Biomarkers of hepatocellular carcinoma: status and prospects
Zorina E.S.1, Naryzhny S.N.2
1. Institute of Biomedical Chemistry, Moscow, Russia 2. Petersburg Institute of Nuclear Physics B.P. Konstantinova National Research Center “Kurchatov Institute”, Gatchina, Leningrad Region, Russia
Hepatocellular carcinoma (HCC) also known as hepatocellular cancer is one of the most common and aggressive types of primary malignant liver neoplasms. This type of cancer accounts for up to 90% of all primary liver tumors and is the third leading cause of cancer death worldwide. Despite the advances in modern medicine, diagnostics and treatment of HCC remain challenging, especially in the later stages, when the patient's prognosis significantly worsens and treatment options are very limited. More than half a century has passed since Yu.S. Tatarinov discovered embryo-specific α-globulin in the blood of people with primary liver cancer in 1963, which was later called alpha-fetoprotein (AFP), but unfortunately, the number of specific and sensitive biomarkers for HCC remains very limited. In this regard, many scientific papers are devoted to the search and study of potential HCC biomarkers, which are essential for early diagnostics, prognosis, and development of new therapeutic strategies. Proteomic studies represent one of the promising approaches to investigate both molecular mechanisms of HCC occurrence and HCC biomarkers. Identification of specific protein profiles characteristic of tumor cells can contribute to the identification of new biomarkers that can be used not only for early detection of the disease, but also for monitoring its progression, assessing the response to therapy and predicting the clinical outcome. This review discusses current achievements in the search for potential biomarkers of HCC, as well as the prospects for their clinical use.
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Keywords: hepatocellular cancer, biomarkers, protein profiles, proteoforms
Citation:
Zorina E.S., Naryzhny S.N. (2025) Biomarkers of hepatocellular carcinoma: status and prospects. Biomeditsinskaya Khimiya, 71(1), 7-18.
Zorina E.S. et al. Biomarkers of hepatocellular carcinoma: status and prospects // Biomeditsinskaya Khimiya. - 2025. - V. 71. -N 1. - P. 7-18.
Zorina E.S. et al., "Biomarkers of hepatocellular carcinoma: status and prospects." Biomeditsinskaya Khimiya 71.1 (2025): 7-18.
Zorina, E. S., Naryzhny, S. N. (2025). Biomarkers of hepatocellular carcinoma: status and prospects. Biomeditsinskaya Khimiya, 71(1), 7-18.
References
Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CACancer J. Clin., 74(3), 229–263. CrossRef Scholar google search
Aleksandrova G.A., Akhmetzyanova R.R., Golubev N.A., Kirillova G.N., Ogryzko E.V., Oskov Yu.I., Romanenko O.I., Kharkova T.L., Chumarina V.G. (2023) Healthcare in Russia 2023. Federal State Statistics Service (Rosstat), pp. 1–179. Scholar google search
Park J.-W., Chen M., Colombo M., Roberts L.R., Schwartz M., Chen P.-J., Kudo M., Johnson P., Wagner S., Orsini L.S., Sherman M. (2015) Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int., 35(9), 2155–2166. CrossRef Scholar google search
El-Serag H.B. (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology, 142(6), 1264–1273e1. CrossRef Scholar google search
Zamor P.J., de Lemos A.S., Russo M.W. (2017) Viral hepatitis and hepatocellular carcinoma: etiology and management. J. Gastrointest. Oncol., 8(2), 229–242. CrossRef Scholar google search
Arzumanyan A., Reis H.M.G.P.V., Feitelson M.A. (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer, 13(2), 123–135. CrossRef Scholar google search
Ganne-Carrie N., Nahon P. (2019) Hepatocellular carcinoma in the setting of alcohol-related liver disease. J. Hepatology, 70(2), 284–293. CrossRef Scholar google search
