Methylation-regulated tumor suppressor gene PDE7B promotes HCC invasion and metastasis through the PI3K/AKT signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high mortality rate, and the mechanisms underlying tumor development and progression remain unclear. However, inactivated tumor suppressor genes might play key roles. DNA methylation is a critical regulatory mechanism for inactivating tumor suppressor genes in HCC. Therefore, this study investigated methylation-related tumor suppressors in HCC to identify potential biomarkers and therapeutic targets. METHODS: We assessed genome-wide DNA methylation in HCC using whole genome bisulfite sequencing (WGBS) and RNA sequencing, respectively, and identified the differential expression of methylation-related genes, and finally screened phosphodiesterase 7B (PDE7B) for the study. The correlation between PDE7B expression and clinical features was then assessed. We then analyzed the changes of PDE7B expression in HCC cells before and after DNA methyltransferase inhibitor treatment by MassArray nucleic acid mass spectrometry. Furthermore, HCC cell lines overexpressing PDE7B were constructed to investigate its effect on HCC cell function. Finally, GO and KEGG were applied for the enrichment analysis of PDE7B-related pathways, and their effects on the expression of pathway proteins and EMT-related factors in HCC cells were preliminarily explored. RESULTS: HCC exhibited a genome-wide hypomethylation pattern. We screened 713 hypomethylated and 362 hypermethylated mCG regions in HCC and adjacent normal tissues. GO analysis showed that the main molecular functions of hypermethylation and hypomethylation were "DNA-binding transcriptional activator activity" and "structural component of ribosomes", respectively, whereas KEGG analysis showed that they were enriched in "bile secretion" and "Ras-associated protein-1 (Rap1) signaling pathway", respectively. PDE7B expression was significantly down-regulated in HCC tissues, and this low expression was negatively correlated with recurrence and prognosis of HCC. In addition, DNA methylation regulates PDE7B expression in HCC. On the contrary, overexpression of PDE7B inhibited tumor proliferation and metastasis in vitro. In addition, PDE7B-related genes were mainly enriched in the PI3K/ATK signaling pathway, and PDE7B overexpression inhibited the progression of PI3K/ATK signaling pathway-related proteins and EMT. CONCLUSION: PDE7B expression in HCC may be regulated by promoter methylation. PDE7B can regulate the EMT process in HCC cells through the PI3K/AKT pathway, which in turn affects HCC metastasis and invasion.

Prognostic significance and immune characteristics of CMTM4 in hepatocellular carcinoma.

BACKGROUND: Previous study has shown that chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family member 4 (CMTM4) can bind and maintain programmed cell death ligand 1 (PD-L1) expression to promote tumor progression by alleviating the suppression of tumor-specific T cell activity, suggesting its potential role in tumor immunotherapy. However, the role of CMTM4 in tumor immunity has not been well clarified, especially in hepatocellular carcinoma (HCC). METHODS: The protein expression of CMTM4/PD-L1/CD4/CD8 was detected by immunohistochemistry (IHC) detection in 90 cases of HCC tissues. The mRNA expression profiles and related prognosis data were obtained from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC). Two immune therapy cohorts were from Imvigor210 and GSE176307. RESULTS: Though the single protein expression of CMTM4, PD-L1, CD4 or CD8 in HCC tissues by IHC detection didn't show a significant relationship with the prognosis of HCC patients, we found that high co-expression of CMTM4/PD-L1/CD4 showed a good prognosis of HCC patients. Further Timer 2.0 analysis identified that HCC patients with high expression of CMTM4/PD-L1 and high infiltration of CD4+ T cells had a better overall survival than those with low infiltration of CD4+ T cells. Moreover, a series of bioinformatics analyses revealed that CMTM4-related genes posed important effects on prognosis and immunity in HCC patients, and CMTM4 had a positive correlation with infiltration of CD4+ and CD8+ T cells in HCC. At last, we used two immunotherapy cohorts to verify that the combination of CMTM4 with PD-L1 could improve the prognosis of tumor patients underwent immunotherapy. CONCLUSIONS: CMTM4 and PD-L1 co-expression with T cell infiltration shows prognostic significance in HCC, suggesting combined effect from multiple proteins should be considered in HCC treatment.

