ACOX2 Serves as a Favorable Indicator Related to Lipid Metabolism and Oxidative Stress for Biochemical Recurrence in Prostate Cancer.

Given the heterogeneity of tumors, there is an urgent need for accurate prognostic parameters in prostate cancer (PCa) patients. Lipid metabolism (LM) reprogramming and oxidative stress (OS) play a vital role in the progression of PCa. In this work, we identified five LM-OS-related genes (including ACOX2, PPRAGC1A, PTGS1, PTGS2, and HAO1) associated with the biochemical recurrence (BCR) of PCa. Subsequently, a prognostic signature was established based on these five genes. Kaplan-Meier survival estimates, receiver operating characteristic curves, and relationship analysis between risk score and clinical characters were applied to measure the robustness of the signature in an external cohort. A nomogram of risk score combined with clinical characteristics was constructed for clinical application. Functional enrichment analysis suggested that the underlying mechanism related to the signature included the calcium signaling, lipid transport, and cell cycle signaling pathways. Furthermore, WEE1 inhibitor was identified as a potential agent related to the cell cycle for high-risk patients. The mRNA expression and the prognostic value of the five genes were determined, and ACOX2 was identified as the key gene related to the prognostic signature. The protein expression of ACOX2 was measured in a prostate tissue microarray through an immunohistochemistry assay, confirming the bioinformatics results. By constructing the ACOX2-overexpressing PCa cell lines PC-3 and 22Rv1, the biological function of PCa cells was investigated. The cell viability, colony formation, migration, and invasion ability of PCa cell lines overexpressing ACOX2 were hindered. Decreased cellular lipid content and elevated cellular ROS content were observed in ACOX2-overexpressing PCa cell lines with reduced G2/M phases. In conclusion, this work presents the first prognostic signature specifically focused on LM-OS for PCa. ACOX2 could serve as a favorable indicator for the BCR in PCa. Further experiments are required to identify the potential underlying mechanism.

Machine learning-based integration develops a stress response stated T cell (Tstr)-related score for predicting outcomes in clear cell renal cell carcinoma.

BACKGROUND: Establishment of a reliable prognostic model and identification of novel biomarkers are urgently needed to develop precise therapy strategies for clear cell renal cell carcinoma (ccRCC). Stress response stated T cells (Tstr) are a new T-cell subtype, which are related to poor disease stage and immunotherapy response in various cancers. METHODS: 10 machine-learning algorithms and their combinations were applied in this work. A stable Tstr-related score (TCs) was constructed to predict the outcomes and PD-1 blockade treatment response in ccRCC patients. A nomogram based on TCs for personalized prediction of patient prognosis was constructed. Functional enrichment analysis and TimiGP algorithm were used to explore the underlying role of Tstr in ccRCC. The key TCs-related gene was identified by comprehensive analysis, and the bioinformatics results were verified by immunohistochemistry using a tissue microarray. RESULTS: A robust TCs was constructed and validated in four independent cohorts. TCs accurately predicted the prognosis and PD-1 blockade treatment response in ccRCC patients. The novel nomogram was able to precisely predict the outcomes of ccRCC patients. The underlying biological process of Tstr was related to acute inflammatory response and acute-phase response. Mast cells were identified to be involved in the role of Tstr as a protective factor in ccRCC. TNFS13B was shown to be the key TCs-related gene, which was an independent predictor of unfavorable prognosis. The protein expression analysis of TNFSF13B was consistent with the mRNA analysis results. High expression of TNFSF13B was associated with poor response to PD-1 blockade treatment. CONCLUSIONS: This study provides a Tstr cell-related score for predicting outcomes and PD-1 blockade therapy response in ccRCC. Tstr cells may exert their pro-tumoral role in ccRCC, acting against mast cells, in the acute inflammatory tumor microenvironment. TNFSF13B could serve as a key biomarker related to TCs.

Evaluation of the TLR3 involvement during Schistosoma japonicum-induced pathology.

