Knockdown of SIK3 in the CA1 Region can Reduce Seizure Susceptibility in Mice by Inhibiting Decreases in GABAAR α1 Expression.

Imbalance between excitation and inhibition is an important cause of epilepsy. Salt-inducible kinase 1 (SIK1) gene mutation can cause epilepsy. In this study, we first found that the expression of SIK3 is increased after epilepsy. Furthermore, the role of SIK3 in epilepsy was explored. In cultured hippocampal neurons, we used Pterosin B, a selective SIK3 inhibitor that can inhibit epileptiform discharges induced by the convulsant drug cyclothiazide (a positive allosteric modulator of AMPA receptors, CTZ). Knockdown of SIK3 inhibited epileptiform discharges and increased the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). In mice, knockdown of SIK3 reduced epilepsy susceptibility in a pentylenetetrazole (a GABAA receptor antagonist, PTZ) acute kindling experiment and increased the expression of GABAA receptor α1. In conclusion, our results suggest that blockade or knockdown of SIK3 can inhibit epileptiform discharges and that SIK3 has the potential to be a novel target for epilepsy treatment.

The role of ROS-pyroptosis in PM2.5 induced air-blood barrier destruction.

Fine particulate matter (PM2.5) has attracted increasing attention due to its health-threatening effects. Although numerous studies have investigated the impact of PM2.5 on lung injuries, the specific mechanisms underlying the damage to the air-blood barrier after exposure to PM2.5 remain unclear. In this study, we established an in vitro co-culture system using lung epithelial cells and capillary endothelial cells. Our findings indicated that the tight junction (TJ) proteins were up-regulated in the co-cultured system compared to the monolayer-cultured cells, suggesting the establishment of a more closely connected in vitro system. Following exposure to PM2.5, we observed damage to the air-blood barrier in vitro. Concurrently, PM2.5 exposure induced significant oxidative stress and activated the NLRP3 inflammasome-mediated pyroptosis pathway. When oxidative stress was inhibited, we observed a decrease in pyroptosis and an increase in TJ protein levels. Additionally, disulfiram reversed the adverse effects of PM2.5, effectively suppressing pyroptosis and ameliorating air-blood barrier dysfunction. Our results indicate that the oxidative stress-pyroptosis pathway plays a critical role in the disruption of the air-blood barrier induced by PM2.5 exposure. Disulfiram may represent a promising therapeutic option for mitigating PM2.5-related lung damage.

Pregnane X receptor (PXR) deficiency protects against spinal cord injury by activating NRF2/HO-1 pathway.

INTRODUCTION: As a devastating neurological disease, spinal cord injury (SCI) results in severe tissue loss and neurological dysfunction. Pregnane X receptor (PXR) is a ligand-activated nuclear receptor with a major regulatory role in xenobiotic and endobiotic metabolism and recently has been implicated in the central nervous system. In the present study, we aimed to investigate the role and mechanism of PXR in SCI. METHODS: The clip-compressive SCI model was performed in male wild-type C57BL/6 (PXR+/+ ) and PXR-knockout (PXR-/- ) mice. The N2a H2 O2 -induced injury model mimicked the pathological process of SCI in vitro. Pregnenolone 16α-carbonitrile (PCN), a mouse-specific PXR agonist, was used to activate PXR in vivo and in vitro. The siRNA was applied to knock down the PXR expression in vitro. Transcriptome sequencing analysis was performed to discover the relevant mechanism, and the NRF2 inhibitor ML385 was used to validate the involvement of PXR in influencing the NRF2/HO-1 pathway in the SCI process. RESULTS: The expression of PXR decreased after SCI and reached a minimum on the third day. In vivo, PXR knockout significantly improved the motor function of mice after SCI, meanwhile, inhibited apoptosis, inflammation, and oxidative stress induced by SCI. On the contrary, activation of PXR by PCN negatively influenced the recovery of SCI. Mechanistically, transcriptome sequencing analysis revealed that PXR activation downregulated the mRNA level of heme oxygenase-1 (HO-1) after SCI. We further verified that PXR deficiency activated the NRF2/HO-1 pathway and PXR activation inhibited this pathway in vitro. CONCLUSION: PXR is involved in the recovery of motor function after SCI by regulating NRF2/HO-1 pathway.

The Efficacy of Adjuvant Chloroquine for Glioblastoma: A Meta-Analysis of Randomized Controlled Studies.

