vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-23-91vavilov-3978Research ArticleСИСТЕМНАЯ КОМПЬЮТЕРНАЯ БИОЛОГИЯSYSTEMS COMPUTATIONAL BIOLOGYПриоритизация потенциальных фармакологических мишеней для создания лекарств против гепатокарциномы, модулирующих внешний путь апоптоза, на основе реконструкции и анализа ассоциативных генных сетейPrioritization of potential pharmacological targets for the development of anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway: the reconstruction and analysis of associative gene networks helphttps://orcid.org/0000-0001-9433-8341ДеменковП. С.DemenkovP. S.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-2158-3252АнтроповаЕ. А.AntropovaE. A.

Новосибирск

Novosibirsk

nzhenia@bionet.nsc.ruАдамовскаяА. В.AdamovskayaA. V.

Новосибирск

Novosibirsk

МищенкоЕ. Л.MishchenkoE. I.

Новосибирск

Novosibirsk

ХлебодароваТ. М.KhlebodarovaT. M.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-0005-9155ИванисенкоТ. В.IvanisenkoT. V.

Новосибирск

Novosibirsk

ИванисенкоН. В.IvanisenkoN. V.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-7419-5168ВензельА. С.VenzelA. S.

Новосибирск

Novosibirsk

ЛаврикИ. Н.LavrikI. N.

Магдебург

Magdeburg

https://orcid.org/0000-0002-1859-4631ИванисенкоВ. А.IvanisenkoV. A.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Курчатовский геномный центр ИЦиГ СО РАН; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Kurchatov Genomic Center of ICG SB RAS; Novosibirsk State UniversityRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Курчатовский геномный центр ИЦиГ СО РАНРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationМедицинский факультет Магдебургского университета им. Отто фон ГерикеГерманияMedical Faculty, Otto von Guericke University MagdeburgGermany202311122023277784793Copyright © Деменков П.С., Антропова Е.А., Адамовская А.В., Мищенко Е.Л., Хлебодарова Т.М., Иванисенко Т.В., Иванисенко Н.В., Вензель А.С., Лаврик И.Н., Иванисенко В.А., 20232023Деменков П.С., Антропова Е.А., Адамовская А.В., Мищенко Е.Л., Хлебодарова Т.М., Иванисенко Т.В., Иванисенко Н.В., Вензель А.С., Лаврик И.Н., Иванисенко В.А.Demenkov P.S., Antropova E.A., Adamovskaya A.V., Mishchenko E.I., Khlebodarova T.M., Ivanisenko T.V., Ivanisenko N.V., Venzel A.S., Lavrik I.N., Ivanisenko V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3978

Гепатоцеллюлярная карцинома (ГЦК) – распространенный тяжелый тип рака печени, характеризующийся крайне агрессивным течением и низкой выживаемостью. Известно, что нарушения регуляции активации апоптоза являются одной из ключевых особенностей, свойственной большинству раковых клеток, что определяет фармакологическую индукцию апоптоза как важную стратегию терапии рака. Компьютерный дизайн химических соединений, способных целевым образом регулировать внешний сигнальный путь индукции апоптоза, представляет перспективный подход для создания новых эффективных средств терапии рака печени и других онкологических заболеваний. Однако в настоящее время большинство исследований посвящено фармакологическим воздействиям на внутренний (митохондриальный) путь апоптоза, тогда как внешний путь, индуцируемый посредством клеточных рецепторов смерти, остается вне поля зрения. Аберрантное метилирование генов наряду с инфекцией вирусом гепатита С считаются важными факторами риска развития ГЦК. Реконструкция генных сетей, описывающих молекулярные механизмы взаимодействия аберрантно метилированных генов с ключевыми участниками внешнего пути апоптоза, а также пути их регуляции белками вируса гепатита С, может дать важную информацию при поиске фармакологических мишеней. В настоящей работе были предложены 13 критериев приоритизации потенциальных фармакологических мишеней для создания лекарств против гепатокарциномы, модулирующих внешний путь апоптоза. В основу критериев легли показатели структурно-функциональной организации реконструированных с использованием ANDSystem генных сетей ГЦК, внешнего пути апоптоза и регуляторных путей взаимодействия «вирус – внешний путь апоптоза» и «аберрантное метилирование генов – внешний путь апоптоза». Список наиболее приоритетных 100 генов-мишеней, ранжированных согласно рейтингу приоритизации, оказался статистически значимо ( p-value = 0.0002) обогащен известными фармакологическими мишенями, одобренными FDA, что указывает на корректность примененного метода приоритизации. Среди перспективных потенциальных фармакологических мишеней могут быть представлены шесть генов-кандидатов (JUN, IL10, STAT3, MYC, TLR4 и KHDRBS1), занимающих высокое положение в ранжированном списке согласно результатам приоритизации. 

Hepatocellular carcinoma (HCC) is a common severe type of liver cancer characterized by an extremely aggressive course and low survival rates. It is known that disruptions in the regulation of apoptosis activation are some of the key features inherent in most cancer cells, which determines the pharmacological induction of apoptosis as an important strategy for cancer therapy. The computer design of chemical compounds capable of specifically regulating the external signaling pathway of apoptosis induction represents a promising approach for creating new effective ways of therapy for liver cancer and other oncological diseases. However, at present, most of the studies are devoted to pharmacological effects on the internal (mitochondrial) apoptosis pathway. In contrast, the external pathway induced via cell death receptors remains out of focus. Aberrant gene methylation, along with hepatitis C virus (HCV) infection, are important risk factors for the development of hepatocellular carcinoma. The reconstruction of gene networks describing the molecular mechanisms of interaction of aberrantly methylated genes with key participants of the extrinsic apoptosis pathway and their regulation by HCV proteins can provide important information when searching for pharmacological targets. In the present study, 13 criteria were proposed for prioritizing potential pharmacological targets for developing anti-hepatocarcinoma drugs modulating the extrinsic apoptosis pathway. The criteria are based on indicators of the structural and functional organization of reconstructed gene networks of hepatocarcinoma, the extrinsic apoptosis pathway, and regulatory pathways of virus-extrinsic apoptosis pathway interaction and aberrant gene methylation-extrinsic apoptosis pathway interaction using ANDSystem. The list of the top 100 gene targets ranked according to the prioritization rating was statistically significantly (p-value = 0.0002) enriched for known pharmacological targets approved by the FDA, indicating the correctness of the prioritization method. Among the promising potential pharmacological targets, six highly ranked genes (JUN, IL10, STAT3, MYC, TLR4, and KHDRBS1) are likely to deserve close attention. 

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