BACKGROUND: Despite the functions of TLRs in the parasitic infections have been extensively reported, few studies have addressed the role of TLR3 in the immune response to Schistosoma japonicum infections. The aim of this study was to investigate the properties of TLR3 in the liver of C57BL/6 mice infected by S. japonicum. METHODS: The production of TLR3+ cells in CD4+T cells (CD4+CD3+), CD8+T cells (CD8+CD3+), γδT cells (γδTCR+CD3+), NKT cells (NK1.1+CD3+), B cells (CD19+CD3-), NK (NK1.1-CD3+) cells, MDSC (CD11b+Gr1+), macrophages (CD11b+F4/80+), DCs (CD11c+CD11b+) and neutrophils (CD11b+ Ly6g+) were assessed by flow cytometry. Sections of the liver were examined by haematoxylin and eosin staining in order to measure the area of granulomas. Hematological parameters including white blood cell (WBC), red blood cell (RBC), platelet (PLT) and hemoglobin (HGB) were analyzed. The levels of ALT and AST in the serum were measured using biochemical kits. The relative titers of anti-SEA IgG and anti-SEA IgM in the serum were measured by enzyme-linked immunosorbent assay (ELISA). CD25, CD69, CD314 and CD94 molecules were detected by flow cytometry. RESULTS: Flow cytometry results showed that the expression of TLR3 increased significantly after S. japonicum infection (P < 0.05). Hepatic myeloid and lymphoid cells could express TLR3, and the percentages of TLR3-expressing MDSC, macrophages and neutrophils were increased after infection. Knocking out TLR3 ameliorated the damage and decreased infiltration of inflammatory cells in infected C57BL/6 mouse livers.,The number of WBC was significantly reduced in TLR3 KO-infected mice compared to WT-infected mice (P < 0.01), but the levels of RBC, platelet and HGB were significantly increased in KO infected mice. Moreover, the relative titers of anti-SEA IgG and anti-SEA IgM in the serum of infected KO mice were statistically decreased compared with the infected WT mice. We also compared the activation-associated molecules expression between S.japonicum-infected WT and TLR3 KO mice. CONCLUSIONS: Taken together, our data indicated that TLR3 played potential roles in the context of S. japonicum infection and it may accelerate the progression of S. japonicum-associated liver pathology.

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer.

The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformin's therapeutic efficacy in PCa.

Prognostic implication of heterogeneity and trajectory progression induced by enzalutamide in prostate cancer.

Background: Enzalutamide, as a second-generation endocrine therapy drug for prostate cancer (PCa), is prominent representative among the synthetic androgen receptor antagonists. Currently, there is lack of enzalutamide-induced signature (ENZ-sig) for predicting progression and relapse-free survival (RFS) in PCa. Methods: Enzalutamide-induced candidate markers were derived from single-cell RNA sequencing analysis integrating three enzalutamide-stimulated models (0-, 48-, and 168-h enzalutamide stimulation). ENZ-sig was constructed on the basis of candidate genes that were associated with RFS in The Cancer Genome Atlas leveraging least absolute shrinkage and selection operator method. The ENZ-sig was further validated in GSE70768, GSE94767, E-MTAB-6128, DFKZ, GSE21034, and GSE70769 datasets. Biological enrichment analysis was used to discover the underlying mechanism between high ENZ-sig and low ENZ-sig in single-cell RNA sequencing and bulk RNA sequencing. Results: We identified a heterogenous subgroup that induced by enzalutamide stimulation and found 53 enzalutamide-induced candidate markers that are related to trajectory progression and enzalutamide-stimulated. The candidate genes were further narrowed down into 10 genes that are related to RFS in PCa. A 10-gene prognostic model (ENZ-sig)-IFRD1, COL5A2, TUBA1A, CFAP69, TMEM388, ACPP, MANEA, FOSB, SH3BGRL, and ST7-was constructed for the prediction of RFS in PCa. The effective and robust predictability of ENZ-sig was verified in six independent datasets. Biological enrichment analysis revealed that differentially expressed genes in high ENZ-sig were more activated in cell cycle-related pathway. High-ENZ-sig patients were more sensitive to cell cycle-targeted drugs (MK-1775, AZD7762, and MK-8776) than low-ENZ-sig patients in PCa. Conclusions: Our results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle-targeted compounds in treating PCa.