Huang D., Mathurin P., Cortez-Pinto H., Loomba R. (2023) Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat. Rev. Gastroenterol. Hepatol., 20(1), 37–49. CrossRef Scholar google search
Schlageter M., Terracciano L., d’Angelo S., Sorrentino P. (2014) Histopathology of hepatocellular carcinoma. World J. Gastroenterol., 20(43), 15955–15964. CrossRef Scholar google search
Nepomnyashchaya E.M., Shaposhnikov A.V., Yurieva E.A. (2020) Hepatocellular carcinoma: New provisions of the WHO classification, 5th edition, 2019. Russian Journal of Archive of Pathology, 82(6), 36–40. CrossRef Scholar google search
Tarao K., Nozaki A., Ikeda T., Sato A., Komatsu H., Komatsu T., Taguri M., Tanaka K. (2019) Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment. Cancer Med., 8(3), 1054–1065. CrossRef Scholar google search
Samant H., Amiri H.S., Zibari G.B. (2020) Addressing the worldwide hepatocellular carcinoma: Epidemiology, prevention and management. J. Gastrointest. Oncol., 12(2), S361–S373. CrossRef Scholar google search
Song B.G., Choi S.C., Goh M.J., Kang W., Sinn D.H., Gwak G.-Y., Paik Y.-H., Choi M.S., Lee J.H., Paik S.W. (2023) Metabolic dysfunction-associated fatty liver disease and the risk of hepatocellular carcinoma. JHEP Reports, 5(9), 100810. CrossRef Scholar google search
Talamantes S., Lisjak M., Gilglioni E.H., Llamoza-Torres C.J., Ramos-Molina B., Gurzov E.N. (2023) Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Reports, 5(9), 100811. CrossRef Scholar google search
Fang J., Celton-Morizur S., Desdouets C. (2023) NAFLD-related HCC: focus on the latest relevant preclinical models. Cancers, 15(14), 3723. CrossRef Scholar google search
Phoolchund A.G.S., Khakoo S.I. (2024) MASLD and the development of HCC: pathogenesis and therapeutic challenges. Cancers, 16(2), 259. CrossRef Scholar google search
Guse’nov A.Z., Guse’nov T.A. (2016) Modern diagnostics of liver cancer (literature review). Journal of New Medical Technologies, 10(4), 359–377. CrossRef Scholar google search
Kushlinsky N.E., Lyubimova N.V. (2016) Tumor markers. General characteristics, clinical significance and recommendations for use. Poliklinika, Special issue 8, 62–77. Scholar google search
Kuo P.-C., Chen S.-C., Shyr Y.-M., Kuo Y.-J., Lee R.-C., Wang S.-E. (2015) Hepatoid carcinoma of the pancreas. World J. Surg. Oncol., 13(1), 185. CrossRef Scholar google search
Pedrazzoli P., Rosti G., Soresini E., Ciani S., Secondino S. (2021) Serum tumour markers in germ cell tumours: from to cure. Crit. Rev. Oncol. Hematol., 159, 103224. CrossRef Scholar google search
O’Neill A.F., Xia C., Krailo M.D., Shaikh F., Pashankar F.D., Billmire D.F., Olson T.A., Amatruda J.F., Villaluna D., Huang L., Malogolowkin M., Rodriguez-Galindo C., Frazier A.L. (2019) α-Fetoprotein as a predictor of outcome for children with germ cell tumors: a report from the Malignant Germ Cell International Consortium. Cancer, 125(20), 3649–3656. CrossRef Scholar google search
Głowska-Ciemny J., Szmyt K., Kuszerska A., Rzepka R., von Kaisenberg C., Kocyłowski R. (2024) Fetal and placental causes of elevated serum alpha-fetoprotein levels in pregnant women. J. Clin. Med., 13(2), 466. CrossRef Scholar google search
Wang X., Shen C., Yang J., Yang X., Qin S., Zeng H., Wu X., Tang S., Zeng W. (2018) Alpha-fetoprotein as a predictive marker for patients with hepatitis B-related acute-on-chronic liver failure. Can. J. Gastroenterol. Hepatol., 2018(1), 1232785. CrossRef Scholar google search
Sia D., Villanueva A., Friedman S.L., Llovet J.M. (2017) Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology, 152(4), 745–761. CrossRef Scholar google search
Chuang S.-C., la Vecchia C., Boffetta P. (2009) Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett., 286(1), 9–14. CrossRef Scholar google search
Karabork A., Kaygusuz G., Ekinci C. (2010) The best immunohistochemical panel for differentiating hepatocellular carcinoma from metastatic adenocarcinoma. Pathol. Res. Pract., 206(8), 572–577. CrossRef Scholar google search
