A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer-associated death worldwide. The mitochondrial unfolded protein response (UPRmt) not only maintains mitochondrial integrity but also regulates cancer progression and drug resistance. However, no study has used the UPRmt to construct a prognostic signature for HCC. This work aimed to establish a novel signature for predicting patient prognosis, immune cell infiltration, immunotherapy, and chemotherapy response based on UPRmt-related genes (MRGs). Transcriptional profiles and clinical information were obtained from the TCGA and ICGC databases. Cox regression and LASSO regression analyses were applied to select prognostic genes and develop a risk model. The TIMER algorithm was used to investigate immunocytic infiltration in the high- and low-risk subgroups. Here, two distinct clusters were identified with different prognoses, immune cell infiltration statuses, drug sensitivities, and response to immunotherapy. A risk score consisting of seven MRGs (HSPD1, LONP1, SSBP1, MRPS5, YME1L1, HDAC1 and HDAC2) was developed to accurately and independently predict the prognosis of HCC patients. Additionally, the expression of core MRGs was confirmed by immunohistochemistry (IHC) staining, single-cell RNA sequencing, and spatial transcriptome analyses. Notably, the expression of prognostic MRGs was significantly correlated with sorafenib sensitivity in HCC and markedly downregulated in sorafenib-treated HepG2 and Huh7 cells. Furthermore, the knockdown of LONP1 decreased the proliferation, invasion, and migration of HepG2 cells, suggesting that upregulated LONP1 expression contributed to the malignant behaviors of HCC cells. To our knowledge, this is the first study to investigate the consensus clustering algorithm, prognostic potential, immune microenvironment infiltration and drug sensitivity based on the expression of MRGs in HCC. In summary, the UPRmt-related classification and prognostic signature could assist in determining the prognosis and personalized therapy of HCC patients from the perspectives of predictive, preventative and personalized medicine.

Transcription factors-related molecular subtypes and risk prognostic model: exploring the immunogenicity landscape and potential drug targets in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, with a high mortality rate and poor prognosis. Mutated or dysregulated transcription factors (TFs) are significantly associated with carcinogenesis. The aim of this study was to develop a TF-related prognostic risk model to predict the prognosis and guide the treatment of HCC patients. METHODS: RNA sequencing data were obtained from the TCGA database. The ICGC and GEO databases were used as validation datasets. The consensus clustering algorithm was used to classify the molecular subtypes of TFs. Kaplan‒Meier survival analysis and receiver operating characteristic (ROC) analysis were applied to evaluate the prognostic value of the model. The immunogenic landscape differences of molecular subtypes were evaluated by the TIMER and xCell algorithms. Autodock analysis was used to predict possible binding sites of trametinib to TFs. RT‒PCR was used to verify the effect of trametinib on the expression of core TFs. RESULTS: According to the differential expression of TFs, HCC samples were divided into two clusters (C1 and C2). The survival time, signaling pathways, abundance of immune cell infiltration and responses to chemotherapy and immunotherapy were significantly different between C1 and C2. Nine TFs with potential prognostic value, including HMGB2, ESR1, HMGA1, MYBL2, TCF19, E2F1, FOXM1, CENPA and ZIC2, were identified by Cox regression analysis. HCC patients in the high-risk group had a poor prognosis compared with those in the low-risk group (p < 0.001). Moreover, the area under the ROC curve (AUC) values of the 1-year, 2-year and 3-year survival rates were 0.792, 0.71 and 0.695, respectively. The risk model was validated in the ICGC database. Notably, trametinib sensitivity was highly correlated with the expression of core TFs, and molecular docking predicted the possible binding sites of trametinib with these TFs. More importantly, the expression of core TFs was downregulated under trametinib treatment. CONCLUSIONS: A prognostic signature with 9 TFs performed well in predicting the survival rate and chemotherapy/immunotherapy effect of HCC patients. Trimetinib has potential application value in HCC by targeting TFs.

Apoptosis-related prognostic biomarkers and potential targets for acute kidney injury based on machine learning algorithm and in vivo experiments.