Introduction The efficacy of adjuvant chloroquine for glioblastoma remains controversial. We conduct a systematic review and meta-analysis to explore the influence of adjuvant chloroquine on treatment efficacy for recurrent glioblastoma. Methods We search PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through January 2020 for randomized controlled trials (RCTs) assessing the efficacy of adjuvant chloroquine for glioblastoma. This meta-analysis is performed using the random-effect model. Results Three RCTs are included in the meta-analysis. Overall, compared with control group for glioblastoma, adjuvant chloroquine is associated with significantly reduced mortality (risk ratio [RR] = 0.59; 95% confidence interval [CI] = 0.47-0.72; p < 0.00001), improved remission (RR = 11.53; 95% CI = 1.53-86.57; p = 0.02), and prolonged survival time (Std.MD = 11.53; 95% CI = 1.53-86.57; p = 0.02), but has no substantial effect on recurrence (RR = 0.42; 95% CI = 0.12-1.49; p = 0.18). Conclusion Adjuvant chloroquine may provide additional benefits for the treatment of glioblastoma.

CDKL5 promotes proliferation, migration, and chemotherapeutic drug resistance of glioma cells via activation of the PI3K/AKT signaling pathway.

Gliomas, the most prevalent cancer in the central nervous system, are characterized by high morbidity and mortality, emphasizing the need to understand their etiology. Here, we report that cyclin-dependent kinase-like 5 (CDKL5) is highly expressed in gliomas, and CDKL5 overexpression promotes invasion, proliferation, migration and drug (ß-lapachone) resistance of glioma cells. In vitro, CDKL5 overexpression enhanced invasion, growth and migration of glioma cells, and stimulated the phosphoinositide 3-kinase (PI3K)/AKT axis. Furthermore, CDKL5 overexpression in vivo promoted glioma proliferation, whereas CDKL5 knockdown had opposing effects. The effect of CDKL5 on drug resistance was eliminated if the PI3K/AKT axis was suppressed, and cisplatin combined with the PI3K/AKT suppressor XL147 remarkably prohibited proliferation in xenografts overexpressing CDKL5. Collectively, our findings suggest that CDKL5 acts through the PI3K/AKT axis in glioma cells, and indicate a possible role for CDKL5 in glioma therapy.

E2F1 interactive with BRCA1 pathway induces HCC two different small molecule metabolism or cell cycle regulation via mitochondrion or CD4+T to cytosol.

Breast cancer 1 (BRCA1) and E2F transcription factor 1 (E2F1) are related to metabolism and cell cycle regulation. However, the corresponding mechanism is not clear in HCC. High BRCA1 direct pathway was constructed with 11 molecules from E2F1 feedback-interactive network in HCC by GRNInfer based on 39 Pearson mutual positive corelation CC ≥0.25 molecules with E2F1. Integration of GRNInfer with GO, KEGG, BioCarta, GNF_U133A, UNIGENE_EST, Disease, GenMAPP databases by DAVID and MAS 3.0, E2F1 feedback-interactive BRCA1 indirect mitochondrion to cytosol pathway was identified as upstream LAPTM4B activation, feedback UNG, downstream BCAT1-HIST1H2AD-TK1 reflecting protein, and DNA binding with enrichment of small molecule metabolism; The corresponding BRCA1 indirect membrane to cytosol pathway as upstream CCNB2-NUSAP1 activation, feedback TTK-HIST1H2BJ-CENPF, downstream MCM4-TK1 reflecting ATP, and microtubule binding with enrichment of CD4+T-related cell cycle regulation in HCC. Therefore, we propose that E2F1 interactive with BRCA1 pathway induces HCC two different small molecule metabolism or cell cycle regulation via mitochondrion or CD4+T to cytosol. Knowledge analysis demonstrates our E2F1 feedback-interactive BRCA1 pathway wide disease distribution and reflects a novel common one of tumor and cancer.

Low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384.

