Migration Of Liver Cancer Cells Research Articles

SNRPB2 in the pan-cancer landscape: A bioinformatics exploration and validation in hepatocellular carcinoma

Aberrant splicing is a significant contributor to gene expression abnormalities in cancer. SNRPB2, a component of U2 small nuclear ribonucleoprotein particles (snRNPs), contributes to the assembly of the spliceosome, the molecular machinery responsible for splicing. To date, few studies have investigated the role of SNRPB2 in tumorigenesis. We examined data sourced from various public databases, such as The Cancer Genome Atlas(TCGA), the Clinical Proteomic Tumor Analysis Consortium(CPTAC), and Gene Expression Omnibus(GEO). Our investigation included gene expression, genomic and epigenomic scrutiny, gene set enrichment assessment(GSEA), and immune cell infiltration evaluation. Furthermore, we performed empirical validation to ascertain the impact of SNRPB2 suppression on the proliferation and migration of liver cancer cells. Analysis of gene expression revealed widespread upregulation of SNRPB2 across a spectrum of cancer types, with heightened levels of SNRPB2 expression in numerous tumors linked to unfavorable prognosis. Genomic and epigenomic assessments revealed connections between SNRPB2 expression and variations in SNRPB2 copy number, DNA methylation patterns, and RNA modifications. Through gene set enrichment analysis, the involvement of SNRPB2 in vital biological processes and pathways related to cancer was identified. Furthermore, scrutiny of immune cell infiltration suggested a potential relationship between SNRPB2 and the tumor microenvironment, which was reinforced by multiple single-cell sequencing profiles. Subsequent experimental validation revealed that silencing SNRPB2 effectively impeded the proliferation and migration of liver cancer cells. Taken together, these findings underscore the prospective utility of SNRPB2 as a prognostic biomarker and a promising candidate for immunotherapy in cancer. It is necessary to engage in additional exploration into its underlying mechanisms and clinical treatment potential.

Dihydroartemisinin inhibits ATP6 activity, reduces energy metabolism of hepatocellular carcinoma cells, promotes apoptosis and inhibits metastasis via CANX.

Dihydroartemisinin (DHA) may inhibit the migration and invasion of liver cancer cells by reducing ATP synthase production (specifically ATP1A1 and ATP5H) through the calcium/calmodulin dependent protein kinase kinase 2/solute carrier family 8 member B1 signaling pathway. However, it is unclear whether DHA regulates ATP synthase activity by modulating other calcium ion signals to inhibit the energy metabolism and the transfer of hepatocellular carcinoma (HCC) cells. Using the Gene Expression Profiling Interactive Analysis database, a search for specific expression genes in liver cancer tissues was performed. Human HCC HuH-7 and Li-7 cells were used to produce CANX overexpression and small interfering RNA cell models. The study assessed changes in cell proliferation, apoptosis, migration and invasion. Reactive oxygen species production, ATP production, mitochondrial membrane potential (JC-1), NAD+/NADH ratio and mitochondrial fluorescence were also evaluated. Western blotting was used to assess changes in CANX, ATP6V1 domain (ATP6V1F) and V0 domain (ATP6V0B) protein expression levels. The results demonstrated that CANX is highly expressed in liver cancer tissues. Furthermore, CANX regulated malignant biological behavior, mediated mitochondrial function and energy metabolism. However, these effects were inhibited by DHA, which decreased the expression of CANX, ATP6V0B and ATP6V1F. The findings of the present study underscore the central role of CANX in affecting the malignant biological behavior of liver cancer cells by regulating mitochondrial function and energy metabolism. Additionally, they indicate that DHA serves an anticancer role by inhibiting CANX expression.

The Prognostic Significance of CTSV Expression in Patients with Hepatocellular Carcinoma.

