# Transcriptional and epigenetic regulation of Ca2+-signaling genes in hepatitis B-derived hepatocellular carcinoma and their association with the cancer hallmarks **Authors:** Guadalupe Hernández-Martínez, Andrés Hernández-Oliveras, Ángel Zarain-Herzberg, Juan Santiago-García PMC · DOI: 10.1093/bioadv/vbaf331 · Bioinformatics Advances · 2026-01-27 ## TL;DR This study explores how calcium-signaling genes are regulated in hepatitis B-related liver cancer and identifies a four-gene signature that could predict patient outcomes. ## Contribution The study introduces a novel four-gene prognostic signature specific to hepatitis B-derived hepatocellular carcinoma. ## Key findings - 432 Ca2+-signaling genes are differentially expressed in HBV-HCC, with 134 unique to this condition. - Fifty-three genes are linked to cancer hallmarks, and 17 show potential for predicting prognosis. - A four-gene signature (FBLN1, STC2, C1R, F2RL2) robustly stratifies patient outcomes. ## Abstract Dysregulation of Ca2+-signaling genes has been shown in some types of cancer; however, it is virtually unknown in hepatitis B-derived hepatocellular carcinoma (HBV-HCC). Here, we evaluate the transcriptional and epigenetic regulation of Ca2+-signaling genes in HBV-HCC and whether their expression is associated with cancer hallmarks, and prognostic potential. We identified 432 differentially expressed Ca2+-signaling genes in HBV-HCC, including 134 that are specific to this condition, and were not found in non-HBV HCC. Fifty-three of these genes were associated with cancer hallmarks, of which 17 exhibited potential prognostic value by Cox multivariate analyses. We also provide new evidence for epigenetic regulation by post-transcriptional histone modifications and DNA methylation at the promoter of some of these genes. Finally, using Least Absolute Shrinkage and Selection Operator (LASSO) regression, we identified a four-gene prognostic signature (FBLN1, STC2, C1R, and F2RL2) that robustly stratified patient outcomes. This study presents the first integrative transcriptomic and epigenetic analysis of Ca2+-signaling genes in HBV-HCC, introducing a novel four-gene signature with prognostic potential. These findings highlight the relevance of a dysregulation of a subset of Ca2+-signaling genes as a distinctive feature of HBV-HCC. All data generated or analyzed during this study are included in this article. ## Linked entities - **Genes:** FBLN1 (fibulin 1) [NCBI Gene 2192], STC2 (stanniocalcin 2) [NCBI Gene 8614], C1R (complement C1r) [NCBI Gene 715], F2RL2 (coagulation factor II thrombin receptor like 2) [NCBI Gene 2151] ## Full-text entities - **Genes:** MGP (matrix Gla protein) [NCBI Gene 4256] {aka GIG36, MGLAP, NTI}, FBN1 (fibrillin 1) [NCBI Gene 2200] {aka ACMICD, ECTOL1, FBN, GPHYSD2, MASS, MFLS}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, MYOD1 (myogenic differentiation 1) [NCBI Gene 4654] {aka CMYO17, CMYP17, MYF3, MYOD, MYODRIF, PUM}, DSC3 (desmocollin 3) [NCBI Gene 1825] {aka CDHF3, DSC, DSC1, DSC2, DSC4, HT-CP}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, RYR3 (ryanodine receptor 3) [NCBI Gene 6263] {aka CMYO20, CMYP20, RYR-3}, OXTR (oxytocin receptor) [NCBI Gene 5021] {aka OT-R, OTR}, PROS1 (protein S) [NCBI Gene 5627] {aka PROS, PS21, PS22, PS23, PS24, PS25}, F12 (coagulation factor XII) [NCBI Gene 2161] {aka HAE3, HAEX, HAF}, ORAI1 (ORAI calcium release-activated calcium modulator 1) [NCBI Gene 84876] {aka CRACM1, IMD9, ORAT1, TAM2, TMEM142A}, MEF2C (myocyte enhancer factor 2C) [NCBI Gene 4208] {aka C5DELq14.3, DEL5q14.3, NEDHSIL}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, LGR5 (leucine rich repeat containing G protein-coupled receptor 5) [NCBI Gene 8549] {aka FEX, GPR49, GPR67, GRP49, HG38}, ATP2B4 (ATPase plasma membrane Ca2+ transporting 4) [NCBI Gene 493] {aka ATP2B2, MXRA1, PMCA4, PMCA4b, PMCA4x}, C1R (complement C1r) [NCBI Gene 715] {aka EDS8, EDSPD1}, SRC (SRC proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 6714] {aka ASV, SRC1, THC6, c-SRC, p60-Src}, ITPR3 (inositol 1,4,5-trisphosphate receptor type 3) [NCBI Gene 3710] {aka