Acetyl-CoA carboxylase 1 depletion suppresses de novo fatty acid synthesis and mitochondrial ß-oxidation in castration-resistant prostate cancer cells.

Cancer cells, including those of prostate cancer (PCa), often hijack intrinsic cell signaling to reprogram their metabolism. Part of this reprogramming includes the activation of de novo synthesis of fatty acids that not only serve as building blocks for membrane synthesis but also as energy sources for cell proliferation. However, how de novo fatty acid synthesis contributes to PCa progression is still poorly understood. Herein, by mining public datasets, we discovered that the expression of acetyl-CoA carboxylase alpha (ACACA), which encodes acetyl-CoA carboxylase 1 (ACC1), was highly expressed in human PCa. In addition, patients with high ACACA expression had a short disease-free survival time. We also reported that depletion of ACACA reduced de novo fatty acid synthesis and PI3K/AKT signaling in the human castration-resistant PCa (CRPC) cell lines DU145 and PC3. Furthermore, depletion of ACACA downregulates mitochondrial beta-oxidation, resulting in mitochondrial dysfunction, a reduction in ATP production, an imbalanced NADP+/NADPhydrogen(H) ratio, increased reactive oxygen species, and therefore apoptosis. Reduced exogenous fatty acids by depleting lipid or lowering serum supplementation exacerbated both shRNA depletion and pharmacological inhibition of ACACA-induced apoptosis in vitro. Collectively, our results suggest that inhibition of ectopic ACACA, together with suppression of exogenous fatty acid uptake, can be a novel strategy for treating currently incurable CRPC.

Identification and experimental validation of a tumor-infiltrating lymphocytes-related long noncoding RNA signature for prognosis of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common aggressive malignant tumor of the urinary system. Given the heterogeneity of the tumor microenvironment, immunotherapy may not fully exert its role in the treatment of advanced patients. Long noncoding RNA (lncRNA) has been reported to be critically associated with the differentiation and maturation of tumor-infiltrating lymphocytes (TILs), which work against tumor cells. In this study, we identified 10 TIL-related lncRNAs (AL590094.1, LINC02027, LINC00460, AC147651.1, AC026401.3, LINC00944, LINC01615, AP000439.2, AL162586.1, and AC084876.1) by Pearson correlation, univariate Cox regression, Lasso regression, and multivariate Cox regression based on The Cancer Genome Atlas (TCGA) database. A risk score model was established based on these lncRNAs. Next, a nomogram was constructed to predict the overall survival. By employing differentially expressed genes (DEGs) between groups with high and low risk scores, gene ontology (GO) enrichment analysis was performed to identify the major biological processes (BP) related to immune DEGs. We analyzed the mutation data of the groups and demonstrated that SETD2 and BAP1 had the highest mutation frequency in the high-risk group. The "CIBERSORT" R package was used to detect the abundance of TILs in the groups. The expression of lymphocyte markers was compared. We also determined the expression of two lncRNAs (AC084876.1 and AC026401.3) and their relationship with lymphocyte markers in the kidney tissue of ccRCC patients and showed that there was a positive correlation between AC084876.1 and FoxP3. Proliferation, migration, and invasion of AC084876.1-downregulated ccRCC cell lines were inhibited, and the expression of PD-L1 and TGF-ß secretion decreased. To our knowledge, this is the first bioinformatics study to establish a prognostic model for ccRCC using TIL-related lncRNAs. These lncRNAs were associated with T-cell activities and may serve as biomarkers of disease prognosis.

TLR7 controls myeloid-derived suppressor cells expansion and function in the lung of C57BL6 mice infected with Schistosoma japonicum.

