S.V., Kolomiets S.A., Sevostianova N.V., Vlassov V.V. Extracellular circulating nucleic acids in human plasma in health and disease // Nucleosides Nucleotides Nucleic Acids.- 2004.- Oct.- Vol. 23 (6-7).- P. 879-83.- URL: http://www.ncbi.nlm.nih.gov/pubmed/15560076.Laktionov P.P., Tamkovich S.N., Rykova E.Y., Bryzgunova O.E., Starikov A.V., Kuznetsova N.P., Sumarokov S.V., Kolomiets S.A., Sevostianova N.V., Vlassov V.V. Extracellular circulating nucleic acids in human plasma in health and disease // Nucleosides Nucleotides Nucleic Acids.- 2004.- Oct.- Vol. 23 (6-7).- P. 879-83.- URL: http://www.ncbi.nlm.nih.gov/pubmed/15560076.Vlassov V.V., Laktionov P.P., Rykova E.Y. Circulating nucleic acids asa potential source for cancer biomarkers // Curr. Mol. Med.- 2010.- Mar.- Vol. 10 (2).- P. 142-165.Vlassov V.V., Laktionov P.P., Rykova E.Y. Circulating nucleic acids asa potential source for cancer biomarkers // Curr. Mol. Med.- 2010.- Mar.- Vol. 10 (2).- P. 142-165.Mittra I., Nair N.K., Mishra P.K Nucleic acids in circulation: are they harmful to the host? // J. Biosci.- 2012.- Vol. 37.- P. 301-312.Mittra I., Nair N.K., Mishra P.K Nucleic acids in circulation: are they harmful to the host? // J. Biosci.- 2012.- Vol. 37.- P. 301-312.RenN., QinLX, TuH., Liu Y.K., ZhangB.H., TangZ.Y. The prognostic value of circulating plasma DNA level and its allelic imbalance on chromosome 8p in patients with hepatocellular carcinoma // J. Cancer. Res. Clin. Oncol.- 2006.- Vol. 132.- P. 399-407.RenN., QinLX, TuH., Liu Y.K., ZhangB.H., TangZ.Y. The prognostic value of circulating plasma DNA level and its allelic imbalance on chromosome 8p in patients with hepatocellular carcinoma // J. Cancer. Res. Clin. Oncol.- 2006.- Vol. 132.- P. 399-407.Fu X., WanS., HannH.W., Myers R.E, HannR.S, Au J., Chen B., Xing J., Yang H. Relative telomere length: a novel non-invasive biomark-er for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection // Eur. J. Cancer.- 2012.- Vol. 48.- P. 1014-1022.Fu X., WanS., HannH.W., Myers R.E, HannR.S, Au J., Chen B., Xing J., Yang H. Relative telomere length: a novel non-invasive biomark-er for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection // Eur. J. Cancer.- 2012.- Vol. 48.- P. 1014-1022.Scaggiante B., Dapas B., Farra R., Grassi M., Pozzato G., Giansante C., Fiotti N., Grassi G. Improving siRNA bio-distribution and minimizing side effects // Curr. Drug. Metab.-2011- Vol. 12.- P. 11-23.Scaggiante B., Dapas B., Farra R., Grassi M., Pozzato G., Giansante C., Fiotti N., Grassi G. Improving siRNA bio-distribution and minimizing side effects // Curr. Drug. Metab.-2011- Vol. 12.- P. 11-23.Grassi G., Scaggiante B., Dapas B., Farra R., Tonon F., Lamberti G., Barba A., Fiorentino S., Fiotti N, Zanconati F., Abrami M., Grassi M. Therapeutic potential of nucleic acid-based drugs in coronary hyper-proliferative vascular diseases // Curr Med Chem.- 2013.- Vol. 20.- P. 3515-3538.Grassi G., Scaggiante B., Dapas B., Farra R., Tonon F., Lamberti G., Barba A., Fiorentino S., Fiotti N, Zanconati F., Abrami M., Grassi M. Therapeutic potential of nucleic acid-based drugs in coronary hyper-proliferative vascular diseases // Curr Med Chem.