Cathepsin V (CTSV) is a cysteine protease peptidase, which is typically upregulated in cancer and is associated with various oncogenic processes, such as angiogenesis, proliferation, apoptosis, and invasion. The study explored the role of CTSV in hepatocellular carcinoma (HCC) and its potential as a potential biomarker. This study collected tumor and peritumoral archived specimens from 180HCC patients who underwent surgical resection at Zhongshan Hospital, Fudan University (Shanghai, China) between 2009 and 2010. We extracted data from the TCGA and GEO databases and conducted differential expression analysis, univariate Cox regression, and Kaplan-Meier analysis. Ultimately, we determined that CTSV may emerge as a potential biomarker. Then, immunohistochemical staining for CTSV was performed on tumors and adjacent tissues of HCC patients, and a Cox proportional hazards model was constructed to evaluate the prognostic significance of CTSV expression levels. Applied functional enrichment analysis to reveal the underlying molecular mechanisms. Utilized ssGSEA enrichment analysis and TIMER2.0 algorithm to explore the correlation between CTSV expression and immune cells in HCC. In vitro and in vivo experiments were conducted using human liver cancer cell lines to further validate the clinical application value of CTSV. In this study, we observed that CTSV expression was notably elevated in HCC (P < 0.001), and identified a significant association between elevated CTSV expression and reduced overall survival rates in patients. In vitro and in vivo experiments indicated that CTSV knockdown could significantly inhibit the proliferation, migration, and invasion of liver cancer cells, and it was found that the combination of CTSV knockdown with PD-1 inhibitors might enhance the therapeutic effect of PD-1 inhibitors in HCC. CTSV serves as a standalone negative prognostic indicator and possesses clinical significance in HCC.

Effects of Dexmedetomidine on Proliferation, Invasion, Migration and Angiogenesis of Hypoxia-Induced HepG2 Liver Cancer Cells

Effects of Dexmedetomidine on Proliferation, Invasion, Migration and Angiogenesis of Hypoxia-Induced HepG2 Liver Cancer Cells

In Vitro Simulated Ketogenic Diet Inhibits the Proliferation and Migration of Liver Cancer Cells by Reducing Insulin Production and Down-regulating FOXC2 Expression.

Ketogenic diet (KD) may benefit patients with liver cancer, but the underlying mechanism of its anti-cancer effect remains an open issue. This work aimed to explore the influence of simulated KD on the proliferation and migration of cultured hepatoma cells. The low-glucose medium supplemented with β-hydroxybutyrate (BHB-Glow) was utilized to simulate clinical KD treatment. Western blot was utilized for detecting the expression of glycolysis-related proteins, Seahorse XF96 for oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), and ELISA for insulin content. Expression of FOXC2 in liver cancer cells was analyzed by bioinformatics and qPCR. Cell Count Kit-8 (CCK-8) testing kit was utilized for testing cell viability. KD treatment significantly reduced the expression of glycolysis-related proteins in Huh-7 cells, inhibited insulin production in β islet cells, reduced ECAR, and increased OCR. FOXC2 was significantly up-regulated in Huh-7 cell line, and sh-FOXC2 hindered the proliferation and migration of Huh-7 cells. The exogenous addition of insulin promoted the malignant progression of Huh-7 cells. Together, the medium simulating KD environment strengthened the protection of liver cancer cells by reducing insulin production and down-regulating FOXC2 expression. This study confirmed through in vitro cell experiments that KD could inhibit the proliferation and migration of liver cancer cells by targeting down regulation of insulin and FOXC2 expression, providing new theoretical basis for the treatment of liver cancer patients.

KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression.

Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression. We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo. Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice. KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

ZFC3H1 as an Indicator of Poor Prognosis in Hepatocellular Carcinoma: Bioinformatic Analysis and Experimental Verification.