Eighteen different Pearson mutual-positive-correlation BIK-activatory molecular feedback upstream and downstream networks were constructed from 79 overlapping of 376 GRNInfer and 98 Pearson under BIK CC ≥ 0.25 in low normal adjacent tissues of Taiwan compared with high lung adenocarcinoma. Our identified BIK interactive total feedback molecular network showed FUT3 [fucosyltransferase 3 (galactoside 3(4)-L-fucosyltransferase Lewis blood group)], PMM2 (phosphomannomutase 2), SQSTM1 (sequestosome 1), SFN_2 [REX2 RNA exonuclease 2 homolog (S. cerevisiae)] and ZNF384 (zinc finger protein 384) in low normal adjacent tissues of lung adenocarcinoma. BIK interactive total feedback terms included mitochondrial envelope, endomembrane system, integral to membrane, Golgi apparatus, cytoplasm, nucleus, cytosol, intracellular signaling cascade, mitochondrion, extracellular space, inflammation, immune response, apoptosis, cell differentiation, cell cycle, regulation of cell cycle, cell proliferation, estrogen-responsive protein Efp controls cell cycle and breast tumors growth, induction or regulation of apoptosis based on integrative GO, KEGG, GenMAPP, BioCarta and disease databases in low normal adjacent tissues of lung adenocarcinoma. Therefore, we propose low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384 in normal adjacent tissues of lung adenocarcinoma.

High EGFR_1 Inside-Out Activated Inflammation-Induced Motility through SLC2A1-CCNB2-HMMR-KIF11-NUSAP1-PRC1-UBE2C.

48 different Pearson mutual-positive-correlation epidermal growth factor receptor (EGFR_1)-activatory molecular feedback, up- and down-stream network was constructed from 171 overlapping of 366 GRNInfer and 223 Pearson under EGFR_1 CC ≥0.25 in high lung adenocarcinoma compared with low human normal adjacent tissues. Our identified EGFR_1 inside-out upstream activated molecular network showed SLC2A1 (solute carrier family 2 (facilitated glucose transporter) member 1), CCNB2 (cyclin B2), HMMR (hyaluronan-mediated motility receptor (RHAMM)), KIF11 (kinesin family member 11), NUSAP1 (nucleolar and spindle associated protein 1), PRC1 (protein regulator of cytokinesis 1), UBE2C (ubiquitin-conjugating enzyme E2C) in high lung adenocarcinoma. EGFR_1 inside-out upstream activated terms network includes intracellular, membrane fraction, cytoplasm, plasma membrane, integral to membrane, basolateral plasma membrane, transmembrane transport, nucleus, cytosol, cell surface; T cell homeostasis, inflammation; microtubule cytoskeleton, embryonic development (sensu Mammalia), cell cycle, mitosis, thymus development, cell division, regulation of cell cycle, Contributed--cellular process--Hs cell cycle KEGG, cytokinesis, M phase, M phase of mitotic cell cycle, estrogen-responsive protein Efp controls cell cycle and breast tumors growth, cell motility, locomotion, locomotory behavior, neoplasm metastasis, spindle pole, spindle microtubule, microtubule motor activity, microtubule-based movement, mitotic spindle organization and biogenesis, mitotic centrosome separation, spindle pole body organization and biogenesis, microtubule-based process, microtubule, cytokinesis after mitosis, mitotic chromosome condensation, establishment of mitotic spindle localization, positive regulation of mitosis, mitotic spindle elongation, spindle organization and biogenesis, positive regulation of exit from mitosis, regulation of cell proliferation, positive regulation of cell proliferation based on integrative GO, KEGG, GenMAPP, BioCarta and disease databases in high lung adenocarcinoma. Therefore, we propose high EGFR_1 inside-out activated inflammation-induced motility through SLC2A1-CCNB2-HMMR-KIF11-NUSAP1-PRC1-UBE2C in lung adenocarcinoma.

Low glucose transporter SLC2A5-inhibited human normal adjacent lung adenocarcinoma cytoplasmic pro-B cell development mechanism network.

Solute carrier family 2 (facilitated glucose/fructose transporter) member 5 (SLC2A5)-inhibited seven different molecular Pearson mutual-positive-correlation networks constructed by 24 overlapping molecules from 368 GRNInfer and 34 Pearson under SLC2A5 CC ≤-0.25 in low human normal adjacent tissues were compared with high lung adenocarcinoma. Based on GO, KEGG, GenMAPP, BioCarta, and disease databases, our result showed that low SLC2A5-inhibited network included Golgi apparatus of AP1M2_1; cell cycle of CUL7, SAC3D1; protein amino acid dephosphorylation of STYXL1; pro-B cell-cell differentiation of SOX4_3; and FAD biosynthesis of FLAD1. Thus, we propose low glucose transporter SLC2A5-inhibited human normal adjacent lung adenocarcinoma cytoplasmic pro-B cell development mechanism network through repression of protein amino acid dephosphorylation to FAD biosynthesis.