Acute kidney injury (AKI) is a common critical illness in hospitalized patients, characterized by a rapid decline in kidney function over a short period, which can seriously endanger the patient's life. Currently, there is a lack of precise and universal AKI diagnostic biomarkers in clinical practice. In this study, weighted gene coexpression network analysis (WGCNA), differential expression analysis, univariate and multivariate logistic regression analyses, receiver operating characteristic (ROC) curves, and immune cell infiltration were performed to identify apoptosis-related biomarkers that can be used for AKI diagnosis. Three core apoptosis-related genes (ARGs), CBFB, EGF and COL1A1, were identified as AKI biomarkers. More importantly, an apoptosis-related signature containing three hub ARGs was validated as a diagnostic model. The hub genes exhibited good correlations with glomerular filtration rate (GFR) and serum creatinine (SCr) in the Nephroseq kidney disease database. Additionally, CIBERSORT immune infiltration analysis indicated that these core ARGs may affect immune cell recruitment and infiltration in AKI patients. Subsequently, we investigated the alteration of the expression levels of three core ARGs in AKI samples using single-cell RNA sequencing analysis and analyzed the cell types that mainly expressed these ARGs. More importantly, the expression of core ARGs was validated in folic acid- and cisplatin-induced AKI mouse models. In summary, our study identified three diagnostic biomarkers for AKI, explored the roles of ARGs in AKI progression and provided new ideas for the clinical diagnosis and treatment of AKI.

Vitamin E stabilizes iron and mitochondrial metabolism in pulmonary fibrosis.

Introduction: Pulmonary fibrosis (PF) is a fatal chronic lung disease that causes structural damage and decreased lung function and has a poor prognosis. Currently, there is no medicine that can truly cure PF. Vitamin E (VE) is a group of natural antioxidants with anticancer and antimutagenic properties. There have been a few reports about the attenuation of PF by VE in experimental animals, but the molecular mechanisms are not fully understood. Methods: Bleomycin-induced PF (BLM-PF) mouse model, and cultured mouse primary lung fibroblasts and MLE 12 cells were utilized. Pathological examination of lung sections, immunoblotting, immunofluorescent staining, and real-time PCR were conducted in this study. Results: We confirmed that VE significantly delayed the progression of BLM-PF and increased the survival rates of experimental mice with PF. VE suppressed the pathological activation and fibrotic differentiation of lung fibroblasts and epithelial-mesenchymal transition and alleviated the inflammatory response in BLM-induced fibrotic lungs and pulmonary epithelial cells in vitro. Importantly, VE reduced BLM-induced ferritin expression in fibrotic lungs, whereas VE did not exhibit iron chelation properties in fibroblasts or epithelial cells in vitro. Furthermore, VE protected against mitochondrial dysmorphology and normalized mitochondrial protein expression in BLM-PF lungs. Consistently, VE suppressed apoptosis in BLM-PF lungs and pulmonary epithelial cells in vitro. Discussion: Collectively, VE markedly inhibited BLM-induced PF through a complex mechanism, including improving iron metabolism and mitochondrial structure and function, mitigating inflammation, and decreasing the fibrotic functions of fibroblasts and epithelial cells. Therefore, VE presents a highly potential therapeutic against PF due to its multiple protective effects with few side effects.

Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases.

Kidney diseases remain one of the leading causes of human death and have placed a heavy burden on the medical system. Regulated cell death contributes to the pathology of a plethora of renal diseases. Recently, with in-depth studies into kidney diseases and cell death, a new iron-dependent cell death modality, known as ferroptosis, has been identified and has attracted considerable attention among researchers in the pathogenesis of kidney diseases and therapeutics to treat them. The majority of studies suggest that ferroptosis plays an important role in the pathologies of multiple kidney diseases, such as acute kidney injury (AKI), chronic kidney disease, and renal cell carcinoma. In this review, we summarize recently identified regulatory molecular mechanisms of ferroptosis, discuss ferroptosis pathways and mechanisms of action in various kidney diseases, and describe the protective effect of ferroptosis inhibitors against kidney diseases, especially AKI. By summarizing the prominent roles of ferroptosis in different kidney diseases and the progress made in studying ferroptosis, we provide new directions and strategies for future research on kidney diseases. In summary, ferroptotic factors are potential targets for therapeutic intervention to alleviate different kidney diseases, and targeting them may lead to new treatments for patients with kidney diseases.