Zinc finger C3H1-type containing (ZFC3H1) might regulate RNA processes. However, research lacks the prognostic value of ZFC3H1 in hepatocellular carcinoma (HCC). The study analyzed ZFC3H1 expression in HCC cells and its correlation with patient prognosis using transcriptomics, immunohistochemistry, and quantitative real-time reverse transcription PCR, as well as single-cell RNA expression data. Additionally, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were used to investigate the potential ZFC3H1-related cellular functions and signaling pathways. The impact of ZFC3H1 expression on the tumor microenvironment and tumor mutational burden (TMB) was assessed using the ESTIMATE algorithm. Cell-based assays, including cell counting kit 8, proliferation, colony formation, cell cycle, wound healing, and Transwell assays, were conducted to evaluate the influence of ZFC3H1 on hepatocellular carcinoma proliferation and migration. ZFC3H1 is upregulated in HCC and linked to tumor progression. High ZFC3H1 expression is a prognostic risk factor for HCC, according to Kaplan-Meier and Cox regression analyses. ESTIMATE analysis suggested that ZFC3H1 reduces immune cell infiltration and increases the TMB. Patients with low ZFC3H1 expression might respond better to immunotherapy. High ZFC3H1 expression is associated with increased half-maximal inhibitory concentration (IC50) of sorafenib. Functional experiments demonstrated that reducing ZFC3H1 expression inhibited HCC cell proliferation and migration. ZFC3H1 is upregulated in HCC, promoting the proliferation and migration of liver cancer cells, impacting the prognosis of HCC patients and the effectiveness of immunotherapy. ZFC3H1 might serve as a therapeutic target and biomarker for HCC.

JDF promotes the apoptosis of M2 macrophages and reduces epithelial-mesenchymal transition and migration of liver cancer cells by inhibiting CSF-1/PI3K/AKT signaling pathway

BackgroundThe interaction between cancer cells and the tumor microenvironment is of critical importance in liver cancer. Jiedu Granule formula (JDF) has been shown to minimize the risk of recurrence and metastasis following liver cancer resection. Investigating the mechanism underlying the therapeutic effects of JDF can extend its field of application and develop novel treatment approaches. MethodsWe established a rat liver orthotopic transplantation tumor model, and recorded the prognostic effects of JDF adjuvant therapy on the recurrence and metastasis of liver cancer. Liver and lung tissues were collected for immunofluorescence staining and H&E staining, respectively. In addition, THP-1 cells were incubated with PMA and IL-4 to induce them to differentiate into M2 macrophages. CSF-1 expression was knocked down using lentivirus to determine the function of CSF-1. Liver cancer cells were cultured with a conditioned medium (CM) or co-cultured with macrophages. Cell viability was determined using the MTT assay. The levels of CSF-1, CSF-1R, E-cadherin, N-cadherin, PI3K, AKT, and cleaved caspase-3 were detected using ELISA, Western blotting and qPCR. The ability of cells to migrate was assessed using cell scratch and transwell assays. Apoptosis was evaluated using flow cytometry. ResultsThe JDF treatment decreased the risk of liver cancer metastasis after surgery and the infiltration of CD206/CD68 cells in liver cancer tissue. In cell experiments, JDF showed effects in suppressing M2 macrophages activity and downregulating the expression of CSF-1 and CSF-1R. The concentration of CSF-1 in the supernatant was also lower in the JDF-treated group. Futhermore, M2-CM was found to promote cancer cell migration and epithelial-mesenchymal transition (EMT); however, these effects were weakened after administering JDF. Knocking down endogenous CSF-1 in M2 macrophages resulted in a comparable suppression of cancer cell migration and EMT. Additionally, JDF treatment inhibited activation of the PI3K/AKT pathway, thus promoting the apoptosis of M2 macrophages. ConclusionsTreatment with JDF reduced the EMT and migratory capacity of liver cancer cells, which might be attributed to the inhibition of M2 macrophage infiltration and interruption of the CSF-1/PI3K/AKT signaling pathway. This mechanism may hold significant implications for mitigating the risk of metastatic spread in the aftermath of hepatic surgery.

