MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development

Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor-derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1-specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2(-/-)) produced 28 times as much MCP-1 protein as did EEF Tsc2(+/+) cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2(-/-) cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2(-/-) cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target.     

The Bb fragment of complement factor B acts as a B cell growth factor

The process of B cell growth and differentiation into plasma cells is highly regulated and may be influenced by a large number of inflammatory mediators, including complement components. We have studied the regulatory influence of Bb, a 60-kD peptide created during the cleavage of complement Factor B by Factor D and C3b. Purified Bb alone had no effect on proliferation and differentiation of human splenic or tonsillar B cells. However, when B cells were activated by Staphylococcus aureus Cowan I (SAC), Bb enhanced proliferation in a dose-dependent manner. Bb also enhanced proliferation when cocultured with SAC and suboptimal concentrations of purified 60-kD B cell growth factor (HMW-BCGF), a previously described lymphokine that is known to possess growth-promoting activity. However, Bb had no effect on cells treated with optimal concentrations of HMW-BCGF. Like HMW-BCGF, Bb's major effect was on the larger in vivo activated B cells. Half-maximal enhancement of proliferation was reached at a Bb concentration of 1-10 nM. Of note is the fact that antibody to Factor B recognized HMW-BCGF, and an mAb to HMW-BCGF also recognized Factor B and Bb, but not Ba. Moreover, radiolabeled Bb bound saturably to activated B cells and to an EBV-transformed human B cell line. The binding of Bb was inhibited by HMW-BCGF but not by Ba or IgG. Thus, Bb is antigenically and functionally related to HMW-BCGF, and can act as a B cell growth and differentiation factor at potentially physiologic concentrations. These data suggest that Bb may be important in amplifying the immune response in areas of inflammation. Since complement activation occurs at inflammatory sites long before induction of HMW-BCGF synthesis, Bb may be an early signal for the clonal expansion of antigen-activated B cells.     

Epidermal growth factor acts as a corticotropin-releasing factor in chronically catheterized fetal lambs.

Epidermal growth factor (EGF) has been reported to stimulate adrenocorticotropin hormone (ACTH), growth hormone and prolactin secretion from pituitary tissue in vitro, and in large doses evokes ACTH secretion in adult sheep in vivo. In order to assess a possible role for EGF in the pituitary hyperfunction characteristic of the in utero fetus, we measured changes in plasma immunoreactive ACTH concentrations after acute administration of saline, purified mouse EGF or synthetic ovine corticotropin releasing factor (CRF) to chronically catheterized fetal sheep. Both CRF and EGF were associated with increases in plasma immunoreactive ACTH concentrations. Peak values 60 min after 10-micrograms injections of either EGF or CRF increased from baseline ACTH values of 61 +/- 11 pg/ml to 191 +/- 37 and 178 +/- 25 pg/ml, respectively. Dose-response studies indicate that at low doses (less than 20 micrograms) EGF is as potent a stimulus for ACTH release as CRF. EGF infusion was not associated with detectable changes in circulating CRF, catecholamines, arginine vasopressin levels, or plasma growth hormone concentrations. We speculate that EGF may be important in the regulation of pituitary function in the developing mammalian fetus.     

Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival

Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand- or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation.     

Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-kappa B activation

The bacterial pathogens of the genus Yersinia, the causative agents of plague, septicemia, and gastrointestinal syndromes, use a type III secretion system to inject virulence factors into host target cells. One virulence factor, YopJ, is essential for the death of infected macrophages and can block host proinflammatory responses by inhibiting both the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways, which might be important for evasion of the host immune response and aid in establishing a systemic infection. Here, we show that YopJ is a promiscuous deubiquitinating enzyme that negatively regulates signaling by removing ubiquitin moieties from critical proteins, such as TRAF2, TRAF6, and IkappaBalpha. In contrast to the cylindromatosis tumor suppressor CYLD, which attenuates NF-kappaB signaling by selectively removing K63-linked polyubiquitin chains that activate IkappaB kinase, YopJ also cleaves K48-linked chains and thereby inhibits proteasomal degradation of IkappaBalpha. YopJ, but not a catalytically inactive YopJ mutant, promoted deubiquitination of cellular proteins and cleaved both K48- and K63-linked polyubiquitin. Moreover, an in vitro assay was established to demonstrate directly the deubiquitinating activity of purified YopJ.     