Immunogenic landscape and risk score prediction based on unfolded protein response (UPR)-related molecular subtypes in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common type of cancer and causes a significant number of cancer-related deaths worldwide. The molecular mechanisms underlying the development of HCC are complex, and the heterogeneity of HCC has led to a lack of effective prognostic indicators and drug targets for clinical treatment of HCC. Previous studies have indicated that the unfolded protein response (UPR), a fundamental pathway for maintaining endoplasmic reticulum homeostasis, is involved in the formation of malignant characteristics such as tumor cell invasiveness and treatment resistance. The aims of our study are to identify new prognostic indicators and provide drug treatment targets for HCC in clinical treatment based on UPR-related genes (URGs). Methods: Gene expression profiles and clinical information were downloaded from the TCGA, ICGC and GEO databases. Consensus cluster analysis was performed to classify the molecular subtypes of URGs in HCC patients. Univariate Cox regression and machine learning LASSO algorithm were used to establish a risk prognosis model. Kaplan-Meier and ROC analyses were used to evaluate the clinical prognosis of URGs. TIMER and XCell algorithms were applied to analyze the relationships between URGs and immune cell infiltration. Real time-PCR was performed to analyze the effect of sorafenib on the expression levels of four URGs. Results: Most URGs were upregulated in HCC samples. According to the expression pattern of URGs, HCC patients were divided into two independent clusters. Cluster 1 had a higher expression level, worse prognosis, and higher expression of immunosuppressive factors than cluster 2. Patients in cluster 1 were more prone to immune escape during immunotherapy, and were more sensitive to chemotherapeutic drugs. Four key UPR genes (ATF4, GOSR2, PDIA6 and SRPRB) were established in the prognostic model and HCC patients with high risk score had a worse clinical prognosis. Additionally, patients with high expression of four URGs are more sensitive to sorafenib. Moreover, ATF4 was upregulated, while GOSR2, PDIA6 and SRPRB were downregulated in sorafenib-treated HCC cells. Conclusion: The UPR-related prognostic signature containing four URGs exhibits high potential application value and performs well in the evaluation of effects of chemotherapy/immunotherapy and clinical prognosis.

Effects of donkey milk on UVB-induced skin barrier damage and melanin pigmentation: A network pharmacology and experimental validation study.

Introduction: Dairy products have long been regarded as a controversial nutrient for the skin. However, a clear demonstration of donkey milk (DM) on skincare is required. Methods: In this study, spectrum and chemical component analyses were applied to DM. Then, the effects of DM on UVB-induced skin barrier damage and melanin pigmentation were first evaluated in vitro and in vivo. Cell survival, animal models, and expression of filaggrin (FLG) were determined to confirm the effect of DM on UVB-induced skin barrier damage. Melanogenesis and tyrosinase (TYR) activity were assessed after UVB irradiation to clarify the effect of DM on whitening activities. Further, a network pharmacology method was applied to study the interaction between DM ingredients and UVB-induced skin injury. Meanwhile, an analysis of the melanogenesis molecular target network was developed and validated to predict the melanogenesis regulators in DM. Results: DM was rich in cholesterols, fatty acids, vitamins and amino acids. The results of evaluation of whitening activities in vitro and in vivo indicated that DM had a potent inhibitory effect on melanin synthesis. The results of effects of DM on UVB­induced skin barrier damage indicated that DM inhibited UVB-induced injury and restored skin barrier function via up-regulation expression of FLG (filaggrin). The pharmacological network of DM showed that DM regulated steroid biosynthesis and fatty acid metabolism in keratinocytes and 64 melanin targets which the main contributing role of DM might target melanogenesis, cell adhesion molecules (CAMs), and Tumor necrosis factor (TNF) pathway. Discussion: These results highlight the potential use of DM as a promising agent for whitening and anti-photoaging applications.

A novel risk score model based on pyroptosis-related genes for predicting survival and immunogenic landscape in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer worldwide, with high incidence and mortality. Pyroptosis, a form of inflammatory-regulated cell death, is closely associated with oncogenesis. METHODS: Expression profiles of HCC were downloaded from the TCGA database and validated using the ICGC and GEO databases. Consensus clustering analysis was used to determine distinct clusters. The pyroptosis-related genes (PRGs) included in the pyroptosis-related signature were selected by univariate Cox regression and LASSO regression analysis. Kaplan-Meier and receiver operating characteristic (ROC) analyses were performed to estimate the prognostic potential of the model. The characteristics of infiltration of immune cells between different groups of HCC were explored. RESULTS: Two independent clusters were identified according to PRG expression. Cluster 2 showed upregulated expression, poor prognosis, increased immune cell infiltration and worse immunotherapy response than cluster 1. A prognostic risk signature consisting of five genes (GSDME, NOD1, PLCG1, NLRP6 and NLRC4) was identified. In the high-risk score group, HCC patients showed decreased survival rates. In particular, multiple clinicopathological characteristics and immune cell infiltration were significantly associated with the risk score. Notably, the 5 PRGs in the risk score have been implicated in carcinogenesis, immunological pathways and drug sensitivity. CONCLUSIONS: A prognostic signature comprising five PRGs can be used as a potential prognostic factor for HCC. The PRG-related signature provides an in-depth understanding of the association between pyroptosis and chemotherapy or immunotherapy for HCC patients.