Glioma-associated oncogene (GLI)-specific decoy oligodeoxynucleotide induces apoptosis and attenuates proliferation, colony formation, and migration in liver cancer cells

Aim: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. The Sonic Hedgehog (SHH) signaling pathway participates in the initiation, progression, migration, and recurrence of HCC cancer stem cells. Furthermore, SHH regulates various cellular behaviors such as proliferation, differentiation, survival, self-renewal, epithelial-mesenchymal transition (EMT), and SHH autoregulation. Glioma-associated oncogene (GLI) family zinc finger are key transcription factors in the development of many organs and are deregulated in cancer. In this study, Huh-7 cells were treated with GLI-specific decoy oligodeoxynucleotide (ODN) to evaluate its anticancer impact. Methods: The transfection efficiency of GLI-specific decoy ODN was measured using fluorescent microscopy. Then, the effects of GLI-specific decoy ODN on apoptosis, viability, proliferation rate, colony formation, and migration capacities of Huh-7 cells were assessed. Furthermore, the expression of genes associated with the alteration of SHH was assessed. Results: Treatment of Huh-7 cells with GLI-specific decoy ODN decreased cell viability (56.36% ± 3%). Expression of certain genes such as c-MYC , SNAI2 , ZEB1 , and PROM1 decreased dramatically, while the expression of CDH1 increased significantly. Furthermore, the treated cells’ proliferation, colony formation, and migration capacity decreased considerably. This treatment induced apoptosis in the Huh-7 cells. Conclusion: Inhibition of the SHH signaling pathway using GLI-specific decoy ODN led to a decline in the growth rate of HCC cells, decreased migration, and attenuated EMT progression.

Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

FGA influences invasion and metastasis of hepatocellular carcinoma through the PI3K/AKT pathway.

Fibrinogen is an important plasma protein composed of three polypeptide chains, fibrinogen alpha (FGA), beta, and gamma. Apart from being an inflammation regulator, fibrinogen also plays a role in tumor progression. Liver cancer usually has a poor prognosis, with chronic hepatitis being the main cause of liver cirrhosis and hepatocellular carcinoma (HCC). FGA serves as a serological marker for chronic hepatitis, but its relationship with liver cancer remains unclear. Through bioinformatics analysis and agarose gel electrophoresis, we found that FGA was downregulated in HCC and correlated with tumor stage and grade. By constructing both FGA gene knockout and overexpression cell models, we demonstrated that overexpressing FGA inhibited migration and invasion of liver cancer cells through Transwell migration/invasion and wound healing assays. Western blotting experiments showed that FGA overexpression increased the expression of the epithelial-mesenchymal transition marker protein E-cadherin while decreasing N-cadherin and slug protein expression. In addition, FGA knockout activated the PI3K/AKT pathway. In a mouse model of metastatic tumors, overexpression of FGA restricted the spread of tumor cells. In conclusion, FGA exhibits an inhibitory effect on tumor metastasis, providing new insights for the treatment of advanced HCC metastatic tumors.

Comprehensive analysis of PSMG3 in pan-cancer and validation of its role in hepatocellular carcinoma.

Proteasome assembly chaperone 3 (PSMG3), a subunit of proteasome, has been found to be associated with lung cancer. However, the role of PSMG3 in other cancers has not been elucidated. The objective of this study was to explore the immune role of PSMG3 in pan-cancer and confirm the oncogenic significance in liver hepatocellular carcinoma (LIHC). We examined the differential expression of PSMG3 across various cancer types using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. We investigated the prognostic value of PSMG3 and examined its relationship with tumor mutation burden (TMB), microsatellite instability (MSI), and immune infiltration. The functional enrichment analysis was performed to explore the potential molecular mechanism of PSMG3. To elucidate the biological function of PSMG3, we conducted in vitro experiments using liver cancer cell lines. PSMG3 was highly expressed in most cancers. The high PSMG3 expression value of PSMG3 was closely related to poor prognosis. We observed correlations between PSMG3 and TMB, and MSI immune infiltration. PSMG3 may be involved in metabolic reprogramming, cell cycle, and PPAR pathways. The over-expression of PSMG3 promoted the proliferation, migration, and invasion capabilities of liver cancer cells. Our study demonstrated that PSMG3 was a pivotal oncogene in multiple cancers. PSMG3 contributed to the progression and immune infiltration in pan-cancer, especially in LIHC.