Interleukine-8 acts as a strong peripheral blood granulocyte-recruiting agent rather than as a hematopoietic progenitor cell-mobilizing factor

Intravenous infusion of Interleukine-8 has been shown to lead to a rapid mobilization of hematopoietic cells in mice and rhesus monkeys. We report in this study that the IL-8-mediated mobilizing effect results in low levels of circulating CD34+ cells, whereas a rapid and strong recruitment of mature granulocytes occurs. This would be of great interest for harvesting large numbers of functional granulocytes to fight infection in immunodepressed patients. We performed a kinetic study of the mobilization in a nonhuman primate model (Papio ursinus), mobilized with a single or double infusion of IL-8 with a dose range of 30-50 microg/kg of body weight. Blood was sampled every 15 min after the IL-8 infusion, and IL-8 plasma levels, complete blood counts, differential WBCC, colony-forming unit assays, and CD34+ cell evaluation assays were performed. At the same time, leukapheresis was performed on the anesthetized animal to collect either hematopoietic stem and progenitor cells (HSPC) or peripheral blood granulocytes (PBG) according to different collection settings. IL-8 induced a rapid increase of PBG (7-12-fold the basal values). The HSPC leukapheresis concentrate showed poor ex vivo expansion abilities. IL-8-mobilized peripheral blood polymorphonuclear cells showed normal oxidative, chemotactic, phagocytic, and adherence abilities. We suggest that IL-8-induced neutrophilia could be used as an allogeneic source of granulocytes for transfusion in neutropenic patients or in granulocyte dysfunction.     

Lysophosphatidic acid is a major serum noncytokine survival factor for murine macrophages which acts via the phosphatidylinositol 3-kinase signaling pathway.

Lysophosphatidic acid (LPA) is the smallest and structurally simplest of all the glycerophospholipids. It occurs normally in serum and binds with high affinity to albumin, while retaining its biological activity. The effects of LPA are pleiotropic and range from mitogenesis to stress fiber formation. We show a novel role for LPA: as a macrophage survival factor with potency equivalent to serum. Administration of LPA protects macrophages from apoptosis induced by serum deprivation, and protection is equivalent to that with conventional survival factors such as macrophage colony stimulating factor. The ability of LPA to act as a survival factor is mediated by the lipid kinase phosphatidylinositol 3-kinase (PI3K), since LPA activated both the p85-p110 and p110gamma isoforms of PI3K and macrophage survival was blocked completely by wortmannin or LY294002, two mechanistically dissimilar inhibitors of PI3K. pp70(s6k), a downstream kinase activated by PI3K, also contributes to survival, because inhibitors of pp70(s6k), such as rapamycin, blocked macrophage survival in the presence of LPA. Modified forms of LPA and phospholipids, such as phosphatidylcholine and phosphatidylethanolamine, had no survival effect, thereby showing the specificity of LPA. These results show that LPA acts as a potent macrophage survival factor. Based on striking similarities between our LPA and serum data, we suggest that LPA is a major noncytokine survival factor in serum.     

Metallothionein acts as a cytoprotectant against doxorubicin toxicity

The protective role of metallothionein (MT) against the myocardiotoxicity and hepatotoxicity of doxorubicin (Dox) was investigated in mice. Dox-induced elevations of plasma creatine kinase activity, a measure of myocardiac damage, and plasma glutamate pyruvate transaminase activity, reflecting hepatic damage, were prevented by pretreatment with an MT inducer. Pretreatment with zinc induced MT in the liver and heart, thereby reducing Dox toxicity in these two organs. Pretratment with n-hexane also induced MT and reduced Dox toxicity, but only in the liver. In primary hepatocyte cultures, the leakage of lactate dehydrogenase induced by Dox was prevented by zinc pretreatment. These results suggest that MT induction prevents Dox toxicity in vivo and in vitro. Furthermore, we determined that MT-null mice were more sensitive to the myocardiotoxic and hepatotoxic effects of Dox. These findings indicate that both basal and induced MT protect against Dox toxicity.     