CMT1J, IMD132, IMD133, IP3R, IP3R-3, IP3R3}, FKBP1B (FKBP prolyl isomerase 1B) [NCBI Gene 2281] {aka FKBP12.6, FKBP1L, OTK4, PKBP1L, PPIase}, S100P (S100 calcium binding protein P) [NCBI Gene 6286] {aka MIG9}, CDH11 (cadherin 11) [NCBI Gene 1009] {aka CAD11, CDHOB, ESWS, OB, OSF-4, TBHS2}, PROZ (protein Z, vitamin K dependent plasma glycoprotein) [NCBI Gene 8858] {aka PZ}, MASP2 (MBL associated serine protease 2) [NCBI Gene 10747] {aka MAP-2, MAP19, MASP-2, MASP1P1, sMAP}, F2RL2 (coagulation factor II thrombin receptor like 2) [NCBI Gene 2151] {aka PAR-3, PAR3}, SPHK1 (sphingosine kinase 1) [NCBI Gene 8877] {aka SPHK}, CACNG1 (calcium voltage-gated channel auxiliary subunit gamma 1) [NCBI Gene 786] {aka CACNLG}, C1S (complement C1s) [NCBI Gene 716] {aka EDSPD2}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, CDH2 (cadherin 2) [NCBI Gene 1000] {aka ACOGS, ADHD8, ARVD14, CD325, CDHN, CDw325}, SPARC (secreted protein acidic and cysteine rich) [NCBI Gene 6678] {aka BM-40, OI17, ON, ONT}, VDAC3 (voltage dependent anion channel 3) [NCBI Gene 7419] {aka HD-VDAC3, VDAC-3}, CDH13 (cadherin 13) [NCBI Gene 1012] {aka CDHH, P105}, VCAN (versican) [NCBI Gene 1462] {aka CSPG2, ERVR, GHAP, PG-M, WGN, WGN1}, DAPK2 (death associated protein kinase 2) [NCBI Gene 23604] {aka DRP-1, DRP1}, CXCL1 (C-X-C motif chemokine ligand 1) [NCBI Gene 2919] {aka FSP, GRO1, GROa, MGSA, MGSA-a, NAP-3}, ATP2A3 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3) [NCBI Gene 489] {aka SERCA3}, FBLN1 (fibulin 1) [NCBI Gene 2192] {aka FBLN, FIBL1}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, VIM (vimentin) [NCBI Gene 7431], ITIH1 (inter-alpha-trypsin inhibitor heavy chain 1) [NCBI Gene 3697] {aka H1P, IATIH, ITI-HC1, ITIH, SHAP}, BDKRB2 (bradykinin receptor B2) [NCBI Gene 624] {aka B2R, BK-2, BK2, BKR2, BRB2}, EDIL3 (EGF like and discoidin domains 3) [NCBI Gene 10085] {aka DEL1}, F2 (coagulation factor II, thrombin) [NCBI Gene 2147] {aka PT, RPRGL2, THPH1}, STC2 (stanniocalcin 2) [NCBI Gene 8614] {aka STC-2, STCRP}, THY1 (Thy-1 cell surface antigen) [NCBI Gene 7070] {aka CD90, CDw90}, MECP2 (methyl-CpG binding protein 2) [NCBI Gene 4204] {aka AUTSX3, MRX16, MRX79, MRXS13, MRXSL, PPMX}, S100A4 (S100 calcium binding protein A4) [NCBI Gene 6275] {aka 18A2, 42A, CAPL, FSP1, MTS1, P9KA}, TGM2 (transglutaminase 2) [NCBI Gene 7052] {aka G(h), TG(C), TGC, hTG2, tTG} - **Diseases:** infected liver (MESH:D017093), cardiac, renal, neurodegenerative diseases (MESH:D019636), alcoholism (MESH:D000437), non-alcoholic steatohepatitis (MESH:D005235), pancreatic cancer (MESH:D010190), glioma (MESH:D005910), colon, gastric, breast, choroid plexus, lung, and liver cancer (MESH:D013274), HBV- (MESH:D006509), Cancer (MESH:D009369), HCC (MESH:D006528), cirrhosis (MESH:D005355), blood coagulation (MESH:D001778), inflammatory liver diseases (MESH:D008107), acute myeloid leukemia (MESH:D015470), cervical cancer (MESH:D002583), liver damage (MESH:D056486), viral infection (MESH:D014777), non-alcoholic fatty liver disease (MESH:D065626), diabetes (MESH:D003920), metastasis (MESH:D009362), breast cancer (MESH:D001943), carcinogenesis (MESH:D063646), Lung adenocarcinoma (MESH:D000077192), steatohepatitis (MESH:D005234), hepatic inflammation (MESH:D007249), alcoholic hepatitis (MESH:D006519), metabolic dysfunction (MESH:D008659), autoimmune hepatitis (MESH:D019693), colon cancer (MESH:D015179) - **Chemicals:** Calcium (MESH:D002118), 5-Aza (-), reactive oxygen species (MESH:D017382), aflatoxins (MESH:D000348) - **Species:** Human papillomavirus (species) [taxon 10566], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** JHH-7 — Homo sapiens (Human), Adult hepatocellular carcinoma, Cancer cell line (CVCL_2805), HLF — Homo sapiens (Human), Adult hepatocellular carcinoma, Cancer cell line (CVCL_2947) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12866915/full.md ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12866915/full.md ## References 79 references — full list in the complete paper: https://tomesphere.com/paper/PMC12866915/full.md --- Source: https://tomesphere.com/paper/PMC12866915