Pinheiro P.S., Jones P.D., Medina H., Cranford H.M., Koru-Sengul T., Bungum T., Wong R., Kobetz E.N., McGlynn K.A. (2024) Incidence of etiology-specific hepatocellular carcinoma: diverging trends and significant heterogeneity by race and ethnicity. Clin. Gastroenterol. Hepatol., 22(3), 562–571.e8. CrossRef Scholar google search
Chidambaranathan-Reghupaty S., Fisher P.B., Sarkar D. (2021) Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification. Adv. Cancer Res., 149, 1–61. CrossRef Scholar google search
Manzoni C., Kia D.A., Vandrovcova J., Hardy J., Wood N.W., Lewis P.A., Ferrari R. (2018) Genome, transcriptome and proteome: the rise of omics data and their integration in biomedical sciences. Brief. Bioinform., 19(2), 286–302. CrossRef Scholar google search
Substantial equivalence determination decision summary assay and instrument combination. Review memorandum K100464. Retrieved May 15, 2024, from: https://www.accessdata.fda.gov/cdrh_docs/reviews/ K100464.pdf. Scholar google search
Behne T., Copur M.S. (2012) Biomarkers for hepatocellular carcinoma. Int. J. Hepatol., 2012, 859076. CrossRef Scholar google search
Tatarinov Yu.S. (1964) Detection of embryo-specific alpha-globulin in the blood serum of a patient with primary liver cancer. Voprosy Meditsinskoy Khimii, 10(1), 90–91. Scholar google search
He C., Peng W., Liu X., Li C., Li X., Wen T.-F. (2019) Post-treatment alpha-fetoprotein response predicts prognosis of patients with hepatocellular carcinoma: a meta-analysis. Medicine, 98(31), e16557. CrossRef Scholar google search
Hu X., Chen R., Wei Q., Xu X. (2022) The landscape of alpha fetoprotein in hepatocellular carcinoma: where are we? Int. J. Biol. Sci., 18(2), 536–551. CrossRef Scholar google search
Clinical guidelines “Liver Cancer (Hepatocellular)”. Ministry of Health of the Russian Federation. Retrieved September 9, 2023, from: https://oncology-association.ru/wp-content/uploads/ 2020/09/rak_pecheni.pdf. Scholar google search
Li D., Mallory T., Satomura S. (2001) AFP-L3: a new generation of tumor marker for hepatocellular carcinoma. Clin. Chim. Acta, 313(1), 15–19. CrossRef Scholar google search
Wang J., Wang F., Wang N., Zhang M.-Y., Wang H.-Y., Huang G.-L. (2023) Diagnostic and prognostic value of protein post-translational modifications in hepatocellular carcinoma. J. Clin. Transl. Hepatol., 11(5), 1192–1200. CrossRef Scholar google search
DCP Test. Retrieved August 05, 2024, from: https://healthcaresolutions-us.fujifilm.com/products/ in-vitro-diagnostics/hcc-risk-biomarkers/dcp-test/. Scholar google search
Feng X., Song P., Bie P., Jiang P., Ma K., Li X., Wang S., Wang Z., Tang W., Zheng S. (2016) Des-γ-carboxyprothrombin plasma level in diagnosis of hepatocellular carcinoma in a Chinese population undergoing surgery. Med. Sci. Monit., 22, 1663–1672. CrossRef Scholar google search
Devan A.R., Nair B., Pradeep G.K., Alexander R., Vinod B.S., Nath L.R., Calina D., Sharifi-Rad J. (2024) The role of glypican-3 in hepatocellular carcinoma: insights into diagnosis and therapeutic potential. Eur. J. Med. Res., 29(1), 490. CrossRef Scholar google search
BioCity announces FDAclearance of the investigational new drug application for its frst-in-class antibody drug conjugate targeting glypican 3_iGPC3). Retrieved June 06, 2024, from: https://www.biocitypharma.com/news/item?id=43. Scholar google search
Shafizadeh N., Kakar S. (2011) Diagnosis of well-differentiated hepatocellular lesions: role of immunohistochemistry and other ancillary techniques. Adv. Anat. Pathol., 18(6), 438–445. CrossRef Scholar google search
Chau G.-Y., Lui W.-Y., Chi C.-W., Chau Y.-P., Li A.-F., Kao H.-L., Wu C.-W. (2008) Significance of serum hepatocyte growth factor levels in patients with hepatocellular carcinoma undergoing hepatic resection. Eur. J. Surg. Oncol., 34(3), 333–338. CrossRef Scholar google search