Hb New York, preliminary results concerning the hematologic characteristics and the effects on thalassemia.

BACKGROUND: The hematological phenotype and genotype analysis of hemoglobin New York (Hb New York) combined with α or ß thalassemia has been rarely reported, and whether there is any effect of Hb New York on thalassemia has not been well explored. METHODS AND RESULTS: In this study, peripheral blood samples from 346 Hb New York carriers were collected for blood cell parameter analysis. When comparing Hb New York heterozygotes, Hb New York combined with α0 thalassemia or α+ thalassemia, we found that the differences in hemoglobin (HGB), MCV and MCH values were statistically significant (P < 0.05). The HGB, MCV and MCH values of α thalassemia patients were not different from Hb New York combined with α thalassemia group (P > 0.05). When Hb New York heterozygotes were compared to Hb New York combined with ß0 thalassemia or ß+ thalassemia, the differences in MCV and MCH values were statistically significant (P < 0.05). However, the differences in MCV and MCH values were not statistically significant between Hb New York combined with ß thalassemia and ß thalassemia (P > 0.05). CONCLUSIONS: Our study shows that the hematological characteristics of Hb New York combined with thalassemia are similar to the corresponding thalassemia, and Hb New York does not aggravate the clinical manifestations of thalassemia.

Okadaic acid promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells by inhibiting protein phosphatase 2A.

As a specific inhibitor of serine/threonine protein phosphatases, okadaic acid (OA) has been found to be a tumor promoter. However, whether OA plays a role in metastasis of hepatocellular carcinoma (HCC) has not been well elucidated. In this study, Hep3B and HepG2 cells were treated with different doses of OA and the cell viability was determined by CCK8 test. As a result, Hep3B and HepG2 cells showed no obvious cytotoxicity after OA treatment below 20 or 25 nM for 12 or 24 hours. However, wound healing, invasion, and migration abilities of HCC cells were significantly enhanced in the OA-treated groups than those of the control group (P < .05), measured by cell scratching and BD transwell assays. Moreover, we found that the expression of epithelial-mesenchymal transition (EMT)-related key factors was changed upon OA treatment in a dose-dependent manner. In addition, the activity of protein phosphatase 2A (PP2A) in OA-treated cells was also decreased significantly compared with the control cells (P < .05). Interfering of PP2A subunit A or C caused a similar expression change of EMT-related key factors as the OA treatment in HCC cells. Our results suggest that OA promotes the EMT process of HCC cells by inhibiting the activity of PP2A.

Retraction Note to: Correlations between chromobox homolog 8 and key factors of epithelial-mesenchymal transition in hepatocellular carcinoma.

[This retracts the article DOI: 10.1186/s12935-019-1063-z.].

Potential role of CFTR in bisphenol A-induced malignant transformation of prostate cells via mitochondrial apoptosis.

Bisphenol A (BPA) is an environmental endocrine disruptor and a risk factor for prostate cancer. The cystic fibrosis transmembrane conductance regulator (CFTR) is proposed to be a prostate cancer suppressor in some recent researches. However, the potential role and mechanism of CFTR in BPA-induced prostate cancer cells has not been well identified. In this study, BPA decreased the viability of human normal prostate RWPE-1 cells detected with a CCK-8 kit. The capacity of the cell line on soft agar colony formation, wound healing, and transwell invasion indicated malignant transformation induced by BPA. Western blot analysis demonstrated that the levels of CFTR and Bcl-2 decreased, whereas Bax level increased, and ELISA detection showed a decreased ATP level in BPA-exposed cells. Cell apoptosis was analyzed with Annexin V-FITC Detection Kit by flow cytometry. However, no significant difference was observed in cell viability and apoptosis rates compared to normal RWPE-1 cells. Our research revealed a potential role of CFTR in BPA-induced malignant transformation via mitochondrial apoptosis of normal prostate cells.