- 2013.- Vol. 20.- P. 3515-3538.Fabian M.R., Sonenberg N. The mechanics of miRNAmediated gene silencing: a look under the hood of miRISC // Nat. Struct. Mol. Biol.- 2012.- Vol. 19.- P. 586-593.Fabian M.R., Sonenberg N. The mechanics of miRNAmediated gene silencing: a look under the hood of miRISC // Nat. Struct. Mol. Biol.- 2012.- Vol. 19.- P. 586-593.WiemerE.A. The role of microRNAsin cancer: no small matter // Eur J Cancer.- 2007.- Vol. 43.- P. 1529-1544.WiemerE.A. The role of microRNAsin cancer: no small matter // Eur J Cancer.- 2007.- Vol. 43.- P. 1529-1544.Gao Y., He Y., Ding J., Wu K., Hu B., Liu Y., Wu Y., Guo B., Shen Y., Landi D., Landi S, Zhou Y, Liu H. An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1alpha 3' untranslated region confers risk for hepatocellular carcinoma // Carcinogenesis.- 2009.- Vol. 30.- P. 2064-2069.Gao Y., He Y., Ding J., Wu K., Hu B., Liu Y., Wu Y., Guo B., Shen Y., Landi D., Landi S, Zhou Y, Liu H. An insertion/deletion polymorphism at miRNA-122-binding site in the interleukin-1alpha 3' untranslated region confers risk for hepatocellular carcinoma // Carcinogenesis.- 2009.- Vol. 30.- P. 2064-2069.Volinia S., Calin G.A., Liu C.G., Ambs S., Cimmino A., Petrocca F., Visone R., Iorio M., Roldo C., Ferracin M, Prueitt R.L., Yanaihara N., Lanza G., Scarpa A., Vecchione A., NegriniM, Harris C.C., Croce C.M. A microRNA expression signature of human solid tumors defines cancer gene targets // Proc. Natl. Acad. Sci.-2006.- USA.- Vol. 103.- P. 2257-2261.Volinia S., Calin G.A., Liu C.G., Ambs S., Cimmino A., Petrocca F., Visone R., Iorio M., Roldo C., Ferracin M, Prueitt R.L., Yanaihara N., Lanza G., Scarpa A., Vecchione A., NegriniM, Harris C.C., Croce C.M. A microRNA expression signature of human solid tumors defines cancer gene targets // Proc. Natl. Acad. Sci.-2006.- USA.- Vol. 103.- P. 2257-2261.Tomimaru Y., Eguchi H., Nagano H., Wada H., Kobayashi S., Marubashi S., Tanemura M., Tomokuni A., Takemasa I., Umeshita K., Kanto T., Doki Y., MoriM. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma // J. Hepatol.- 2012.- Vol. 56.- P. 167 - 175.Tomimaru Y., Eguchi H., Nagano H., Wada H., Kobayashi S., Marubashi S., Tanemura M., Tomokuni A., Takemasa I., Umeshita K., Kanto T., Doki Y., MoriM. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma // J. Hepatol.- 2012.- Vol. 56.- P. 167 - 175.Wei X., Xiang T., Ren G, Tan C., Liu R., Xu X., Wu Z. miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A // Cell. Signal.- 2013.- Vol. 25.- P. 439-446.Wei X., Xiang T., Ren G, Tan C., Liu R., Xu X., Wu Z. miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A // Cell. Signal.- 2013.- Vol. 25.- P. 439-446.Ballestar E., Esteller M. Epigenetic gene regulation in cancer // Adv. Genet.- 2008.- Vol. 61.- P. 247-267.Ballestar E., Esteller M. Epigenetic gene regulation in cancer // Adv. Genet.- 2008.- Vol. 61.- P. 247-267.CalvisiD.F., Ladu S., GordenA., FarinaM., Lee J.S., ConnerE.A., SchroederI., Factor V.M., Thorgeirsson S.S. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma // J. Clin. Invest.- 2007.- Sep.- Vol. 117 (9).