Wang H., Rao B., Lou J., Li J., Liu Z., Li A., Cui G., Ren Z., Yu Z. (2020) The function of the HGF/c-Met axis in hepatocellular carcinoma. Front. Cell Dev. Biol., 8, 55. CrossRef Scholar google search
Chen J., Dai W., Zhu C., Liu H., Li Y., Zhang P. (2020) Circulating levels of growth differentiation factor 15 and sex hormones in male patients with HBV-associated hepatocellular carcinoma. Biomed. Pharmacother., 121, 109574. CrossRef Scholar google search
Li Y., Zhang J., Chen S., Ke Y., Li Y., Chen Y. (2024) Growth differentiation factor 15: emerging role in liver diseases. Cytokine, 182, 156727. CrossRef Scholar google search
Du Y.-N., Zhao J.-W. (2024) GDF15: immunomodulatory role in hepatocellularcarcinoma pathogenesis and therapeutic implications. J. Hepatocell. Carcinoma, 11, 1171–1183. CrossRef Scholar google search
Zhang X., Wu L.-N., Li X.-Q., Luo X., Liu S.-W., Zhang L., Nawaz S., Ma L.-N., Ding X.-C. (2023) Whether the Golgi protein 73 could be a diagnostic serological marker in hepatocellular carcinoma: a meta analysis. BMC Gastroenterol., 23(1), 85. CrossRef Scholar google search
Wang Y., Wan Y.-J.Y. (2020) Golgi protein 73, hepatocellular carcinoma and other types of cancers. Liver Res., 4(4), 161–167. CrossRef Scholar google search
Matsui D., Nagai H., Mukozu T., Ogino Y., Sumino Y. (2015) VEGF in patients with advanced hepatocellular carcinoma receiving intra-arterial chemotherapy. Anticancer Res., 35(4), 2205–2210. Scholar google search
Zucman-Rossi J., Villanueva A., Nault J.-C., Llovet J.M. (2015) Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology, 149(5), 1226–1239. CrossRef Scholar google search
Huang Z., Zhou P., Li S., Li K. (2022) Prediction of the Ki-67 marker index in hepatocellular carcinoma based on dynamic contrast-enhanced ultrasonography with sonazoid. Insights Imaging, 13(1), 199. CrossRef Scholar google search
Qiu L.-W., Liu Y.-F., Cao X.-Q., Wang Y., Cui X.-H., Ye X., Huang S.-W., Xie H.-J., Zhang H.-J. (2020) Annexin A2 promotion of hepatocellular carcinoma tumorigenesis via the immune microenvironment. World J. Gastroenterol., 26(18), 2126–2137. CrossRef Scholar google search
Zhang H.-J., Yao D.-F., Yao M., Huang H., Wu W., Yan M.-J., Yan X.-D., Chen J. (2012) Expression characteristics and diagnostic value of annexin A2 in hepatocellular carcinoma. World J. Gastroenterol., 18(41), 5897–5904. CrossRef Scholar google search
Mohammad H.S., Kurokohchi K., Yoneyama H., Tokuda M., Morishita A., Jian G., Shi L., Murota M., Tani J., Kato K., Miyoshi H., Deguchi A., Himoto T., Usuki H., Wakabayashi H., Izuishi K., Suzuki Y., Iwama H., Deguchi K., Uchida N., Sabet E.A., Arafa U.A., Hassan A.T., El-Sayed A.A., Masaki T. (2008) Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma. Int. J. Oncol., 33(6), 1157–1163. CrossRef Scholar google search
El-Abd N., Fawzy A., Elbaz T., Hamdy S. (2016) Evaluation of annexin A2 and as potential biomarkers for hepatocellular carcinoma. Tumor Biol., 37(1), 211–216. CrossRef Scholar google search
Zhang H., Yao M., Wu W., Qiu L., Sai W., Yang J., Zheng W., Huang J., Yao D. (2015) Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma. Tumor Biol., 36(12), 9373–9383. CrossRef Scholar google search
Tang L., Liu J.-X., Zhang Z.-J., Xu C.-Z., Zhang X.-N., Huang W.-R., Zhou D.-H., Wang R.-R., Chen X.-D., Xiao M.-B., Qu L.-S., Lu C.-H. (2019) High expression of ANXA2 and STAT3 promote progression of hepatocellular carcinoma and predict poor prognosis. Pathol. Res. Pract., 215(6), 152386. CrossRef Scholar google search
Morishita A., Oura K., Tadokoro T., Fujita K., Tani J., Masaki T. (2021) MicroRNAs in the pathogenesis of hepatocellular carcinoma: a review. Cancers, 13(3), 514. CrossRef Scholar google search
Gramantieri L., Fornari F., Callegari E., Sabbioni S., Lanza G., Croce C.M., Bolondi L., Negrini M. (2008) MicroRNA involvement in hepatocellular carcinoma. J. Cell. Mol. Med., 12(6A), 2189–2204. CrossRef Scholar google search