Development and Validation of a Novel Ferroptosis-Related Gene Signature for Prognosis and Immunotherapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a cancer that is sensitive to ferroptosis, and immunotherapy has emerged as a promising treatment for HCC patients. However, the prognostic potential of ferroptosis-related genes (FRGs) and the effect of ferroptosis on the tumor immune microenvironment in HCC remain largely obscure. Here, we analyzed the expression pattern of FRGs using the TCGA, ICGC and GEO databases. The expression of most FRGs was upregulated in HCC tissues compared with normal liver tissues. Three independent clusters were determined by consensus clustering analysis based on FRG expression in HCC. Cluster 3 exhibited higher expression, unfavorable prognosis, and higher histological tumor stage and grade than clusters 1 and 2. CIBERSORT analysis indicated different infiltrating levels of various immune cells among the three clusters. Moreover, most immune checkpoint genes were highly expressed in cluster 3. Univariate Cox regression and LASSO regression analyses were performed to develop a five FRG-based prognostic risk model using the TCGA and ICGC datasets. Kaplan-Meier analysis and ROC curves were performed to verify the prognostic potential of the risk model. A nomogram containing independent prognostic factors was further developed. Compared with low-risk patients, high-risk HCC patients exhibited worse overall survival (OS). In addition, this risk model was significantly correlated with the infiltrating levels of six major types of immune cells in HCC. Finally, the relationships between the five FRGs and drug sensitivity were investigated. The present study suggests that the five FRGs could elucidate the molecular mechanisms of HCC and lead to a new direction for the improvement of predictive, preventive, and personalized medicine for HCC.

The mitochondrial unfolded protein response: A multitasking giant in the fight against human diseases.

Mitochondria, which serve as the energy factories of cells, are involved in cell differentiation, calcium homeostasis, amino acid and fatty acid metabolism and apoptosis. In response to environmental stresses, mitochondrial homeostasis is regulated at both the organelle and molecular levels to effectively maintain the number and function of mitochondria. The mitochondrial unfolded protein response (UPRmt) is an adaptive intracellular stress mechanism that responds to stress signals by promoting the transcription of genes encoding mitochondrial chaperones and proteases. The mechanism of the UPRmt in Caenorhabditis elegans (C. elegans) has been clarified over time, and the main regulatory factors include ATFS-1, UBL-5 and DVE-1. In mammals, the activation of the UPRmt involves eIF2α phosphorylation and the uORF-regulated expression of CHOP, ATF4 and ATF5. Several additional factors, such as SIRT3 and HSF1, are also involved in regulating the UPRmt. A deep and comprehensive exploration of the UPRmt can provide new directions and strategies for the treatment of human diseases, including aging, neurodegenerative diseases, cardiovascular diseases and diabetes. In this review, we mainly discuss the function of UPRmt, describe the regulatory mechanisms of UPRmt in C. elegans and mammals, and summarize the relationship between UPRmt and various human diseases.

Deferasirox shows inhibition activity against cervical cancer in vitro and in vivo.

OBJECTIVE: Iron depletion may be a novel therapeutic strategy for cancer. This study aimed to assess the inhibition effects of deferasirox (DFX), an oral iron chelator, on cervical cancer. METHODS: In this study, we performed immunohistochemical analysis, enzyme-linked immunoassay, cell viability and invasive ability assay, cell cycle and apoptosis analysis, protein expression investigation, molecular mechanism investigation, and in vivo murine xenograft model to evaluate the impact of DFX on cervical cancer. RESULTS: The cervical cancer cell lines viability decreased and cell apoptosis was induced after DFX incubation. Additionally, DFX promoted cell cycle arrest by regulating the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in cervical cancer cell lines. DFX also decreased cell invasion by upregulating the expression of NDRG1 and downregulating c-Myc. The activation of Akt and the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth, decreased the levels of ferritin in serum and tumor tissue, reduced iron deposits and reactive oxygen species (ROS) levels in xenografts of DFX-treated group compared with the control group, with no serious side effects. CONCLUSION: Present study demonstrated the inhibitory effect of DFX against cervical cancer, and provided a potential therapeutic agent for cervical cancer.