Neurotoxicity and related mechanisms of flame retardant TCEP exposure in mice.

Objective: To explore the neurotoxicity and mechanism of tris(2-chloroethyl) phosphate (TCEP) exposure in mice.Methods: Total 30 adult Kunming mice were randomly divided into normal control group (0 mg/kg·d), low-dose TCEP group (10 mg/kg·d), and high-dose TCEP group (100 mg/kg·d), and administered continuously by gavage for 30 days.Results: Compared with the control group, the water intake of high-dose TCEP group was declined significantly (p < 0.05), and the organ index of liver and spleen were increased significantly (p < 0.05). In addition, the escape latency of TCEP exposed mice were longer than that in the control group in water maze test (p < 0.05), while the total swimming course of high-dose TCEP group was elevated and the swimming time in target quadrant was obviously shortened compared with the control group (p < 0.05). The serum levels of total-triiodothyronine (TT3) and free triiodothyronine (FT3) were significantly higher in the high-dose TCEP group than in the control group (p＜0.05). Compared with the control group, the activities of glutathione transferase (GST) and super oxide dismutase (SOD) in the high-dose TCEP group were increased, and GST in the low-dose TCEP group were decreased, while the content of malonaldehyde (MDA) in both groups was increased (p＜0.05). In the CCK8 assay, the viability of PC12 cells decreased with an increase of TCEP concentration, indicating a concentration dependent neurotoxicity.Conclusion: TCEP exposure can cause neurotoxicity by increasing thyroid hormones and inducing oxidative damage in mice.

A novel role and mechanism of cystic fibrosis transmembrane conductance regulator in bisphenol A-induced prostate cancer.

Bisphenol A (BPA) is a well known environmental endocrine disruptor that may cause human prostate cancer through disturbing cell mitosis, proliferation, and apoptosis. As one of the most important anion channels in organisms, cystic fibrosis transmembrane conductance regulator (CFTR) is proposed as a tumor suppressor in carcinogenesis and development of prostate cancer in recent studies. Whether CFTR plays a role in BPA-induced prostate cancer needs to be further identified. In this study, two prostate cancer cell lines PC-3 and LNCaP were exposed to BPA for detecting the cytotoxic reactions by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assays. After the treatment with BPA for 24 hours, the cell viability was decreased significantly with increased cell apoptosis in the two cell lines. Moreover, both PC-3 and LNCaP cells had a reduced expression level of cAMP, CFTR, and adenosine triphosphate upon BPA treatment. In addition, AMPKα kinase was found upregulated to promote cell apoptosis through increasing Bax expression and decreasing Bcl-2 expression. Our study suggests a role and mechanism of CFTR in BPA-induced prostate cancer via cell apoptosis for the first time.

Correlations between chromobox homolog 8 and key factors of epithelial-mesenchymal transition in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC. Methods: A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis. Results: We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues. Conclusions: Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.

Associations between single nucleotide polymorphisms in RYBP and the prognosis of hepatocellular carcinoma in a Chinese population.

Down-regulated RINGl and YYl binding protein (RYBP) is reported to be an independent predictor of a poor prognosis in patients with hepatocellular carcinoma (HCC). However, the genetic association of RYBP polymorphisms with HCC risk and prognosis has not been investigated now. In this study, five RYBP SNPs, rs12956, rs2118593, rs17009699, rs4676875 and rs4532099, were studied from a hospital-based case-control study including 1100 cases (HCC patients) and 1100 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. Compared to the CC genotype, patients with TT genotype of rs12956 had a decreased risk of HCC (OR = 0.587, 95% CI = 0.403~0.923) and an increased survival time (Co-dominant, HR = 0.745, 95% CI = 0.594~0.934), while those with TT genotype of rs2118593 had an increased risk of HCC (OR = 1.538, 95% CI = 1.093~2.735) and a decreased survival time (Co-dominant, HR = 1.447, 95% CI = 1.174~1.782). No significant difference was found between the other three RYBP polymorphisms with HCC risk and prognosis. Furthermore, we found that tumor number, tumor staging, metastasis and rs2118593 were associated with the overall survival of HCC patients by multivariate COX regression analysis. Our study suggests RYBP SNP, rs2118593 as a new predictor for poor prognosis of HCC patients.

Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen-induced cell transformation.

Identification of aberrant histone H3 phosphorylation during chemical carcinogenesis will lead to a better understanding of the substantial roles of histone modifications in cancer development. To explore whether aberrant H3 phosphorylation contributes to chemical carcinogenesis, we examined the dynamic changes of H3 phosphorylation at various residues in chemical carcinogen-induced transformed human cells and human cancers. We found that histone H3 phosphorylation at Ser10 (p-H3S10) and Ser28 (p-H3S28) was upregulated by 1.5-4.8 folds and 2.1-4.3 folds, respectively in aflatoxin B1 -transformed hepatocytes L02 cells (L02RT-AFB1 ), benzo(a)pyrene-transformed HBE cells (HBERT-BaP), and coke oven emissions-transformed HBE cells (HBERT-COE). The ectopic expression of histone H3 mutant (H3S10A or H3S28A) in L02 cells led to the suppression of an anchorage-independent cell growth as well as tumor formation in immunodeficient mice. In addition, an enhanced p-H3S10 was found in 70.6% (24/34) of hepatocellular carcinoma (HCC), and 70.0% (21/30) of primary lung cancer, respectively. Notably, we found that expression of H3 carrying a mutant H3S10A or H3S28A conferred to cells the ability to maintain a denser chromatin and resistance to induction of DNA damage and carcinogen-induced cell transformation. Particularly, we showed that introduction of a mutant H3S10A abolished the bindings of p-H3S10 to the promoter of DNA repair genes, PARP1 and MLH1 upon AFB1 treatment. Furthermore, we revealed that PP2A was responsible for dephosphorylation of p-H3S10. Taken together, these results reveal a key role of persistent H3S10 or H3S28 phosphorylation in chemical carcinogenesis through regulating gene transcription of DNA damage response (DDR) genes.

Aberrant methylation of nucleotide excision repair genes is associated with chronic arsenic poisoning.

OBJECTIVE: To define whether aberrant methylation of DNA repair genes is associated with chronic arsenic poisoning. METHODS: Hundred and two endemic arsenicosis patients and 36 healthy subjects were recruited. Methylight and bisulfite sequencing (BSP) assays were used to examine the methylation status of ERCC1, ERCC2 and XPC genes in peripheral blood lymphocytes (PBLs) and skin lesions of arsenicosis patients and NaAsO2-treated HaCaT cells. RESULTS: Hypermethylation of ERCC1 and ERCC2 and suppressed gene expression were found in PBLs and skin lesions of arsenicosis patients and was correlated with the level of arsenic exposure. Particularly, the expression of ERCC1 and ERCC2 was associated with the severity of skin lesions. In vitro studies revealed an induction of ERCC2 hypermethylation and decreased mRNA expression in response to NaAsO2 treatment. CONCLUSION: Hypermethylation of ERCC1 and ERCC2 and concomitant suppression of gene expression might be served as the epigenetic marks associated with arsenic exposure and adverse health effects.

Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes.

