Circulating miR-21 as a prognostic biomarker in HCC treated by CT-guided high-dose rate brachytherapy
Tóm tắt
Prognostic biomarkers identifying patients with early tumor progression after local ablative therapy remain an unmet clinical need. The aim of this study was to investigate circulating miR-21 and miR-210 levels as prognostic biomarkers of HCC treated by CT-guided high-dose rate brachytherapy (HDR-BT). 24 consecutive HCC patients (BCLC A and B) treated with CT-guided HDR-BT (1 × 15 Gy) were included in this prospective IRB-approved study. RT-PCR was performed to quantify miR-21 and miR-210 levels in blood samples acquired prior to and 2 d after HDR-BT. Follow-up imaging (contrast-enhanced liver MRI and whole-body CT) was performed in 3 months follow-up intervals. Therapy response was assessed with patients classified as either responders or non-responders (12 each). Responders were defined as having no local or diffuse systemic progression within 6 months and no diffuse systemic progression exceeding 3 nodules/nodule diameter > 3 cm from 6 months to 2 years. Non-responders had recurrence within 6 months and/or tumor progression with > 3 nodules or individual lesion diameter > 3 cm or extrahepatic disease within two years, respectively. Biostatistics included parametric and non-parametric testing (Mann–Whitney-U-test), as well as Kaplan–Meier curve construction. The responder group demonstrated significantly decreasing miR-21 values 2 d post therapy compared to non-responders (median miR-21 2−ΔΔCт: responders 0.73 [IQR 0.34], non-responders 1.53 [IQR 1.48]; p = 0.0102). miR-210 did not show any significant difference between responders and non-responders (median miR-210 2−ΔΔCт: responders 0.74 [IQR 0.45], non-responders 0.99 [IQR 1.13]; p = 0.8399). Kaplan–Meier curves demonstrated significantly shorter time to systemic progression for increased miR-21 (p = 0.0095) but not miR-210 (p = 0.7412), with events accumulating > 1 year post therapy in non-responders (median time to systemic progression 397 days). Increasing circulating miR-21 levels are associated with poor response and shorter time to systemic progression in HDR-BT-treated HCC. This proof-of-concept study provides a basis for further investigation of miR-21 as a prognostic biomarker and potential stratifier in future clinical trials of interventional oncology therapies. Trial registration: In this monocentric clinical study, we analyzed prospectively acquired data of 24 patients from the “ESTIMATE” patient cohort (Studiennummer: DRKS00010587, Deutsches Register Klinischer Studien). Ethical approval was provided by the ethics committee “Ethikkommission bei der LMU München” (reference number “17-346”) on June 20, 2017 and August 26, 2020.
Tài liệu tham khảo
citation_journal_title=Ann Oncol; citation_title=Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up; citation_author=A Vogel, A Cervantes, I Chau, B Daniele, JM Llovet, T Meyer; citation_volume=30; citation_issue=5; citation_publication_date=2019; citation_pages=871-873; citation_doi=10.1093/annonc/mdy510; citation_id=CR1
citation_journal_title=Int J Radiat Oncol Biol Phys; citation_title=Computed tomography-guided high-dose-rate brachytherapy in hepatocellular carcinoma: safety, efficacy, and effect on survival; citation_author=K Mohnike, G Wieners, F Schwartz, M Seidensticker, M Pech, R Ruehl; citation_volume=78; citation_issue=1; citation_publication_date=2010; citation_pages=172-179; citation_doi=10.1016/j.ijrobp.2009.07.1700; citation_id=CR2
citation_journal_title=Strahlenther Onkol; citation_title=CT-guided high-dose-rate brachytherapy of unresectable hepatocellular carcinoma; citation_author=F Collettini, N Schreiber, D Schnapauff, T Denecke, P Wust, E Schott; citation_volume=191; citation_issue=5; citation_publication_date=2015; citation_pages=405-412; citation_doi=10.1007/s00066-014-0781-3; citation_id=CR3
citation_journal_title=Nat Rev Mol Cell Biol; citation_title=Regulation of microRNA function in animals; citation_author=LFR Gebert, IJ MacRae; citation_volume=20; citation_issue=1; citation_publication_date=2019; citation_pages=21-37; citation_doi=10.1038/s41580-018-0045-7; citation_id=CR4