AGR2-mediated lung adenocarcinoma metastasis novel mechanism network through repression with interferon coupling cytoskeleton to steroid metabolism-dependent humoral immune response.

7 anterior gradient homolog 2 (AGR2)-inhibited different molecular mutual positive correlation network was constructed in lung adenocarcinoma compared with human normal adjacent tissues by 17 overlapping molecules of 358 GRNInfer and 19 Pearson (AGR2 CC⩽-0.25). Based on GO, KEGG, GenMAPP, BioCarta and disease databases, we determined AGR2-mediated lung adenocarcinoma metastasis through repression with cytoskeleton of MAST1; steroid metabolism of SOAT2; humoral immune response of POU2AF1; interferon alpha-inducible of IFI6; immunoglobulin of IGKC_3, CTA_246H3.1. Thus we proposed AGR2-mediated lung adenocarcinoma metastasis novel mechanism network through repression with interferon coupling cytoskeleton to steroid metabolism-dependent humoral immune response.

CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) by biocomputation.

We data-analyzed and constructed the high-expression CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) compared with low-expression (fold change ≥ 2) no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) in GEO data set, using integration of gene regulatory network inference method with gene ontology (GO). Our result showed that CAMK1 transport subnetwork upstream KCNQ3, LCN2, NKX2_5, NUP62, SORT1, STX1A activated CAMK1, and downstream CAMK1-activated AFP, ENAH, KPNA2, SLC4A3; CAMK1 signal subnetwork upstream BRCA1, DKK1, GPSM2, LEF1, NR5A1, NUP62, SORT1, SSTR5, TBL3 activated CAMK1, and downstream CAMK1-activated MAP2K6, SFRP4, SSTR5, TSHB, UBE2C in HCC. We proposed that CAMK1 activated network enhanced endosome to lysosome transport, endosome transport via multivesicular body sorting pathway, Golgi to endosome transport, intracellular protein transmembrane transport, intracellular protein transport, ion transport, mRNA transport, plasma membrane to endosome transport, potassium ion transport, protein transport, vesicle-mediated transport, anion transport, intracellular transport, androgen receptor signaling pathway, cell surface receptor-linked signal transduction, hormone-mediated signaling, induction of apoptosis by extracellular signals, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, signal transduction resulting in induction of apoptosis, phosphoinositide-mediated signaling, Wnt receptor signaling pathway, as a result of inducing phosphoinositide signal-mediated protein sorting, and transport in HCC. Our hypothesis was verified by CAMK1 functional regulation subnetwork containing positive regulation of calcium ion transport via voltage gated calcium channel, cell proliferation, DNA repair, exocytosis, I-kappaB kinase/NF-kappaB cascade, immunoglobulin-mediated immune response, mast cell activation, natural killer cell-mediated cytotoxicity directed against tumor cell target, protein ubiquitination, sodium ion transport, survival gene product activity, T cell-mediated cytotoxicity, transcription, transcription from RNA polymerase II promoter, transcription initiation from RNA polymerase II promoter, transcription via serum response element binding, exit from mitosis, ubiquitin ligase activity during mitotic cell cycle, regulation of angiogenesis, apoptosis, cell growth, cell proliferation, cyclin-dependent protein kinase activity, gene expression, insulin secretion, steroid biosynthesis, transcription from RNA polymerase II promoter, transcription from RNA polymerase III promoter, cell cycle, cell migration, DNA recombination, and protein metabolism; also by CAMK1 negative functional regulation subnetwork including negative regulation of apoptosis, cell proliferation, centriole replication, fatty acid biosynthesis, lipoprotein lipase activity, MAPK activity, progression through cell cycle, transcription, transcription from RNA polymerase II promoter, cell growth, phosphorylation, and ubiquitin ligase activity during mitotic cell cycle in HCC.

Adenosylmethionine decarboxylase 1 (AMD1)-mediated mRNA processing and cell adhesion activated & inhibited transition mechanisms by different comparisons between chimpanzee and human left hemisphere.