Xu X., Tao Y., Shan L., Chen R., Jiang H., Qian Z., Cai F., Ma L., Yu Y. (2018) The role of microRNAs in hepatocellular carcinoma. J. Cancer, 9(19), 3557–3569. CrossRef Scholar google search
Singh P., Solanki R., Tasneem A., Suri S., Kaur H., Shah S.R., Dohare R. (2024) Screening of miRNAs as prognostic biomarkers and their associated hub targets across hepatocellular carcinoma using survival-based bioinformatics approach. J. Genet. Eng. Biotechnol., 22(1), 100337. CrossRef Scholar google search
Lv Y., Sun X. (2024) Role of miRNA in pathogenesis, diagnosis, and prognosis in hepatocellular carcinoma. Chem. Biol. Drug Des., 103(1), e14352. CrossRef Scholar google search
El Hayek T., Alnaser-Almusa O.A., Alsalameh S.M., Alhalabi M.T., Sabbah A.N., Alshehri E.A., Mir T.A., Mani N.K., Al-Kattan K., Chinnappan R., Yaqinuddin A. (2024) Emerging role of exosomal microRNA in liver cancer in the era of precision medicine; potential and challenges. Front. Mol. Biosci., 11, 1381789. CrossRef Scholar google search
Bardol T., Pageaux G.-P., Assenat E., Alix-Panabières C. (2024) Circulating tumor DNA clinical applications in hepatocellular carcinoma: current trends and future perspectives. Clin. Chem., 70(1), 33–48. CrossRef Scholar google search
Ikeda S., Tsigelny I.F., Skjevik Å.A., Kono Y., Mendler M., Kuo A., Sicklick J.K., Heestand G., Banks K.C., Talasaz A., Lanman R.B., Lippman S., Kurzrock R. (2018) Next-generation sequencing of circulating tumor DNA reveals frequent alterations in advanced hepatocellular carcinoma. Oncologist, 23(5), 586–593. CrossRef Scholar google search
von Felden J., Craig A.J., Garcia-Lezana T., Labgaa I., Haber P.K., d’Avola D., Asgharpour A., Dieterich D., Bonaccorso A., Torres-Martin M., Sia D., Sung M.W., Tabrizian P., Schwartz M., Llovet J.M., Villanueva A. (2021) Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene, 40(1), 140–151. CrossRef Scholar google search
Li Y., Zheng Y., Wu L., Li J., Ji J., Yu Q., Dai W., Feng J., Wu J., Guo C. (2021) Current status of ctDNA in precision oncology for hepatocellular carcinoma. J. Exper. Clin. Cancer Res., 40(1), 140. CrossRef Scholar google search
Ye Q., Ling S., Zheng S., Xu X. (2019) Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. Mol. Cancer, 18(1), 114. CrossRef Scholar google search
Wu X., Li J., Gassa A., Buchner D., Alakus H., Dong Q., Ren N., Liu M., Odenthal M., Stippel D., Bruns C., Zhao Y., Wahba R. (2020) Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int. J. Biol. Sci., 16(9), 1551–1562. CrossRef Scholar google search
Rebouissou S., Franconi A., Calderaro J., Letouzé E., Imbeaud S., Pilati C., Nault J.-C., Couchy G., Laurent A., Balabaud C., Bioulac-Sage P., Zucman-Rossi J. (2016) Genotype-phenotype correlation of CTNNB1 mutations reveals different β-catenin activity associated with liver tumor progression. Hepatology, 64(6), 2047–2061. CrossRef Scholar google search
Ding X., Yang Y., Han B., Du C., Xu N., Huang H., Cai T., Zhang A., Han Z.-G., Zhou W., Chen L. (2014) Transcriptomic characterization of hepatocellular carcinoma with CTNNB1 mutation. PLOS One, 9(5), e95307. CrossRef Scholar google search
Lehrich B.M., Tao J., Liu S., Hirsch T.Z., Yasaka T.M., Cao C., Delgado E.R., Guan X., Lu S., Pan L., Liu Y., Singh S., Poddar M., Bell A., Singhi A.D., Zucman-Rossi J., Wang Y., Monga S.P. (2024) Development of mutated β-catenin gene signature to identify CTNNB1 mutations from whole and spatial transcriptomic data in patients with HCC. JHEP Reports, 6(12), 101186. CrossRef Scholar google search
Tornesello M.L., Buonaguro L., Tatangelo F., Botti G., Izzo F., Buonaguro F.M. (2013) Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics, 102(2), 74–83. CrossRef Scholar google search