Sesquilignans PD from Zanthoxylum nitidum var. tomentosum exerts antitumor effects via the ROS/MAPK pathway in liver cancer cells

Sesquilignans PD is a natural phenylpropanoid compound that was isolated from Zanthoxylum nitidum var. tomentosum. In this study, we assessed the antitumor effect of PD on SK-Hep-1 and HepG2 cells and the underlying molecular mechanisms. The results revealed that PD markedly inhibited the proliferation and migration of both liver cancer cells. Moreover, PD induced apoptosis, autophagy, and reactive oxygen species (ROS) production in liver cancer cells. Notably, PD increased the protein levels of p-p38 MAPK and p-ERK1/2 in liver cancer cells. This is the first report on the anticancer effect of PD, which is mediated via increased ROS production and MAPK signaling activation.

N-glycosylation of Wnt3 regulates the progression of hepatocellular carcinoma by affecting Wnt/β-catenin signal pathway.

Wnt/FZD-mediated signaling pathways are activated in more than 90% of hepatocellular carcinoma (HCC) cell lines. As a well-known secretory glycoprotein, Wnt3 can interact with FZD receptors on the cell surface, thereby activating the Wnt/β-catenin signaling pathway. However, the N-glycosylation modification site of Wnt3 and the effect of this modification on the biological function of the protein are still unclear. To investigate the effect of Wnt3 N-glycosylation on the biological function of HCC cells. Site-directed mutagenesis was used to verify the Wnt3 N-glycosylation sites, actinomycin D treatment was used to detect the stability of Wnt3 after site-directed mutation, the binding of the N-glycosylation site-directed mutant Wnt3 to FZD7 was observed by laser confocal microscopy, and the effects of the N-glycosylation site-directed mutation of Wnt3 on the Wnt/β-catenin signaling pathway and the progression of HCC cells were detected by western blot and cell function experiments. Wnt3 has two N-glycosylation-modified sites (Asn90 and Asn301); when a single site at amino acid 301 is mutated, the stability of Wnt3 is weakened; the binding ability of Wnt3 to FZD7 decreases when both sites are mutated simultaneously; and the level of proteins related to the Wnt/β-catenin signaling pathway is downregulated. Cell proliferation, migration and invasion are also weakened in the case of single 301 site and double-site mutations. These results indicate that by inhibiting the N-glycosylation of Wnt3, the proliferation, migration, invasion and colony formation abilities of liver cancer cells can be weakened, which might provide new therapeutic strategies for clinical liver cancer in the future.

MiR-3680-3p is a novel biomarker for the diagnosis and prognosis of liver cancer and is involved in regulating the progression of liver cancer.

MicroRNAs (miRNAs) are small non-coding RNAs that can actively participate in post-transcriptional regulation of genes. A number of studies have shown that miRNAs can serve as important regulators of cancer cell growth, differentiation, and apoptosis. They can also act as markers for the diagnosis and prognosis of certain cancers. To explore the potential prognosis-related miRNAs in liver cancer patients, to provide theoretical basis for early diagnosis and prognosis of liver cancer, as well as to provide a new direction for the targeted therapy of liver cancer. The miRNA expression profiles of liver cancer patients in the the Cancer Genome Atlas database were comprehensively analyzed and various prognostic-related miRNAs of liver cancer were screened out. The data was further subjected to survival analysis, prognostic analysis, gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis, microenvironment analysis, and drug sensitivity analysis by R Language version 4.2.0. Finally, the screened miRNAs were further validated by different experiments. Thus, miNRAs involved in liver cancer diagnosis and prognosis were identified. MiRNA-3680-3p was found to be significantly different in 10 different cancers, including liver cancer, and was significantly associated with the microenvironment, survival, and prognosis of liver cancer patients. In addition, drug sensitivity analysis revealed that miRNA-3680-3p can provide a useful reference for drug selection in targeted therapy for liver cancer. MiRNA-3680-3p can serve as a biomarker for the diagnosis and prognosis of liver cancer patients and down-regulation of miRNA-3680-3p could significantly inhibit both the proliferation and migration of liver cancer cells.