To understand adenosylmethionine decarboxylase 1 (AMD1)-mediated mRNA processing and cell adhesion activated & inhibited transition mechanisms between chimpanzee and human left hemisphere, AMD1-activated different complete (all no positive correlation, Pearson correlation coefficient < 0.25) and uncomplete (partly no positive correlation except AMD1, Pearson < 0.25) networks were identified in higher human compared with lower chimpanzee left hemisphere from the corresponding AMD1-stimulated (Pearson ≥ 0.25) or inhibited (Pearson ≤ -0.25) overlapping molecules of Pearson and GRNInfer, respectively. This result was verified by the corresponding scatter matrix. As visualized by GO, KEGG, GenMAPP, BioCarta, and disease database integration, we proposed mainly that AMD1-stimulated different complete network was involved in AMD1 activation with cytoplasm ubiquitin specific peptidase (tRNA-guanine transglycosylase) to nucleus paired box-induced mRNA processing, whereas the corresponding inhibited network participated in AMD1 repression with cytoplasm protocadherin gamma and adaptor-related protein complex 3-induced cell adhesion in lower chimpanzee left hemisphere. However, AMD1-stimulated network contained AMD1 activation with plakophilin and phosphodiesterase to SH3 binding glutamic acid-rich protein to dynein and zinc finger-induced cell adhesion, whereas the corresponding inhibited different complete network included AMD1 repression with mitochondrial denine nucleotide translocator, brain protein, and ADH dehydrogenase to ribonucleoprotein-induced mRNA processing in higher human left hemisphere. Our AMD1 different networks were verified by AMD1-activated or -inhibited complete and uncomplete networks within and between chimpanzee left hemisphere or (and) human left hemisphere.

BRAF overexpression induces rampant glioma proliferation independent of phospho-EGFR expression.

BACKGROUND: The prognosis for gliomas is still dismal when treated with traditional approaches. Molecular targeted therapy has become a trend in treating tumors, including gliomas. However, molecular characteristics vary among different kinds of tumors and ethnic groups. OBJECTIVES: The aim of the research was to study the expression characteristics of key components in the EGFR pathway of gliomas in order to contribute new data for the molecular targeted treatment of gliomas. MATERIAL AND METHODS: EGFR, KRAS, BRAF, PI3K, phospho-EGFR and Ki67 expression were detected with immunohistochemistry in 82 glioma specimens. RESULTS: The expression of EGFR was positively correlated with the patients' age. There were no significant differences in clinicopathological characteristics between gliomas with and without phospho-EGFR expression. EGFR overexpression was significantly correlated with phospho-EGFR expression. In gliomas with EGFR activation, overexpressions of EGFR, BRAF and PI3K were significantly correlated with proliferation. However, in gliomas without phospho-EGFR expression, only BRAF overexpression was significantly related to the proliferation of tumor cells. CONCLUSIONS: BRAF overexpression could be an independent factor causing tumorigenesis in gliomas regardless of phospho-EGFR expression. The molecular characteristics can vary with the increasing age of glioma patients.

BRCA1-mediated inflammation and growth activated & inhibited transition mechanisms between no-tumor hepatitis/cirrhotic tissues and HCC.

To understand breast cancer 1 early onset (BRCA1)-mediated inflammation and growth activated and inhibited transition mechanisms between no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) and human hepatocellular carcinoma (HCC), BRCA1-activated different complete (all no positive correlation, Pearson correlation coefficient <0.25) and uncomplete (partly no positive correlation except BRCA1, Pearson <0.25) networks were identified in higher HCC compared with lower no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) from the corresponding BRCA1-stimulated (Pearson ≥0.25) or inhibited (Pearson ≤-0.25) overlapping molecules of Pearson and GRNInfer, respectively. This result was verified by the corresponding scatter matrix. As visualized by GO, KEGG, GenMAPP, BioCarta, and disease database integration, we proposed mainly that BRCA1-stimulated different complete network was involved in BRCA1 activation with integral to membrane killer cell lectin-like receptor C to nucleus interferon regulatory factor 5-induced inflammation, whereas the corresponding inhibited network participated in BRCA1 repression with matrix roundabout axon guidance receptor homolog 1 to plasma membrane versican-induced growth in lower no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection). However, BRCA1-stimulated network contained BRCA1 activation with endothelium-specific to lysosomal transmembrane and carbamoyl synthetase to tastin, histone cluster and cyclin-induced growth, whereas the corresponding inhibited different complete network included BRCA1 repression with ovalbumin, thyroid stimulating hormone beta and Hu antigen C to cytochrome P450 to transducin-induced inflammation in higher HCC. Our BRCA1 different networks were verified by BRCA1-activated or -inhibited complete and uncomplete networks within and between no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) or (and) HCC.