Enzyme-digested Colla Corii Asini (E'jiao) suppresses lipopolysaccharide-induced inflammatory changes in THP-1 macrophages and OP9 adipocytes.

Gut microbial lipopolysaccharides (LPS)-induced inflammatory responses in adipose tissue are associated with the dysfunction of adipocytes, insulin resistance and the development of metabolic syndrome. The aim of this study is to investigate (1) the effects of LPS on the differentiation and inflammatory responses of THP-1 monocytes and OP9 preadipocytes under serum free conditions and (2) the repressive effects of enzyme-digested Colla Corii Asini (CCAD) and fish gelatin (FGD) on LPS-induced inflammatory responses in THP-1 macrophages and OP9 adipocytes. Immunofluorescence and oil red O staining showed that a serum free medium supplied with phorbol 12-myristate 13-acetate (PMA) could induce differentiation and lipid accumulation in THP-1 cells as well as OP9 cells. ELISA showed that LPS significantly increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretions in PMA-differentiated THP-1 macrophages in a dose-dependent manner. LPS significantly suppressed lipid accumulation and adiponectin secretions, and enhanced IL-6 secretions in OP9 adipocytes. Both CCAD and FGD significantly reduced the levels of both macrophages- and adipocytes-derived inflammatory cytokines and increased the level of OP9-secreted adiponectin. In conclusion, LPS could induce inflammatory responses in both THP-1 and OP9 cells and cause dysfunction of OP9 adipocytes under the serum free conditions. CCAD and FGD can repress LPS-induced inflammatory responses in both THP-1 macrophages and OP9 adipocytes, and increase the secretion of adiponectin in OP9 adipocytes. They could be used as health care supplements for improving metabolic syndrome.

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges.

The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved protective transcriptional response that maintains mitochondrial proteostasis by inducing the expression of mitochondrial chaperones and proteases in response to various stresses. The UPRmt-mediated transcriptional program requires the participation of various upstream signaling pathways and molecules. The factors regulating the UPRmt in Caenorhabditis elegans (C. elegans) and mammals are both similar and different. Cancer cells, as malignant cells with uncontrolled proliferation, are exposed to various challenges from endogenous and exogenous stresses. Therefore, in cancer cells, the UPRmt is hijacked and exploited for the repair of mitochondria and the promotion of tumor growth, invasion and metastasis. In this review, we systematically introduce the inducers of UPRmt, the biological processes in which UPRmt participates, the mechanisms regulating the UPRmt in C. elegans and mammals, cross-tissue signal transduction of the UPRmt and the roles of the UPRmt in promoting cancer initiation and progression. Disrupting proteostasis in cancer cells by targeting UPRmt constitutes a novel anticancer therapeutic strategy.

Decreased TMPRSS2 expression by SARS-CoV-2 predicts the poor prognosis of lung cancer patients through metabolic pathways and immune infiltration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world and became a global pandemic in 2020. One promising drug target for SARS-CoV-2 is the transmembrane protease serine 2 (TMPRSS2). This study was designed to explore the expression status, prognostic significance and molecular functions of TMPRSS2 in lung cancer. TMPRSS2 expression was investigated using the TIMER, Oncomine, UALCAN, GEO, HPA and TCGA databases. The prognostic value of TMPRSS2 was examined using Cox regression and a nomogram. KEGG, GO and GSEA were performed to investigate the cellular function of TMPRSS2 in lung cancer. The relationship between TMPRSS2 and immune infiltration was determined using the TIMER and CIBERSORT algorithms. TMPRSS2 mRNA and protein expression was significantly reduced in lung cancer. Decreased TMPRSS2 expression and increased DNA methylation of TMPRSS2 were associated with various clinicopathological parameters in patients with lung cancer. Low TMPRSS2 mRNA expression also correlated with poor outcome in lung cancer patients. Moreover, a nomogram was constructed and exhibited good predictive power for the overall survival of lung cancer patients. KEGG and GO analyses and GSEA implied that multiple immune- and metabolism-related pathways were significantly linked with TMPRSS2 expression. Intriguingly, TMPRSS2 expression associated with immune cell infiltration in lung cancer. More importantly, TMPRSS2 expression was markedly decreased in SARS-CoV-infected cells. These findings indicate that TMPRSS2 may be a promising prognostic biomarker and therapeutic target for lung cancer through metabolic pathways and immune cell infiltration.