Yang C., Huang X., Li Y., Chen J., Lv Y., Dai S. (2021) Prognosis and personalized treatment prediction in TP53-mutant hepatocellular carcinoma: an in silico strategy towards precision oncology. Brief. Bioinform., 22(3), bbaa164. CrossRef Scholar google search
Hussain S.P., Schwank J., Staib F., Wang X.W., Harris C.C. (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene, 26(15), 2166–2176. CrossRef Scholar google search
Long J., Wang A., Bai Y., Lin J., Yang X., Wang D., Yang X., Jiang Y., Zhao H. (2019) Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma. eBioMedicine, 42, 363–374. CrossRef Scholar google search
Fu S., Debes J.D., Boonstra A. (2023) DNA methylation markers in the detection of hepatocellular carcinoma. Eur. J. Cancer, 191, 112960. CrossRef Scholar google search
Ma L.-N., Liu X.-Y., Lu Z.-H., Wu L.-G., Tang Y.-Y., Luo X., Hu Y.-C., Yan T.-T., Wang Q., Ding X.-C., Xie Y. (2017) Assessment of high-sensitivity C-reactive protein tests for the diagnosis of hepatocellular carcinoma in patients with hepatitis B-associated liver cirrhosis. Oncol. Lett., 13(5), 3457–3464. CrossRef Scholar google search
Sieghart W., Pinter M., Hucke F., Graziadei I., Schöniger-Hekele M., Müller C., Vogel W., Trauner M., Peck-Radosavljevic M. (2013) Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma. Hepatology, 57(6), 2224–2234. CrossRef Scholar google search
Jang J.W., Oh B.S., Kwon J.H., You C.R., Chung K.W., Kay C.S., Jung H.S. (2012) Serum interleukin-6 and C-reactive protein as a prognostic indicator in hepatocellular carcinoma. Cytokine, 60(3), 686–693. CrossRef Scholar google search
Nagaoka S., Yoshida T., Akiyoshi J., Akiba J., Torimura T., Adachi H., Kurogi J., Tajiri N., Inoue K., Niizeki T., Koga H., Imaizumi T., Kojiro M., Sata M. (2007) Serum C-reactive protein levels predict survival in hepatocellular carcinoma. Liver Int., 27(8), 1091–1097. CrossRef Scholar google search
Du J., Huang Z., Zhang E. (2024) Nomograms confirm serum IL-6 and CRP as predictors of immune checkpoint inhibitor efficacy in unresectable hepatocellular carcinoma. Front. Immunol., 15, 1329634. CrossRef Scholar google search
Tanouti I.-A., Fellah H., Haddaji A., Zerrad C., Tahiri M., Badre W., Nfaoui K., Pineau P., Benjelloun S., Ezzikouri S. (2024) High plasma interleukin-6 level, but not IL-6 gene variants, as a predictive marker for the development of hepatocellular carcinoma in a Moroccan population. Int. J. Immunogenet., 51(4), 206–216. CrossRef Scholar google search
Porta C., de Amici M., Quaglini S., Paglino C., Tagliani F., Boncimino A., Moratti R., Corazza G.R. (2008) Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann. Oncol., 19(2), 353–358. CrossRef Scholar google search
Mallela V.R., Rajtmajerová M., Trailin A., Liška V., Hemminki K., Ambrozkiewicz F. (2024) miRNA and lncRNA as potential tissue biomarkers in hepatocellular carcinoma. Non-coding RNA Res., 9(1), 24–32. CrossRef Scholar google search
Karakatsanis A., Papaconstantinou I., Gazouli M., Lyberopoulou A., Polymeneas G., Voros D. (2013) Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol. Carcinog., 52(4), 297–303. CrossRef Scholar google search
Zhang B., Zhu B., Yu J., Liu H., Zhou Y., Sun G., Ma Y., Luan Y., Chen M. (2025) A combined model of six serum microRNAs as diagnostic markers for hepatocellular carcinoma. Clin. Chim. Acta, 565, 119977. CrossRef Scholar google search
Qu J., Yang J., Chen M., Cui L., Wang T., Gao W., Tian J., Wei R. (2019) MicroRNA-21 as a diagnostic marker for hepatocellular carcinoma: a systematic review and meta-analysis. Pak. J. Med. Sci., 35(5), 1466–1471. CrossRef Scholar google search
Xue X., Li Y., Yao Y., Zhang S., Peng C., Li Y. (2024) A comprehensive review of miR-21 in liver disease: big impact of little things. Int. Immunopharmacol., 134, 112116. CrossRef Scholar google search