Cartilage oligomeric matrix protein (COMP)-mediated cell differentiation to proteolysis mechanism networks from human normal adjacent tissues to lung adenocarcinoma.

BACKGROUND: To understand cartilage oligomeric matrix protein (COMP) mechanism network from human normal adjacent tissues to lung adenocarcinoma. METHODS: COMP complete different activated (all no positive correlation, Pearson CC < 0.25) and uncomplete (partly no positive correlation except COMP, Pearson CC < 0.25) network were identified in higher lung adenocarcinoma compared with lower human normal adjacent tissues from the corresponding COMP-stimulated (≥0.25) or inhibited (Pearson CC ≤ -0.25) overlapping molecules of Pearson correlation coefficient (CC) and GRNInfer, respectively. COMP complete different activated and inhibited (all no positive correlation, Pearson CC < 0.25) mechanisms networks of higher lung adenocarcinoma and lower human normal adjacent tissues were constructed by integration of Pearson CC, GRNInfer and GO. As visualized by integration of GO, KEGG, GenMAPP, BioCarta and Disease, we deduced COMP complete different activated and inhibited network in higher lung adenocarcinoma and lower human normal adjacent tissues. RESULTS: As visualized by GO, KEGG, GenMAPP, BioCarta and disease database integration, we proposed mainly that the mechanism and function of COMP complete different activated network in higher lung adenocarcinoma was involved in COMP activation with matrix-localized insulin-like factor coupling carboxypeptidase to metallopeptidase-induced proteolysis, whereas the corresponding inhibited network in lower human normal adjacent tissues participated in COMP inhibition with nucleus-localized vasculogenesis, B and T cell differentiation and neural endocrine factors coupling pyrophosphatase-mediated proteolysis. However, COMP complete different inhibited network in higher lung adenocarcinoma included COMP inhibition with nucleus-localized chromatin maintenance, licensing and assembly factors coupling phosphatase-inhibitor to cytokinesis regulators-mediated cell differentiation, whereas the corresponding activated network in lower human normal adjacent tissues contained COMP activation with cytolplasm-localized translation elongation factor coupling fucosyltransferase to ubiquitin-protein ligase-induced cell differentiation. CONCLUSION: COMP different networks were verified not only by complete and uncomplete COMP activated or inhibited networks within human normal adjacent tissues or lung adenocarcinoma, but also by COMP activated and inhibited network between human normal adjacent tissues and lung adenocarcinoma.

Activated amelogenin Y-linked (AMELY) regulation and angiogenesis in human hepatocellular carcinoma by biocomputation.

In the present study, a comparison of the biological processes and gene ontology (GO) in human hepatocellular carcinoma (HCC) with high expression (fold change ≥2) of amelogenin Y-linked (AMELY)-activated upstream regulation networks with non-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) with low expression of activated networks was performed. The principle biological processes involved in non-tumor hepatitis/cirrhotic tissues include positive regulation of mismatch repair, regulation of transcription from RNA polymerase II promoters, negative regulation of cell-cell adhesion, protein ubiquitinatin and protein catabolism. The main biological processes involved in the development of HCC include positive regulation of calcium ion transport into the cytosol, cell proliferation, DNA replication, fibroblast proliferation, immune response, microtubule polymerization and protein secretion. Specific transcription from RNA polymerase II promoters, regulation of angiogenesis, cell growth, protein metabolism, Wnt receptor signaling pathways, negative regulation of endothelial cell differentiation, microtubule depolymerization, peptidase activity and progression through the cell cycle are also involved. Positive regulation of transcription is involved in both processes. An activated AMELY-coupled upstream positive regulation of immune response-mediated protein secretion to Wnt signaling and calcium into cytosol-induced regulation of cell growth and angiogenesis in HCC is proposed. The AMELY upstream regulation molecular network model was constructed with BUB1B, CST6, ESM1, HOXA5, LEF1, MAPT, MYBL2, NOTCH3, PLA2G1B, PROK1, ROBO1, SCML2 and UBE2C in HCC from a Gene Expression Omnibus (GEO) dataset by gene regulation network inference methods and our programming methods.