Toll-like receptors (TLRs) play an important role in the induction of innate and adaptive immune responses against Schistosoma japonicum (S. japonicum) infection. However, the role of Toll-like receptor 7 (TLR7) in the mouse lung during S. japonicum infection and the myeloid-derived suppressor cells (MDSCs) affected by the absence of TLR7 are not clearly understood. In this study, the results indicated that the MDSCs were accumulated and the proportion and activation of CD4+ and CD8+ T cells were decreased in the lung of mice at 6-7 weeks after S. japonicum infection. Then, the expression of TLR7 was detected in isolated pulmonary MDSCs and the results showed that the expression of TLR7 in MDSCs was increased after infection. Furthermore, TLR7 agonist R848 could down-regulate the induction effect of the soluble egg antigen (SEA) on pulmonary MDSCs in vitro. Meanwhile, TLR7 deficiency could promote the pulmonary MDSCs expansion and function by up-regulating the expression of PD-L1/2 and secreting of IL-10 in the mice infected with S. japonicum. Mechanistic studies revealed that S. japonicum infection and the antigen effects are mediated by NF-κB signaling. Moreover, TLR7 deficiency aggravates S. japonicum infection-induced damage in the lung, with more inflammatory cells infiltration, interstitial dilatation and granuloma in the tissue. In summary, this study indicated that TLR7 signaling inhibits the accumulation and function of MDSCs in S. japonicum infected mouse lung by down-regulating the expression of PD-L1/2 and secreting of IL-10, via NF-κB signaling.

MYPT1 inhibits the metastasis of renal clear cell carcinoma via the MAPK8/N-cadherin pathway.

Myosin phosphatase target subunit 1 (MYPT1) is a subunit of myosin phosphatase that is capable of regulating smooth muscle contraction. MYPT1 has been reported to be involved in a wide variety of tumours, but its expression and biological functions in renal clear cell carcinoma (ccRCC) remain obscure. Herein, we analysed the relationship between patient clinicopathological characteristics and MYPT1 expression levels in ccRCC patients using a tissue microarray (TMA) and data retrieved from the TCGA-KIRC dataset. MYPT1 was overexpressed or depleted using siRNA in ccRCC cells to assess the effects on migration and invasion in vitro and in vivo. Additionally, RNA-sequencing and bioinformatics analysis were performed to investigate the precise mechanism. MYPT1 expression in ccRCC tissues was observed to be lower than that in nonmalignant tissues (P < 0.05). In addition, MYPT1 downregulation was closely linked to advanced pathological stage (P < 0.05), and poor OS (overall survival; P < 0.05). Functionally, increased expression of MYPT1 suppressed ccRCC migration and invasion in vitro, and inhibited tumour metastasis in vivo. In addition, MYPT1 overexpression exerted its suppressive effects via the MAPK8/N-cadherin pathway in ccRCC.

Integrated analysis reveals prognostic value and progression-related role of AMIGO2 in prostate cancer.

Background: Even though emerging studies supplied evidence that Adhesion Molecule with Ig Like Domain family 2 (AMIGO2) plays a critical role in numerous cancers, comprehensive analysis of the prognostic value and significant role of AMIGO2 in prostate cancer (PCa) have not been described. Methods: Differentially expressed analysis, survival analysis and univariate cox regression analysis were first performed to explore the diagnostic and prognostic role of AMIGO2 in various cancers, especially in PCa. Tissue microarray were used to examined the association between AMGIO2 and clinical features. Multivariate cox regression analysis, concordance index, nomogram construction, the receiver operator characteristic curve and calibration curves were further used to discover the effects of AMIGO2 on recurrence-free survival (RFS) and clinicopathological characteristics, including age, Gleason score (GS) and tumor stage. Genetic and Epigenetic Alterations analysis were further conducted to explore the potential effect of AMIGO2 in PCa and examined by biological function analysis and in vitro experiments. Results: AMIGO2 was associated with poor RFS (P<0.05) and differentially expressed (P<0.05) in multiple cancer type, especially in PCa. Besides, decreasing the expression of AMIGO2 inhibited PCa cell proliferation and colony formation in vitro. In addition, AMIGO2 was a reliable prognostic marker providing additional information (C-index: 0.7) that supplement the currently used prognosis evaluation system, e.g., T stage (C-index: 0.62) and GS (C-index: 0.65). A novel nomogram was established based on AMIGO2, tumor stage and GS with accuracies (areas under curve) of 0.70, 0.78 and 0.82 for predicting 3-, 5- and 7-year RFS, respectively. Bioinformatic analysis and in vitro examination also suggested that AMIGO2 might involve in the progression of PCa tumors inducing epithelial mesenchymal transition (EMT). Conclusions: We identified AMIGO2 as a pan-cancer gene that could not only be a prognostic biomarker in various cancers, especially in PCa, but may functionally promoting PCa progression via EMT and mediating docetaxel resistance, suggesting AMIGO2 as a potential target for future treatment of PCa.