JNK/Itch Axis Mediates the Lipopolysaccharide-Induced Ubiquitin-Proteasome-Dependent Degradation of Ferritin Light Chain in Murine Macrophage Cells.

Ferritin, which is composed of a heavy chain and a light chain, plays a critical role in maintaining iron homeostasis by sequestering iron. The ferritin light chain (FTL) is responsible for the stability of the ferritin complex. We have previously shown that overexpression of FTL decreases the levels of the labile iron pool (LIP) and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-treated murine macrophage cells. The protein level of FTL was downregulated by LPS within a short treatment period. However, the mechanism underlying the LPS-induced changes in the FTL levels is not known. In the present study, we report that LPS induces the ubiquitin-proteasome-dependent degradation of FTL and that the mechanism of LPS-induced FTL degradation involves the JNK/Itch axis. We found that LPS downregulates the protein and mRNA levels of FTL in a time-dependent manner. The proteasome inhibitor MG-132 significantly reverses the LPS-induced decrease in FTL. Furthermore, we observed that LPS treatment cannot cause ubiquitination of the lysine site (K105 and K144) mutant of FTL. Interestingly, LPS-mediated ubiquitin-dependent degradation of FTL is significantly inhibited by the JNK-specific inhibitor SP600125. Moreover, LPS could upregulate the protein level of E3 ubiquitin ligase Itch, a substrate of JNK kinases. Immunoprecipitation analyses revealed an increase in the association of FTL with Itch, a substrate of JNK kinases, in response to LPS stimulation. SP600125 decreased LPS-induced Itch upregulation. Taken together, these results suggest that LPS stimulation leads to the degradation of FTL through the ubiquitin-proteasome proteolytic pathway, and this FTL degradation is mediated by the JNK/Itch axis in murine macrophage cells.

Integrated Bioinformatics Analysis Identifies Heat Shock Factor 2 as a Prognostic Biomarker Associated With Immune Cell Infiltration in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks as the second leading cause of cancer-related mortality worldwide. Heat shock factor 2 (HSF2) is a transcription factor that plays a critical role in development, particularly corticogenesis and spermatogenesis. However, studies examining the expression and prognostic value of HSF2 and its association with tumor-infiltrating immune cells in HCC are still rare. In the present study, we found that HSF2 expression was significantly upregulated in HCC tissues compared with normal liver tissues using the TCGA, ICGC, GEO, UALCAN, HCCDB and HPA databases. High HSF2 expression was associated with shorter survival of patients with HCC. Cox regression analyses and nomogram were used to evaluate the association of HSF2 expression with the prognosis of patients with HCC. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA) revealed that HSF2 was associated with various signaling pathways, including the immune response. Notably, HSF2 expression was significantly correlated with the infiltration levels of different immune cells using the TIMER database and CIBERSORT algorithm. HSF2 expression also displayed a significant correlation with multiple immune marker sets in HCC tissues. Knockdown of HSF2 significantly inhibited the proliferation, migration, invasion and colony formation ability of HCC cells. In summary, we explored the clinical significance of HSF2 and provided a therapeutic basis for the early diagnosis, prognostic judgment, and immunotherapy of HCC.

Integrated analysis identifies TfR1 as a prognostic biomarker which correlates with immune infiltration in breast cancer.