- P. 2713-2722.CalvisiD.F., Ladu S., GordenA., FarinaM., Lee J.S., ConnerE.A., SchroederI., Factor V.M., Thorgeirsson S.S. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma // J. Clin. Invest.- 2007.- Sep.- Vol. 117 (9).- P. 2713-2722.NishigakiM., AoyagiK., Danjoh I., Fukaya M., Yanagihara K., Sakamoto.H, Yoshida T., SasakiH. Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays // Cancer Res.- 2005.- 15 Mar.- Vol. 65 (6).- P. 2115-2124.NishigakiM., AoyagiK., Danjoh I., Fukaya M., Yanagihara K., Sakamoto.H, Yoshida T., SasakiH. Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays // Cancer Res.- 2005.- 15 Mar.- Vol. 65 (6).- P. 2115-2124.Wu H.C., Wang Q., YangH.I., Tsai W., Chen C.J., Santella R.M. Global dna methylation levels in white blood cells as a biomarker for hepatocellular carcinoma risk: a nested case - control study // Carcinogenesis.- 2012.- Vol. 33 (7).- P. 1340 - 1345.Wu H.C., Wang Q., YangH.I., Tsai W., Chen C.J., Santella R.M. Global dna methylation levels in white blood cells as a biomarker for hepatocellular carcinoma risk: a nested case - control study // Carcinogenesis.- 2012.- Vol. 33 (7).- P. 1340 - 1345.Ho.o. g J.O., Hedberg J.J., Stro.mberg P., Svensson S. http://www.ncbi.nlm.nih.gov/pubmed/11173978 Mammalian alcohol dehydrogenase -functional and structural implications // J. Biomed. Sci.- 2001.- Jan-Feb.- Vol. 8 (1).- P. 71-76.Ho.o. g J.O., Hedberg J.J., Stro.mberg P., Svensson S. http://www.ncbi.nlm.nih.gov/pubmed/11173978 Mammalian alcohol dehydrogenase -functional and structural implications // J. Biomed. Sci.- 2001.- Jan-Feb.- Vol. 8 (1).- P. 71-76.Vasiliou V., Pappa A., Estey T. Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism // Drug Met Rev. -1994.- Vol. 36.- P. 279-299.Vasiliou V., Pappa A., Estey T. Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism // Drug Met Rev. -1994.- Vol. 36.- P. 279-299.Duygu F., KarsenH., Aksoy N., TaskinA. Relationship of oxidative stress in hepatitis B infection activity with HBV DNA and fibrosis // Ann Lab Med.- 2012.- Mar.- Vol. 32(2).- P. 113 - 118.Duygu F., KarsenH., Aksoy N., TaskinA. Relationship of oxidative stress in hepatitis B infection activity with HBV DNA and fibrosis // Ann Lab Med.- 2012.- Mar.- Vol. 32(2).- P. 113 - 118.Seitz H.K., Stickel F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism // Genes. Nutr.- 2010.- Jun.- Vol. 5 (2).- P. 121 - 128.Seitz H.K., Stickel F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism // Genes. Nutr.- 2010.- Jun.- Vol. 5 (2).- P. 121 - 128.Wang M., McIntee E.J., Cheng G., Shi Y., Villalta P.W., Hecht S.S. Identification of DNA adducts of acetaldehyde // Chem. Res. Toxicol.- 2000.- Nov.- Vol. 13 (11).- P. 1149-1157.Wang M., McIntee E.J., Cheng G., Shi Y., Villalta P.W., Hecht S.S. Identification of DNA adducts of acetaldehyde // Chem. Res. Toxicol.- 2000.- Nov.- Vol. 13 (11).- P. 1149-1157.Jelski W., Zalewski B., Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer // J. Clin. Lab. Anal.- 2008.- Vol. 22 (3).- P. 204-209.Jelski W., Zalewski B., Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer // J. Clin. Lab. Anal.- 2008.- Vol. 22 (3).- P. 204-209.

The authors declare that there are no conflicts of interest present.