Differential Expression of E2F Transcription Factors and Their Functional and Prognostic Roles in Human Prostate Cancer.

Given the tumor heterogeneity, most of the current prognostic indicators cannot accurately evaluate the prognosis of patients with prostate cancer, and thus, the best opportunity to intervene in the progression of this disease is missed. E2F transcription factors (E2Fs) have been reported to be involved in the growth of various cancers. Accumulating studies indicate that prostate cancer (PCa) carcinogenesis is attributed to aberrant E2F expression or E2F alteration. However, the expression patterns and prognostic value of the eight E2Fs in prostate cancer have yet to be explored. In this study, The Cancer Genome Atlas (TCGA), Kaplan-Meier Plotter, Metascape, the Kyoto Encyclopedia of Genes and Genomes (KEGG), CIBERSORT, and cBioPortal and bioinformatic analysis were used to investigate E2Fs in patients with PCa. Our results showed that the expression of E2F1-3, E2F5, and E2F6 was higher in prostate cancer tissues than in benign tissues. Furthermore, elevated E2F1-3 and E2F5 expression levels were associated with a higher Gleason score (GS), advanced tumor stage, and metastasis. Survival analysis suggested that high transcription levels of E2F1-3, E2F5, E2F6, and E2F8 were associated with a higher risk of biochemical recurrence. In addition, we developed a prognostic model combining E2F1, E2F6, Gleason score, and the clinical stage that may accurately predict a biochemical recurrence-free survival. Functional enrichment analysis revealed that the E2F family members and their neighboring genes were mainly enriched in cell cycle-related pathways. Somatic mutations in different subgroups were also investigated, and immune components were predicted. Further experiments are warranted to clarify the biological associations between Pca-related E2F family genes, which may influence prognosis via the cell cycle pathway.

Mannose inhibits the growth of prostate cancer through a mitochondrial mechanism.

The limited treatment options for advanced prostate cancer (PCa) lead to the urgent need to discover new anticancer drugs. Mannose, an isomer of glucose, has been reported to have an anticancer effect on various tumors. However, the anticancer effect of mannose in PCa remains unclear. In this study, we demonstrated that mannose inhibits the proliferation and promotes the apoptosis of PCa cells in vitro, and mannose was observed to have an anticancer effect in mice without harming their health. Accumulation of intracellular mannose simultaneously decreased the mitochondrial membrane potential, increased mitochondrial and cellular reactive oxygen species (ROS) levels, and reduced adenosine triphosphate (ATP) production in PCa cells. Mannose treatment of PCa cells induced changes in mitochondrial morphology, caused dysregulated expression of the fission protein, such as fission, mitochondrial 1 (FIS1), and enhanced the expression of proapoptotic factors, such as BCL2-associated X (Bax) and BCL2-antagonist/killer 1 (Bak). Furthermore, lower expression of mannose phosphate isomerase (MPI), the key enzyme in mannose metabolism, indicated poorer prognosis in PCa patients, and downregulation of MPI expression in PCa cells enhanced the anticancer effect of mannose. This study reveals the anticancer effect of mannose in PCa and its clinical significance in PCa patients.