Targeting BMP2 for therapeutic strategies against hepatocellular carcinoma

ObjectivesThis study aimed to investigate the role of BMP2 in hepatocellular carcinoma (HCC) growth and metastasis using a dual approach combining single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. MethodsscRNA-seq data from the GEO database and bulk RNA-seq data from the TCGA database were analyzed. Differentially expressed marker genes of endothelial cells were identified and analyzed using enrichment analysis, PPI analysis, correlation analysis, and GSEA. In vitro, experiments were conducted using the Huh-7 HCC cell line, and in vivo, models of HCC growth and metastasis were established by knocking down BMP2. ResultsThe scRNA-seq analysis identified BMP2 as a key marker gene in endothelial cells of HCC samples. Elevated BMP2 expression correlated with poor prognosis in HCC. In vitro experiments showed that silencing BMP2 inhibited the proliferation, migration, and invasion of liver cancer cells. In vivo studies confirmed increased BMP2 expression in HCC tissues, promoting angiogenesis and HCC growth. ConclusionThis study highlights the role of BMP2 in tumor angiogenesis and HCC progression. Targeting BMP2 could be a promising therapeutic strategy against HCC.

MiR‑576‑3p/M‑phase phosphoprotein 8 axis regulates the malignant progression of hepatocellular carcinoma cells via the PI3K/Akt signaling pathway.

Hepatocellular carcinoma (HCC) is a fatal digestive system cancer with unclear pathogenesis. M-phase phosphoprotein 8 (MPP8) has been shown to play a vital role in several cancer types, such as non-small cell lung cancer, gastric cancer and melanoma; however, there have been no studies into its role in HCC. The present study aimed to evaluate the role of MPP8 in regulating malignant phenotypes of liver cancer cells, and to further investigate the underlying mechanism. Bioinformatics analysis was performed to analyze related data from a public database, and to predict the potential microRNAs (miRNAs) that might target MPP8 mRNA; reverse transcription-quantitative PCR was used to measure the levels of mRNA and miRNA; western blotting was employed to detect protein levels; Cell Counting Kit-8 (CCK-8) and plate colony formation assays, wound healing assay and Transwell invasion assay were performed to evaluate the ability of cell proliferation, migration and invasion, respectively; dual-luciferase reporter gene assay was performed to identify the target association. The results showed that MPP8 was a risk factor for the survival of patients with HCC, and was up-regulated in HCC tissue samples and cell lines; MPP8 knockdown inhibited the proliferation, migration and invasion of liver cancer cells; MPP8 knockdown suppressed the PI3K/Akt pathway, and activation of this pathway reversed the inhibited liver cancer cell phenotypes by down-regulating MPP8; miR-576-3p, which was low in liver cancer cells, negatively regulated MPP8 expression by directly targeting its mRNA; up-regulating MPP8 expression reversed the inhibited signaling pathway and malignant phenotypes of liver cancer cells by miR-576-3p overexpression. In conclusion, the miR-576-3p/MPP8 axis regulates the proliferation, migration, and invasion of liver cancer cells through the PI3K/Akt signaling pathway. These findings lead novel insights into HCC progression, and propose MPP8 as a potential therapeutic target for HCC.