Breast cancer (BC) is the most common malignancy with high morbidity and mortality in females worldwide. Emerging evidence indicates that transferrin receptor 1 (TfR1) plays vital roles in regulating cellular iron import. However, the distinct role of TfR1 in BC remains elusive. TfR1 expression was investigated using the TCGA, GEO, TIMER, UALCAN and Oncomine databases. The prognostic potential of TfR1 was evaluated by Kaplan-Meier (KM) plotter and univariate and multivariate Cox regression analyses. Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to explore the molecular mechanism of TfR1. The potential link between TfR1 expression and infiltrating abundances of immune cells was examined through the TIMER and CIBERSORT algorithm. The expression of TfR1 was dramatically upregulated in BC tissues. Increased TfR1 expression and decreased methylation levels of TfR1 were strongly correlated with multiple clinicopathological parameters. Elevated TfR1 expression was associated with a poor survival rate in BC patients. The nomogram model further confirmed that TfR1 could act as an independent prognostic biomarker in BC. The results of GO, KEGG and GSEA revealed that TfR1 was closely correlated with multiple signaling pathways and immune responses. Additionally, TfR1 was positively associated with the infiltration abundances of six major immune cells, including CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and dendritic cells in BC. Interestingly, TfR1 influenced prognosis partially through immune infiltration. These comprehensive bioinformatics analyses suggest that TfR1 is a new independent prognostic biomarker and a potential target for immunotherapy in BC.

Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer.

Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but its expression profile, prognostic potential and relationship with immune cell infiltration in BRCA are unknown. Ceruloplasmin mRNA and protein expression was significantly decreased in BRCA patients according to the Oncomine, UALCAN, GEPIA and TCGA databases. Ceruloplasmin expression was strongly correlated with various clinicopathological features of BRCA patients. BRCA patients with high ceruloplasmin expression exhibited shorter survival times than those with low ceruloplasmin expression based on the Kaplan-Meier plotter and PrognoScan databases. GO and KEGG analyses and GSEA revealed a strong correlation between ceruloplasmin and various immune-related pathways. Ceruloplasmin expression was significantly associated with the infiltration of immune cells into tumor sites by analyzing the TIMER and CIBERSORT. Additionally, ceruloplasmin was positively correlated with immune checkpoints in BRCA. These findings suggest that low ceruloplasmin expression correlates with a favorable prognosis and tumor immune cell infiltration in BRCA patients. Ceruloplasmin may serve as a therapeutic target and predict the efficacy of immunotherapy for BRCA.

Multifaceted roles of HSF1 in cell death: A state-of-the-art review.

Cell death is a common and active process that is involved in various biological processes, including organ development, morphogenesis, maintaining tissue homeostasis and eliminating potentially harmful cells. Abnormal regulation of cell death significantly contributes to tumor development, progression and chemoresistance. The mechanisms of cell death are complex and involve not only apoptosis and necrosis but also their cross-talk with other types of cell death, such as autophagy and the newly identified ferroptosis. Cancer cells are chronically exposed to various stresses, such as lack of oxygen and nutrients, immune responses, dysregulated metabolism and genomic instability, all of which lead to activation of heat shock factor 1 (HSF1). In response to heat shock, oxidative stress and proteotoxic stresses, HSF1 upregulates transcription of heat shock proteins (HSPs), which act as molecular chaperones to protect normal cells from stresses and various diseases. Accumulating evidence suggests that HSF1 regulates multiple types of cell death through different signaling pathways as well as expression of distinct target genes in cancer cells. Here, we review the current understanding of the potential roles and molecular mechanism of HSF1 in regulating apoptosis, autophagy and ferroptosis. Deciphering HSF1-regulated signaling pathways and target genes may help in the development of new targeted anti-cancer therapeutic strategies.

Pan-Cancer Analysis of the Prognostic and Immunological Role of HSF1: A Potential Target for Survival and Immunotherapy.

Emerging evidence revealed the significant roles of heat shock factor 1 (HSF1) in cancer initiation, development, and progression, but there is no pan-cancer analysis of HSF1. The present study first comprehensively investigated the expression profiles and prognostic significance of HSF1 and the relationship of HSF1 with clinicopathological parameters and immune cell infiltration using bioinformatic techniques. HSF1 is significantly upregulated in various common cancers, and it is associated with prognosis. Pan-cancer Cox regression analysis indicated that the high expression of HSF1 was associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), and kidney renal papillary cell carcinoma (KIRP) patients. The methylation of HSF1 DNA was decreased in most cancers and negatively correlated with the HSF1 expression. Increased phosphorylation of S303, S307, and S363 in HSF1 was observed in some cancers. HSF1 remarkably correlated with the levels of infiltrating cells and immune checkpoint genes. Our pan-cancer analysis provides a deep understanding of the functions of HSF1 in oncogenesis and metastasis in different cancers.