CD68 acts as a major gateway for malaria sporozoite liver infection

After being delivered by the bite from an infected mosquito, Plasmodium sporozoites enter the blood circulation and infect the liver. Previous evidence suggests that Kupffer cells, a macrophage-like component of the liver blood vessel lining, are traversed by sporozoites to initiate liver invasion. However, the molecular determinants of sporozoite–Kupffer cell interactions are unknown. Understanding the molecular basis for this specific recognition may lead to novel therapeutic strategies to control malaria. Using a phage display library screen, we identified a peptide, P39, that strongly binds to the Kupffer cell surface and, importantly, inhibits sporozoite Kupffer cell entry. Furthermore, we determined that P39 binds to CD68, a putative receptor for sporozoite invasion of Kupffer cells that acts as a gateway for malaria infection of the liver.Malaria remains one of the world’s most devastating diseases, afflicting close to 500 million people and causing nearly 1 million deaths every year. Parasite resistance to drugs is of major concern (White et al., 2014), and new drug targets need to be urgently identified. Some progress has recently been made in malaria vaccine development, but identification of new vaccine targets remains a high priority (Moorthy et al., 2004; Moorthy and Kieny, 2010). A better understanding of parasite infection of the human host is crucial for the development of new tools to fight the disease.Infection of a vertebrate host is initiated by the bite of an infected female mosquito. Sporozoites released with the mosquito saliva enter the blood circulation and exit in the liver to establish a productive infection. Hepatocyte infection leads to a dramatic amplification of parasite numbers: 1 sporozoite generates up to 10,000 merozoites that are subsequently released into the bloodstream where they continuously propagate inside red blood cells, causing disease symptoms (Sturm et al., 2006). The pre-erythrocytic liver stages represent a severe bottleneck in parasite numbers and constitute a prime target for induction of sterile immunity. Understanding the mechanisms of parasite liver invasion may provide crucial insights for pre-erythrocytic malaria drug and vaccine development.After delivery by an infected mosquito, sporozoites circulate through the entire body. What cues does the parasite use to exit the blood circulation in the liver and which mechanisms operate for sporozoite exit from the circulation are fundamental questions that are incompletely understood. The liver has specialized blood vessels, the sinusoids, whose walls are made up by two cell types: fenestrated endothelial cells and macrophage-like Kupffer cells (Widmann et al., 1972). Circulating sporozoites are believed to be captured via strong interaction between circumsporozoite protein (CSP), a major sporozoite surface protein, and the highly sulfated heparan sulfate proteoglycans (HSPGs) that are synthesized by stellate cells in the space of Disse and protrude into the vascular lumen through endothelial fenestrations (Frevert et al., 1993, 1996; Cerami et al., 1994; Pradel et al., 2002; Coppi et al., 2007). The “gateway hypothesis,” which has predominated for several decades, suggests that sporozoites glide along the sinusoid wall until they find a Kupffer cell (Frevert et al., 2005), which they traverse to subsequently infect underlying hepatocytes. This hypothesis was supported by ultrastructural data suggesting that sporozoites specifically traverse Kupffer cells and not endothelial cells (Danforth et al., 1980; Meis et al., 1983; Vreden, 1994; Pradel et al., 2002). The molecular basis for this specific recognition is a key unresolved question of the early stages of Plasmodium development in its vertebrate host.We previously used a phage display library screening strategy to identify receptor–ligand combinations used by Plasmodium during its cycle in vector mosquitoes (Ghosh et al., 2001, 2009, 2011). Furthermore, blocking the interactions between parasite ligands and mosquito host cell receptors led to a significant reduction of malaria transmission by mosquitos (Ito et al., 2002). By screening a phage display library, we identified a peptide, P39, that binds to Kupffer cells and, by doing so, inhibits sporozoite entry. Further work determined that P39 interacts specifically with a major Kupffer cell surface protein, CD68, making this a candidate receptor for sporozoite traversal of Kupffer cells and liver infection.     

Embryonic develop-associated gene 1 is overexpressed and acts as a tumor promoter in thyroid carcinoma

Embryonic develop-associated gene 1 (EDAG-1), a hematopoietic tissue-specific protein, is usually highly expressed in the placenta, fetal liver, bone marrow and leukemia cells, but the expression status in normal or solid tumor tissues is rarely reported. In this study, we found that EDAG-1 was up-regulated in thyroid carcinoma tissues and cells. Knockdown of EDAG-1 suppressed proliferation and enhanced cisplatin-induced apoptosis of thyroid carcinoma cells. We also demonstrated that knockdown of EDAG-1 inactivated the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway in vitro and in vivo. Moreover, knockdown of EDAG-1 suppressed tumorigenesis of thyroid carcinoma in vivo. Taken together, these results suggest that EDAG-1 regulates the proliferation and apoptosis of thyroid carcinoma via the PI3K/Akt signaling pathway.     

Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells

The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. ALL cells are derived from B cell precursors in most cases and typically carry rearranged immunoglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph(+) ALLs as compared with 6 of 80 Ph(-) ALLs. Forced expression of BCR-ABL1 in Ph(-) ALL cells and inhibition of the BCR-ABL1 kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph(+) ALL, IGH V region genes and BCL6 were mutated in many Ph(+) but unmutated in most Ph(-) cases. In addition, AID introduced DNA single-strand breaks within the tumor suppressor gene CDKN2B in Ph(+) ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph(+) ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.     