citation_journal_title=Front Med (Lausanne); citation_title=Critical role of microRNA-21 in the pathogenesis of liver diseases; citation_author=T Zhang, Z Yang, P Kusumanchi, S Han, S Liangpunsakul; citation_volume=7; citation_publication_date=2020; citation_pages=7; citation_doi=10.3389/fmed.2020.00007; citation_id=CR5
citation_journal_title=Gut; citation_title=Integrative microRNA profiling in alcoholic hepatitis reveals a role for microRNA-182 in liver injury and inflammation; citation_author=D Blaya, M Coll, D Rodrigo-Torres, M Vila-Casadesus, J Altamirano, M Llopis; citation_volume=65; citation_issue=9; citation_publication_date=2016; citation_pages=1535-1545; citation_doi=10.1136/gutjnl-2015-311314; citation_id=CR6
citation_journal_title=J Clin Med; citation_title=Hepatic stellate cells and microRNAs in pathogenesis of liver fibrosis; citation_author=M Kitano, PM Bloomston; citation_volume=5; citation_issue=3; citation_publication_date=2016; citation_pages=38; citation_doi=10.3390/jcm5030038; citation_id=CR7
citation_journal_title=Biomark Med; citation_title=Clinical significance of microRNA-21 expression in disease progression of patients with hepatocellular carcinoma; citation_author=JS Yoon, G Kim, YR Lee, SY Park, WY Tak, YO Kweon; citation_volume=12; citation_issue=10; citation_publication_date=2018; citation_pages=1105-1114; citation_doi=10.2217/bmm-2018-0096; citation_id=CR8
citation_journal_title=Int J Clin Exp Pathol; citation_title=Increased expression of miR-21 predicts poor prognosis in patients with hepatocellular carcinoma; citation_author=CS Huang, W Yu, H Cui, YJ Wang, L Zhang, F Han; citation_volume=8; citation_issue=6; citation_publication_date=2015; citation_pages=7234-7238; citation_id=CR9
citation_journal_title=Gastroenterology; citation_title=MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer; citation_author=F Meng, R Henson, H Wehbe-Janek, K Ghoshal, ST Jacob, T Patel; citation_volume=133; citation_issue=2; citation_publication_date=2007; citation_pages=647-658; citation_doi=10.1053/j.gastro.2007.05.022; citation_id=CR10
citation_journal_title=J Exp Clin Cancer Res; citation_title=Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts; citation_author=Y Zhou, H Ren, B Dai, J Li, L Shang, J Huang; citation_volume=37; citation_issue=1; citation_publication_date=2018; citation_pages=324; citation_doi=10.1186/s13046-018-0965-2; citation_id=CR11
citation_journal_title=Hepatology; citation_title=Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma; citation_author=Q Ying, L Liang, W Guo, R Zha, Q Tian, S Huang; citation_volume=54; citation_issue=6; citation_publication_date=2011; citation_pages=2064-2075; citation_doi=10.1002/hep.24614; citation_id=CR12
citation_journal_title=Oncol Rep; citation_title=MicroRNA-210 promotes cancer angiogenesis by targeting fibroblast growth factor receptor-like 1 in hepatocellular carcinoma; citation_author=Y Yang, J Zhang, T Xia, G Li, T Tian, M Wang; citation_volume=36; citation_issue=5; citation_publication_date=2016; citation_pages=2553-2562; citation_doi=10.3892/or.2016.5129; citation_id=CR13
citation_journal_title=J Vasc Interv Radiol; citation_title=Thermal ablation and transarterial chemoembolization are characterized by changing dynamics of circulating MicroRNAs; citation_author=T Andrasina, J Juracek, J Zavadil, B Cechova, T Rohan, P Vesela; citation_volume=32; citation_issue=3; citation_publication_date=2021; citation_pages=403-411; citation_doi=10.1016/j.jvir.2020.10.024; citation_id=CR14
citation_journal_title=J Hepatol; citation_title=BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update; citation_author=M Reig, A Forner, J Rimola, J Ferrer-Fabrega, M Burrel, A Garcia-Criado; citation_volume=76; citation_issue=3; citation_publication_date=2022; citation_pages=681-693; citation_doi=10.1016/j.jhep.2021.11.018; citation_id=CR15