Induction of metallothionein (MT) expression is involved in metal homeostasis and detoxification. To identify the key pathways that regulate metal-induced cytotoxicity, we investigate how phosphorylated metal-responsive transcription factor-1 (MTF-1) contributed to induction of MT expression. Immortal human embryonic kidney cells (HEK cells) were treated with seven kinds of metals including cadmium chloride (CdCl2), zinc sulfate (ZnSO4), copper sulfate(CuSO4), lead acetate (PbAc), nickel sulfate (NiSO4), sodium arsenite (NaAsO2), and potassium bichromate (K2Cr2O7). The MT expression was induced in a dose-response and time-dependent manner upon various metal treatments. A cycle of phosphorylation and dephosphorylation was required for translocation of MTF-1 from cytoplasm to nucleus, leading to the up-regulation of MTs expression. Protein phosphatase 2A (PP2A) participated in regulating MT expression through dephosphorylation of MTF-1. A loss-of-function screen revealed that the specific PP2A complexes containing PR110 were involved in metal-induced MT expression. Suppression of PP2A PR110 in HEK cells resulted in the persistent MTF-1 phosphorylation and the disturbance of MTF-1 nuclear translocation, which was concomitant with a significant decrease of MT expression and enhanced cytotoxicity in HEK cells. Notably, MTF-1 was found in complex with specific PP2A complexes containing the PR110 subunit upon metal exposure. Furthermore, we identify that the dephosphorylation of MTF-1 at residue Thr-254 is directly regulated by PP2A PR110 complexes and responsible for MTF-1 activation. Taken together, these findings delineate a novel pathway that determines cytotoxicity in response to metal treatments and provide new insight into the role of PP2A in cellular stress response.

Non-linear association and benchmark dose of blood pressure on carotid artery intima-media thickening in a general population of southern China.

Background and aims: This study aimed to evaluate whether there is a J-curve association between blood pressure (BP) and carotid artery intima-media thickening (CAIT) and estimate the effect of the turning point of BP on CAIT. Methods and results: Data from 111,494 regular physical examinations conducted on workers and retirees (aged 18 years or older) between January 2011 and December 2016, exported from the hospital information system, were analyzed. Restricted cubic splines (RCS) logistic regression was employed to access the association of BP with CAIT, and Bayesian benchmark dose methods were used to estimate the benchmark dose as the departure point of BP measurements. All the pnon-linear values of BP measurements were less than 0.05 in the RCS logistic regression models. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) had J-curve associations with the risk of CAIT at a turning point around 120/70 mmHg in the RCS. The benchmark dose for a 1% change in CAIT risk was estimated to be 120.64 mmHg for SBP and 72.46 mmHg for DBP. Conclusion: The J-curve associations between SBP and DBP and the risk of CAIT were observed in the general population in southern China, and the turning point of blood pressure for significantly reducing the risk of CAIT was estimated to be 120.64/72.46 mmHg for SBP/DBP.

REXO2 up-regulation is positively correlated with poor prognosis and tumor immune infiltration in hepatocellular carcinoma.

BACKGROUND: As a homologous counterpart to the prokaryotic oligonuclease found in the cellular cytoplasm and mitochondrion, REXO2 assumes a pivotal role in the maintenance of mitochondrial homeostasis. Nevertheless, the precise functions and mechanisms by which REXO2 operates within the context of hepatocellular carcinoma (HCC) have hitherto remained unexamined. METHODS: The expression levels of REXO2 in HCC tissues were evaluated through the utilization of the immunohistochemical (IHC) method, and subsequently, the association between REXO2 expression and the clinicopathological characteristics of HCC patients was scrutinized employing the χ2 test. A battery of experimental assays, encompassing CCK8 viability assessment, cell colony formation, wound healing, and transwell assays, were conducted with the aim of elucidating the biological role of REXO2 within HCC cells. Complementary bioinformatics analyses were undertaken to discern potential correlations between REXO2 and immune infiltration in tumor tissues. RESULTS: Our IHC findings have unveiled a notable up-regulation of REXO2 within HCC tissues, and this heightened expression bears the status of an independent prognostic factor, portending an adverse outcome for HCC patients (P < 0.05). Upon the attenuation of REXO2 expression, a discernible reduction in the rates of proliferation, invasion and migration of HCC cells ensued (P < 0.05). Furthermore, transcriptome sequencing analysis has provided insights into the putative influence of REXO2 on the development of HCC through the modulation of TNF and NF-κB signaling pathways. Additionally, our bioinformatics analyses have demonstrated a positive correlation between REXO2 and tumor immune cell infiltration, as well as immune checkpoint CTLA-4. CONCLUSIONS: In summation, our results posit an association between the up-regulation of REXO2 and adverse prognostic outcomes, alongside the involvement of immune-related signaling pathways and tumor immune infiltration within the realm of HCC.