Giordo R., Ahmadi F.A.M., Husaini N.A., Al-Nuaimi N.R.A.M., Ahmad S.M.S., Pintus G., Zayed H. (2024) microRNA 21 and long non-coding RNAs interplays underlie cancer pathophysiology: a narrative review. Non-coding RNA Res., 9(3), 831–852. CrossRef Scholar google search
Chun K.-H. (2022) Molecular targets and signaling pathways of microRNA-122 in hepatocellular carcinoma. Pharmaceutics, 14(7), 1380. CrossRef Scholar google search
Tsai W.-C., Hsu P.W.-C., Lai T.-C., Chau G.-Y., Lin C.-W., Chen C.-M., Lin C.-D., Liao Y.-L., Wang J.-L., Chau Y.-P., Hsu M.-T., Hsiao M., Huang H.-D., Tsou A.-P. (2009) MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology, 49(5), 1571–1582. CrossRef Scholar google search
Bandiera S., Pfeffer S., Baumert T.F., Zeisel M.B. (2015) miR-122 — a key factor and therapeutic target in liver disease. J. Hepatology, 62(2), 448–457. CrossRef Scholar google search
Colaianni F., Zelli V., Compagnoni C., Miscione M.S., Rossi M., Vecchiotti D., di Padova M., Alesse E., Zazzeroni F., Tessitore A. (2024) Role of circulating microRNAs in liver disease and HCC: focus on miR-122. Genes, 15(10), 1313. CrossRef Scholar google search
Song Q., An Q., Niu B., Lu X., Zhang N., Cao X. (2019) Role of miR-221/222 in tumor development and the underlying mechanism. J. Oncology, 2019, 7252013. CrossRef Scholar google search
Li C., Li Y., Lu Y., Niu Z., Zhao H., Peng Y., Li M. (2021) miR-26 family and its target genes in tumorigenesis and development. Crit. Rev. Oncol. Hematol., 157, 103124. CrossRef Scholar google search
Chang L., Li K., Guo T. (2017) miR-26a-5p suppresses tumor metastasis by regulating EMT and is associated with prognosis in HCC. Clin. Transl. Oncol., 19(6), 695–703. CrossRef Scholar google search
Johnson P.J., Pirrie S.J., Cox T.F., Berhane S., Teng M., Palmer D., Morse J., Hull D., Patman G., Kagebayashi C., Hussain S., Graham J., Reeves H., Satomura S. (2014) The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol. Biomarkers Prev., 23(1), 144–153. CrossRef Scholar google search
Wang M., Devarajan K., Singal A.G., Marrero J.A., Dai J., Feng Z., Rinaudo J.A.S., Srivastava S., Evans A., Hann H.-W., Lai Y., Yang H., Block T.M., Mehta A. (2016) The Doylestown algorithm: a test to improve the performance of AFP in the detection of hepatocellular carcinoma. Cancer Prev. Res., 9(2), 172–179. CrossRef Scholar google search
Wang M., Sanda M., Comunale M.A., Herrera H., Swindell C., Kono Y., Singal A.G., Marrero J., Block T., Goldman R., Mehta A. (2017) Changes in the glycosylation of kininogen and the development of a kininogen-based algorithm for the early detection of HCC. Cancer Epidemiol. Biomarkers Prev., 26(5), 795–803. CrossRef Scholar google search
Yang J.D., Addissie B.D., Mara K.C., Harmsen W.S., Dai J., Zhang N., Wongjarupong N., Ali H.M., Ali H.A., Hassan F.A., Lavu S., Cvinar J.L., Giama N.H., Moser C.D., Miyabe K., Allotey L.K., Algeciras-Schimnich A., Theobald J.P., Ward M.M., Nguyen M.H., Befeler A.S., Reddy K.R., Schwartz M., Harnois D.M., Yamada H., Srivastava S., Rinaudo J.A., Gores G.J., Feng Z., Marrero J.A., Roberts L.R. (2019) GALAD score for hepatocellular carcinoma detection in comparison with liver ultrasound and proposal of GALADUS score. Cancer Epidemiol. Biomarkers Prev., 28(3), 531–538. CrossRef Scholar google search
Singal A.G., Tayob N., Mehta A., Marrero J.A., Jin Q., Lau J., Parikh N.D. (2022) Doylestown Plus and GALAD demonstrate high sensitivity for HCC detection in patients with cirrhosis. Clin. Gastroenterol. Hepatol., 20(4), 953–955.e2. CrossRef Scholar google search
Pai S., Parikh N.D. (2024) Novel blood-based biomarkers for HCC. Curr. Hepatol. Rep., 23(1), 174–184. CrossRef Scholar google search
Norman J.S., Li P.J., Kotwani P., Shui A.M., Yao F., Mehta N. (2023) AFP-L3 and DCP strongly predict early hepatocellular carcinoma recurrence after liver transplantation. J. Hepatology, 79(6), 1469–1477. CrossRef Scholar google search