Role of autophagy-related genes in liver cancer prognosis

Autophagy, a highly conserved process of protein and organelle degradation, has emerged as a critical regulator in various diseases, including cancer progression. In the context of liver cancer, the predictive value of autophagy-related genes remains ambiguous. Leveraging chip datasets from the TCGA and GTEx databases, we identified 23 differentially expressed autophagy-related genes in liver cancer. Notably, five key autophagy genes, PRKAA2, BIRC5, MAPT, IGF1, and SPNS1, were highlighted as potential prognostic markers, with MAPT showing significant overexpression in clinical samples. In vitro cellular assays further demonstrated that MAPT promotes liver cancer cell proliferation, migration, and invasion by inhibiting autophagy and suppressing apoptosis. Subsequent in vivo studies further corroborated the pro-tumorigenic role of MAPT by suppressing autophagy. Collectively, our model based on the five key genes provides a promising tool for predicting liver cancer prognosis, with MAPT emerging as a pivotal factor in tumor progression through autophagy modulation.

Mechanism study of tyrosine phosphatase shp-1 in inhibiting hepatocellular carcinoma progression by regulating the SHP2/GM-CSF pathway in TAMs

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Macrophage-mediated innate immune responses play a crucial role in tumor development. This study revealed the mechanism of SHP-1 in regulating HCC progression. SHP-1 inhibits tumour development in vivo. Increasing SHP-1 expression in macrophages promotes the expression of p-SHP-1, SHP2, and p-SHP-2. In macrophages GM-CSF recruits SHP-2 to the GM-CSF receptor GM-CSFR induces p-SHP-2 dephosphorylation. GM-CSF recruits p-SHP-2 for dephosphorylation by up-regulating HoxA10HOXA10 activates the transcription of TGFβ2 by interacting with tandem cis-elements in the promoter thereby regulating the proliferation and migration of liver cancer cells. GM-CSF inhibits SHP-1 regulation of p-SHP-1, SHP2, and p-SHP-2 in macrophages. Detailed studies have shown that SHP-1 regulates SHP2 expression, and SHP-1 and SHP2 are involved in macrophage M2 polarisation. SHP-1 inhibits HOXA10 and TGFβ2 which in turn regulates the expression of the migration-associated proteins, MMP2/9, and the migration of hepatocellular carcinoma cells. Overexpression of SHP-1 inhibits macrophage M2 polarisation via the p-STAT3/6 signalling pathway Classical markers arginase-1, CD206, CD163 and regulate the expression of M2 polarisation cytokines IL-4 and IL-10. In addition, hypoxia-induced ROS inhibited SHP-1 regulation by suppressing the expression of p-SHP-1. The combined effect of GM-CSF and ROS significantly increased p-HOXA10/TGFβ2 and macrophage M2 polarisation, and the regulatory effect of ROS was significantly suppressed by GM-CSF knockdown. These findings suggest that increasing the expression of tyrosine phosphatase SHP-1 can inhibit hepatocellular carcinoma progression by modulating the SHP2/GM-CSF pathway in TAM and thus inhibit the progression of hepatocellular carcinoma.

Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells

High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to hepatocellular carcinoma progression. We aimed at mechanistically understanding the impact of PI4KIIIα on the progression of liver cancer and the potential contribution of HCV in this process. Several hepatic cell culture and mouse models were used to study the functional importance of PI4KIIIα on liver pathogenesis. Antibody arrays, gene silencing, and PI4KIIIα-specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. High PI4KIIIα expression and/or activity induced cytoskeletal rearrangements via increased phosphorylation of paxillin and cofilin. This led to morphologic alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver-specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2γ) working downstream of PI4KIIIα in regulation of the cytoskeleton. PIK3C2γ generates plasma membrane phosphatidylinositol 3,4-bisphosphate-enriched, invadopodia-like structures that regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. PI4KIIIα regulates cytoskeleton organization via PIK3C2γ/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIIIα and HCV to the progression of liver cancer and identify promising targets for therapeutic intervention.