Predicting colorectal cancer risk: a novel approach using anemia and blood test markers.

Background and objectives: Colorectal cancer remains an important public health problem in the context of the COVID-19 (Corona virus disease 2019) pandemic. The decline in detection rates and delayed diagnosis of the disease necessitate the exploration of novel approaches to identify individuals with a heightened risk of developing colorectal cancer. The study aids clinicians in the rational allocation and utilization of healthcare resources, thereby benefiting patients, physicians, and the healthcare system. Methods: The present study retrospectively analyzed the clinical data of colorectal cancer cases diagnosed at the Affiliated Hospital of Guilin Medical University from September 2022 to September 2023, along with a control group. The study employed univariate and multivariate logistic regression as well as LASSO (Least absolute shrinkage and selection operator) regression to screen for predictors of colorectal cancer risk. The optimal predictors were selected based on the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. These predictors were then utilized in constructing a Nomogram Model for predicting colorectal cancer risk. The accuracy of the risk prediction Nomogram Model was assessed through calibration curves, ROC curves, and decision curve analysis (DCA) curves. Results: Clinical data of 719 patients (302 in the case group and 417 in the control group) were included in this study. Based on univariate logistic regression analysis, there is a correlation between Body Mass Index (BMI), red blood cell count (RBC), anemia, Mean Corpuscular Volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), Red Cell Distribution Width-Standard Deviation (RDW-SD), and the incidence of colorectal cancer. Based on the findings of multivariate logistic regression analysis, the variables of BMI and RBC exhibit a decrease, while anemia and PLT demonstrate an increase, all of which are identified as risk factors for the occurrence of colorectal cancer. LASSO regression selected BMI, RBC, anemia, and PLT as prediction factors. LASSO regression and multivariate logistic regression analysis yielded the same results. A nomogram was constructed based on the 4 prediction factors identified by LASSO regression analysis to predict the risk of colorectal cancer. The AUC of the nomogram was 0.751 (95% CI, OR: 0.708-0.793). The calibration curves in the validation and training sets showed good performance, indicating that the constructed nomogram model has good predictive ability. Additionally, the DCA demonstrated that the nomogram model has diagnostic accuracy. Conclusion: The Nomogram Model offers precise prognostications regarding the likelihood of Colorectal Cancer in patients, thereby helping healthcare professionals in their decision-making processes and promoting the rational categorization of patients as well as the allocation of medical resources.

Potential and application of abortive transcripts as a novel molecular marker of cancers.

Abortive transcript (AT) is a 2-19 nt long non-coding RNA that is produced in the abortive initiation stage. Abortive initiation was found to be closely related to RNA polymerase through in vitro experiments. Therefore, the distribution of AT length and the scale of abortive initiation are correlated to the promoter, discriminator, and transcription initiation sequence, and can be affected by transcription elongation factors. AT plays an important role in the occurrence and development of various diseases. Here we summarize the discovery of AT, the factors responsible for AT formation, the detection methods and biological functions of AT, to provide new clues for finding potential targets in the early diagnosis and treatment of cancers.

Prognostic value of CMTM6 protein in hepatocellular carcinoma involving the regulation of the immune microenvironment.

There have been notable irregularities in CMTM6 expression observed in hepatocellular carcinoma (HCC), with an evident correlation between CMTM6 dysregulation and patient prognosis. The cell cycle progression came to a halt at the G2/M phase. In-depth RNA-sequencing analysis of CMTM6 knockdown Hep3B cells revealed that the most prominent effect of CMTM6 perturbation was on the expression of CXCL8, a chemokine involved in immune responses, particularly through the interleukin-17F (IL-17F) signaling pathway. By carefully examining the RNA-sequencing data obtained from CMTM6 knockdown Hep3B cells and cross-referencing it with the TCGA-LIHC database, we were able to discern that CMTM6 and programmed death-ligand 1 (PD-L1) collaboratively partake in immune regulation within T cells. Furthermore, CMTM6 exerted an influential role in modulating the infiltration of CD4+ and CD8+ T cells in the HCC microenvironment, thereby impacting the overall immune response. Our investigation found that HCC cases characterized by an elevated co-expression of CMTM6 and PD-L1, along with augmented CD4+ T cell infiltration, demonstrated comparatively longer overall and progression-free survival rates when contrasted with those displaying lower CD4+ T cell infiltration.