Symptom improvement as prognostic factor for survival in cancer patients undergoing palliative care: a pilot study

Background  

The Edmonton Symptom Assessment Scale (ESAS) is a validated tool for physical symptom assessment in palliative care practice which evaluates symptoms through a numeric scale from 0 to 10. The use of symptom improvement as a prognostic factor is controversial. To this purpose, a pilot study in advanced cancer patients now undergoing only palliative care was conducted.     

Uric acid as a prognostic factor for survival time: a prospective cohort study of terminally ill cancer patients

The aim of this prospective cohort study was to determine whether serum uric acid level is useful as a predictor of survival in terminally ill cancer patients. One hundred eighteen terminally ill cancer patients, including 63 (53.4%) males, were categorized into four groups by serum uric acid levels and followed up until death or to the end of the study. Cox's proportional hazard model was adopted to evaluate the joint effect of some clinicobiological variables on survival. From an initial model containing 51 variables, a final parsimonious model was obtained by means of a stepwise method. Repetitive dispersion analysis was performed for serum uric acid level in 39 subjects for 3 weeks until death. During the study period, 113 (95.76%) subjects expired, and the median survival time was 14 days. In univariate analysis, survival time of the fourth highest group (≥7.2 mg/dL) was significantly shorter than that of the others (hazard ratio (HR) = 2.784, P < 0.001). After adjustment for low performance status, moderate to severe pain, prolonged prothrombin time, hypocholesterolemia, and high lactate dehydrogenase (LDH) level, high serum uric acid level (≥7.2 mg/dL) was significantly and independently associated with short survival time (HR = 2.637, P = 0.001). Serum uric acid levels were also significantly increased between the first and the second week before death. These findings suggest that serum uric acid level can be useful in predicting life expectancy in terminally ill cancer patients.     

Plasma circular RNA panel acts as a novel diagnostic biomarker for colorectal cancer

BackgroundColorectal cancer (CRC) is one of the most common cancers worldwide, and emerging lines of evidence have implicated circular RNAs (circRNAs), a novel class of endogenous noncoding RNAs, in CRC development. However, whether plasma circRNAs might be novel diagnostic biomarkers for CRC remains unclear.MethodsWe investigated the plasma levels of selected circRNAs by quantitative real-time PCR (qRT-PCR). The presence of the candidate circRNAs was confirmed through RNase R assays, qRT-PCR and DNA sequencing, and their diagnostic value was evaluated using a receiver operating characteristic (ROC) curve.ResultsThe plasma levels of three circRNAs (circ-CCDC66, circ-ABCC1 and circ-STIL) were significantly decreased in CRC patients (n = 45) compared with healthy controls (n = 61). The ROC curve analysis showed that the area under the ROC curve (AUC) of the three-circRNA panel was 0.780, which is higher than that of traditional protein biomarkers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA19-9). Combining the circRNA panel with CEA and CA19-9 might improve the ability to diagnose CRC (AUC = 0.855). In addition, the plasma circ-ABCC1 level was related to tumor growth and progression, and the plasma circ-CCDC66 and circ-ABCC1 levels were decreased in precursor lesions of CRC, including colon adenomas and adenomatous polyps. More importantly, circ-CCDC66 and circ-STIL were found to be useful for diagnosing early-stage CRC, and the three-circRNA panel improved the ability to diagnose CEA-negative and CA19-9-negative CRC.ConclusionOur study provides the first identification of a panel of three plasma circRNAs that could serve as a novel and independent diagnostic biomarker for CRC.     

Health-related quality of life as a prognostic factor of survival in critically ill patients

Objective  To evaluate whether health-related quality of life prior to admission into an intensive care unit (ICU) is a prognostic factor of hospital and 1 year mortality. Design  Prospective cohort study. Setting  Fourteen-bed medical–surgical ICU. Patients  A total of 377 patients admitted to the ICU for more than 24 h with 1-year follow-up after discharge from the hospital. Intervention  A health-related quality of life (HRQoL) survey was conducted, using the questionnaire developed by the “Project for the Epidemiological Analysis of Critical Care Patients”, to assess patient’s quality of life 1 month before ICU hospitalization. Results  Hospital mortality was independently associated with severity assessed by APACHE II, odds ratio (OR) 1.14 [95% confidence interval (CI) 1.08–1.2; P < 0.001], high workload assessed by Nine Equivalents of Nursing Manpower Score > 30 OR 3.6 (95% CI 1.4–9.0; P = 0.006), hospital length of stay prior to ICU admission of more than 2 days OR 2.6 (95% CI 1.3–5.4; P = 0.008), and bad quality of life prior to ICU admission assessed by a HRQoL score ≥ 8 points OR 2.2 (95% CI 1.03–4.5; P = 0.04). Patients who scored ≥8 on the HRQoL survey presented a risk of demise 12 months after discharge almost twofold that of those who had good previous HRQoL (0–2 points), Hazard Ratio 1.9 (95% CI 1.3–2.8; P = 0.001). Conclusion  Bad quality of life is associated with hospital mortality and survival 12 months after hospital discharge.     

Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis

BACKGROUND: Prospective studies of the epidemiology and clinical significance of low plasminogen activator inhibitor type 1 (PAI-1) activity are lacking. OBJECTIVE: To evaluate the prevalence of low PAI-1 activity in patients with a bleeding tendency in comparison with a normal population. METHODS: In 586 consecutive patients, referred because of bleeding symptoms, we added analyses of PAI-1 activity and tissue plasminogen activator complex with PAI-1 (t-PA-PAI-1) to the routine investigation, consisting of platelet count, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, von Willebrand factor activity, and antigen. Controls were 100 blood donors and 100 age- and sex-matched healthy individuals. The latter were also evaluated regarding the previous bleeding episodes. The bleeding history was classified as clinically significant or not, and the criteria were fulfilled in 75% of the patients and 18% of the healthy controls. RESULTS: The routine laboratory investigation of the patients was negative in 57%. Low PAI-1 activity, defined as <1.0 U mL(-1), was found in 23% of the patients and in 13% and 10% of the blood donors and healthy controls, respectively (odds ratio and 95% CI, 2.04; 1.11-3.77 and 2.75; 1.39-5.42, respectively). The difference remained statistically significant after the adjustment for body mass index, use of estrogens, sex and age (odds ratio for patients vs. healthy controls 3.23; 95% CI, 1.22-8.56, P = 0.019). The distribution of the 4G/5G genotypes in the patients was not different from that of two control populations. No specific symptom predicted for low PAI-1, which did not aggravate the clinical picture in association with the other hemostatic defects. Low tPA-PAI-1 was not associated with the increased bleeding tendency. CONCLUSION: Low PAI-1 activity is common in patients with a bleeding diathesis, but it is a risk factor of minor clinical importance and not associated with specific bleeding manifestations.     

DACH1 as a multifaceted and potentially druggable susceptibility factor for kidney disease

Kidney diseases affect more than 15% of adults in the US, yet drug development in the kidney field, when compared with that for other common diseases, has been lagging behind. Modifiers that increase the susceptibility to injury and contribute to the pathogenesis and progression of kidney disease include genetic and environmental factors and epigenetic mechanisms. In this issue of the JCI, Cao et al. and Doke et al. independently report the identification of a susceptibility factor called Dachshund homolog 1 (DACH1). Both groups identify an association of reduced DACH1 expression with kidney disease, using different screening approaches, studying different types of human kidney diseases, and using different experimental models, making the fact that both stumbled over the same protein very compelling. Combined, these studies highlight DACH1 as a key safeguard in the kidney, granting various cell types proper function by modulating several molecular pathways.     

Cyclin B1 acts as a tumor microenvironment-related cancer promoter and prognostic biomarker in hepatocellular carcinoma

ObjectivesThe present study aimed to develop a gene signature based on the ESTIMATE algorithm in hepatocellular carcinoma (HCC) and explore possible cancer promoters.MethodsThe ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cells (TICs) in a cohort of HCC patients. The differentially expressed genes (DEGs) were screened by Cox proportional hazards regression analysis and protein–protein interaction (PPI) network construction. Cyclin B1 (CCNB1) function was verified using experiments.ResultsThe stromal and immune scores were associated with clinicopathological factors and recurrence-free survival (RFS) in HCC patients. In total, 546 DEGs were up-regulated in low score groups, 127 of which were associated with RFS. CCNB1 was regarded as the most predictive factor closely related to prognosis of HCC and could be a cancer promoter. Gene Set Enrichment Analysis (GSEA) and CIBERSORT analyses indicated that CCNB1 levels influenced HCC tumor microenvironment (TME) immune activity.ConclusionsThe ESTIMATE signature can be used as a prognosis tool in HCC. CCNB1 is a tumor promoter and contributes to TME status conversion.