citation_journal_title=Methods; citation_title=Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method; citation_author=KJ Livak, TD Schmittgen; citation_volume=25; citation_issue=4; citation_publication_date=2001; citation_pages=402-408; citation_doi=10.1006/meth.2001.1262; citation_id=CR16
citation_journal_title=World J Hepatol; citation_title=Circulating miR-21-5p level has limited prognostic value in patients with hepatocellular carcinoma and is influenced by renal function; citation_author=M Franck, C Thon, K Schutte, P Malfertheiner, A Link; citation_volume=12; citation_issue=11; citation_publication_date=2020; citation_pages=1031-1045; citation_doi=10.4254/wjh.v12.i11.1031; citation_id=CR17
citation_journal_title=Biomed Res Int; citation_title=The prognostic significance of miR-21 expression among surgically resected hepatocellular carcinoma patients: evidence from a meta-analysis and retrospective cohort study; citation_author=X Huang, Y Xiong, J Yang, G Yang, J Li; citation_volume=2020; citation_publication_date=2020; citation_pages=8848158; citation_doi=10.1155/2020/8848158; citation_id=CR18
citation_journal_title=Int J Clin Exp Pathol; citation_title=Prognostic effect of IL-6/JAK2/STAT3 signal-induced microRNA-21-5p expression on short term recurrence of hepatocellular carcinoma after hepatectomy; citation_author=C Zhu, M Zhang, J Hu, H Li, S Liu, T Li; citation_volume=11; citation_issue=8; citation_publication_date=2018; citation_pages=4169-4178; citation_id=CR19
citation_journal_title=Oncotarget; citation_title=Circulating miR-21 serves as a serum biomarker for hepatocellular carcinoma and correlated with distant metastasis; citation_author=X Guo, X Lv, X Lv, Y Ma, L Chen, Y Chen; citation_volume=8; citation_issue=27; citation_publication_date=2017; citation_pages=44050-44058; citation_doi=10.18632/oncotarget.17211; citation_id=CR20
citation_journal_title=Nat Rev Cancer; citation_title=Thermal ablation of tumours: biological mechanisms and advances in therapy; citation_author=KF Chu, DE Dupuy; citation_volume=14; citation_issue=3; citation_publication_date=2014; citation_pages=199-208; citation_doi=10.1038/nrc3672; citation_id=CR21
citation_journal_title=In Vivo; citation_title=TNF-alpha indicates radiation-induced liver injury after interstitial high dose-rate brachytherapy; citation_author=R Damm, M Pech, F Haag, P Cavalli, S Gylstorff, J Omari; citation_volume=36; citation_issue=5; citation_publication_date=2022; citation_pages=2265-2274; citation_doi=10.21873/invivo.12955; citation_id=CR22
citation_journal_title=J Cancer Res Clin Oncol; citation_title=Correlation of chemokines and growth factors with radiation-induced liver injury after interstitial high dose rate (HDR) brachytherapy of liver metastases; citation_author=R Damm, M Pech, P Cavalli, F Haag, S Gylstorff, J Omari; citation_volume=148; citation_issue=10; citation_publication_date=2022; citation_pages=2815-2826; citation_doi=10.1007/s00432-022-04041-x; citation_id=CR23
citation_journal_title=Asian Pac J Cancer Prev; citation_title=Ionizing radiation-inducible microRNA-21 induces angiogenesis by directly targeting PTEN; citation_author=Y Zhang, Z Chen, L Feng, P Jiang, X Li, X Wang; citation_volume=20; citation_issue=5; citation_publication_date=2019; citation_pages=1587-1593; citation_doi=10.31557/APJCP.2019.20.5.1587; citation_id=CR24
citation_journal_title=Evid Based Complement Alternat Med; citation_title=Curcumin inhibits hepatocellular carcinoma via regulating miR-21/TIMP3 Axis; citation_author=J Li, H Wei, Y Liu, Q Li, H Guo, Y Guo; citation_volume=2020; citation_publication_date=2020; citation_pages=2892917; citation_id=CR25
citation_journal_title=Cancer Cell Int; citation_title=Therapeutic inhibition of microRNA-21 (miR-21) using locked-nucleic acid (LNA)-anti-miR and its effects on the biological behaviors of melanoma cancer cells in preclinical studies; citation_author=SH Javanmard, G Vaseghi, A Ghasemi, L Rafiee, GA Ferns, HN Esfahani; citation_volume=20; citation_publication_date=2020; citation_pages=384; citation_doi=10.1186/s12935-020-01394-6; citation_id=CR26