Comprehensive analysis of the protein phosphatase 2A regulatory subunit B56ε in pan-cancer and its role and mechanism in hepatocellular carcinoma.

BACKGROUND: B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At present, the application of B56ε in pan-cancer lacks a comprehensive analysis, and its role and mechanism in hepatocellular carcinoma (HCC) are still unclear. AIM: To analyze B56ε in pan-cancer, and explore its role and mechanism in HCC. METHODS: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Profiling Interactive Analysis, and Tumor Immune Estimation Resource databases were used to analyze B56ε expression, prognostic mutations, somatic copy number alterations, and tumor immune characteristics in 33 tumors. The relationships between B56ε expression levels and drug sensitivity, immunotherapy, immune checkpoints, and human leukocyte antigen (HLA)-related genes were further analyzed. Gene Set Enrichment Analysis (GSEA) was performed to reveal the role of B56ε in HCC. The Cell Counting Kit-8, plate cloning, wound healing, and transwell assays were conducted to assess the effects of B56ε interference on the malignant behavior of HCC cells. RESULTS: In most tumors, B56ε expression was upregulated, and high B56ε expression was a risk factor for adrenocortical cancer, HCC, pancreatic adenocarcinoma, and pheochromocytoma and paraganglioma (all P < 0.05). B56ε expression levels were correlated with a variety of immune cells, such as T helper 17 cells, B cells, and macrophages. There was a positive correlation between B56ε expression levels with immune checkpoint genes and HLA-related genes (all P < 0.05). The expression of B56ε was negatively correlated with the sensitivity of most chemotherapy drugs, but a small number showed a positive correlation (all P < 0.05). GSEA analysis showed that B56ε expression was related to the cancer pathway, p53 downstream pathway, and interleukin-mediated signaling in HCC. Knockdown of B56ε expression in HCC cells inhibited the proliferation, migration, and invasion capacity of tumor cells. CONCLUSION: B56ε is associated with the microenvironment, immune evasion, and immune cell infiltration of multiple tumors. B56ε plays an important role in HCC progression, supporting it as a prognostic marker and potential therapeutic target for HCC.

Prognostic Significance of ZP3 in Hepatocellular Carcinoma.

OBJECTIVE: The study aims to explore the prognostic significance of zona pellucida glycoprotein 3 (ZP3) in hepatocellular carcinoma (HCC) tissues. METHODS: The expression of ZP3 protein in HCC tissues was detected by immunohistochemistry (IHC) to study its effects on the clinicopathological characteristics and prognosis of HCC patients. The Cancer Genome Atlas (TCGA) database was used to confirm the expression of ZP3 in HCC tissues, and Gene set enrichment analysis (GSEA) was performed to obtain potential ZP3-related pathways in HCC. RESULTS: IHC detection found that ZP3 had a high expression in HCC tissues and was associated with cirrhosis and hepatitis B virus infection in HCC patients (p<0.05). TCGA database also showed that ZP3 was up-regulated in HCC tissues. Further survival evaluation confirmed that ZP3 expression caused an impact on the overall survival time and disease-free survival time of HCC patients (p<0.05), implying a potential role in HCC prognosis. GSEA analysis indicated that the 187 differential gene sets were mainly involved in 10 signaling pathways, including 5 up-regulated and 5 down-regulated pathways. CONCLUSION: High expression of ZP3 in HCC tissues is found to have an important role in HCC development and prognosis.