Oka H., Saito A., Ito K., Kumada T., Satomura S., Kasugai H., Osaki Y., Seki T., Kudo M., Tanaka M. (2001) Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein. J. Gastroenterol. Hepatol., 16(12), 1378–1383. CrossRef Scholar google search
Cheng J., Wang W., Zhang Y., Liu X., Li M., Wu Z., Liu Z., Lv Y., Wang B. (2014) Prognostic role of pre-treatment serum AFP-L3% in hepatocellular carcinoma: systematic review and meta-analysis. PLOS One, 9(1), e87011. CrossRef Scholar google search
Zinkin N.T., Grall F., Bhaskar K., Otu H.H., Spentzos D., Kalmowitz B., Wells M., Guerrero M., Asara J.M., Libermann T.A., Afdhal N.H. (2008) Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin. Cancer Res., 14(2), 470–477. CrossRef Scholar google search
Cummings J., Apostolova L., Rabinovici G.D., Atri A., Aisen P., Greenberg S., Hendrix S., Selkoe D., Weiner M., Petersen R.C., Salloway S. (2023) Lecanemab: appropriate use recommendations. J. Prev. Alzheimers Dis., 10(3), 362–377. CrossRef Scholar google search
Cheng K., Shi J., Liu Z., Jia Y., Qin Q., Zhang H., Wan S., Niu Z., Lu L., Sun J., Xue J., Lu C., Wei X., Guo L., Zhang F., Zhou D., Tang Y., Hu Y., Huang Y., Chen Y., Lau W.Y., Cheng S., Liu S. (2020) A panel of five plasma proteins for the early diagnosis of hepatitis B virus-related hepatocellular carcinoma in individuals at risk. eBioMedicine, 52, 102638. CrossRef Scholar google search
Zhao S., Long M., Zhang X., Lei S., Dou W., Hu J., Du X., Liu L. (2020) The diagnostic value of the combination of Golgi protein 73, glypican-3 and alpha-fetoprotein in hepatocellular carcinoma: a diagnostic meta-analysis. Ann. Transl. Med., 8(8), 536. CrossRef Scholar google search
Cao W.-Q., Jiang B.-Y., Huang J.-M., Zhang L., Liu M.-Q., Yao J., Wu M.-X., Zhang L.-J., Kong S.-Y., Wang Y., Yang P.-Y. (2019) Straightforward and highly efficient strategy for hepatocellular carcinoma glycoprotein biomarker discovery using a nonglycopeptide-based mass spectrometry pipeline. Anal. Chem., 91(19), 12435–12443. CrossRef Scholar google search
Xu H., Wang Y., Lin S., Deng W., Peng D., Cui Q., Xue Y. (2018) PTMD: a database of human disease-associated post-translational modifications. Genomics Proteomics Bioinformatics, 16(4), 244–251. CrossRef Scholar google search
Noor A., Zafar S., Shafiq M., Younas N., Siegert A., Mann F.A., Kruss S., Schmitz M., Dihazi H., Ferrer I., Zerr I. (2022) Molecular profiles of amyloid-β proteoforms in typical and rapidly progressive Azheimer’s disease. Mol. Neurobiol., 59(1), 17–34. CrossRef Scholar google search
Pons M.-L., Loftus N., Vialaret J., Moreau S., Lehmann S., Hirtz C. (2022) Proteomics challenges for the assessment of synuclein proteoforms as clinical biomarkers in Parkinson’s disease. Front. Aging Neurosci., 14, 818606. CrossRef Scholar google search
Levine P.M., Galesic A., Balana A.T., Mahul-Mellier A.-L., Navarro M.X., de Leon C.A., Lashuel H.A., Pratt M.R. (2019) α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease. Proc. Natl. Acad. Sci. USA, 116(5), 1511–1519. CrossRef Scholar google search
Luo J.-P., Wang J., Huang J.-H. (2021) CDKN2A is a prognostic biomarker and correlated with immune infiltrates in hepatocellular carcinoma. Biosci. Rep., 41(10), BSR20211103. CrossRef Scholar google search
Li Y., Chen R., Yang J., Mo S., Quek K., Kok C.H., Cheng X.-D., Tian S., Zhang W., Qin J.-J. (2020) Integrated bioinformatics analysis reveals key candidate genes and pathways associated with clinical outcome in hepatocellular carcinoma. Front. Genet., 11, 814. CrossRef Scholar google search
Jiang C.H., Yuan X., Li J.F., Xie Y.F., Zhang A.Z., Wang X.L., Yang L., Liu C.X., Liang W.H., Pang L.J., Zou H., Cui X.B., Shen X.H., Qi Y., Jiang J.F., Gu W.Y., Li F., Hu J.M. (2020) Bioinformatics-based screening of key genes for transformation of liver cirrhosis to hepatocellular carcinoma. J. Transl. Med., 18(1), 40. CrossRef Scholar google search