Circular RNA circ_0000515 adsorbs miR-542-3p to accelerate bladder cancer progression via up-regulating ILK expression.

BACKGROUND: Bladder cancer (BC) is a common cause of cancer-relevant deaths globally. This study is designed to delve into expressions, biological functions and molecular mechanisms of circ_0000515 in BC. METHODS: Quantitative real-time polymerase chain reaction was accomplished to examine circ_0000515, miR-542-3p and integrin-linked kinase (ILK) mRNA expressions in BC tissues and cell lines. In RT-4 and RT-112 cells with circ_0000515 depletion and UMUC3 and BIU-87 cells with this circ RNA overexpression, a cell counting kit-8 assay was adopted to monitor the viability. Besides, transwell assay was conducted to detect cell migration and aggressiveness, and luciferase reporter gene assay was applied to probe the interplay among circ_0000515, miR-542-3p and ILK mRNA. Additionally, Besides, the regulatory function of circ_0000515 on miR-542-3p expression was under the assay of quantitative real-time polymerase chain reaction, and western blot was fulfilled to determine the regulative function of circ_0000515/miR-542-3p axis on ILK protein expressions. A xenograft animal was modeled to examine lung metastasis in vivo. RESULTS: Circ_0000515 and ILK expressions were significantly elevated in BC tissues and cell lines, while that of miR-542-3p was dramatically suppressed. Knocking down circ_0000515 could significantly repress the growth, migration and aggressiveness of BC cells while overexpression of circ_0000515 showed opposite effects. Moreover, circ_0000515 knockdown inhibited pulmonary metastasis in vivo. Circ_0000515 was validated to adsorb miR-542-3p, and ILK was testified as the downriver target of miR-542-3p. Circ_0000515 could ascend ILK expression through repressing that of miR-542-3p. CONCLUSIONS: Circ_0000515, as a tumor promoter, strengthens the viability, migration and aggressiveness of BC cells via modulating miR-542-3p/ILK axis.

The prognostic roles of CYP19A1 expression in bladder cancer patients of different genders.

BACKGROUND: The incidence of bladder cancer (BCa) in male is approximately three to four times higher than in female, but the oncological outcomes in female patients with BCa are significantly worse than in male patients. Although many biomarkers have been identified in recent decades to predict the prognosis of BCa patients, few of them are able to distinguish the prognosis of BCa patients with gender difference. Aromatase encoded by the CYP19A1 gene catalyzes the conversion of androgens to estrogens. In this study, we investigate the prognosis significance of CYP19A1 expression considering the gender difference in BCa patients from four available public databases. METHODS: Four available public databases of BCa, including GSE13507, TCGA-BLCA, E-MTAB-4321, and E-MTAB-1803, were utilized in this analysis. The overall survival (OS) and progression-free survival (PFS) in different stages and genders were evaluated using the Kaplan-Meier analysis based on the optimal cut-off values of CYP19A1 expression. Then, Gene Set Enrichment Analysis (GSEA) were further performed to explore the potential biologic pathways by altering CYP19A1 expression in BCa patients. RESULTS: The results showed that patients with high CYP19A1 expression had a poorer outcome compared with those with low expression in both BCa cohorts in general. Higher CYP19A1 expression in male patients were significantly associated with shorter survival for either non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC). However, female NMIBC patients with high CYP19A1 expression were identified to have a better prognosis, whereas high CYP19A1 expression in female MIBC patients were significantly associated with poorer survival. The result of the GSEA showed that different outcomes in female and male patients with NMIBC were related to the interaction of CYP19A1 and the cell-cycle-related pathways. CONCLUSIONS: These findings demonstrated that CYP19A1 expression might have a potential role in distinguishing the prognosis of female BCa patients dependent on tumor stage. Our results provide new insights for aromatase-mediated BCa therapy.

Prediction of Biochemical Recurrence-Free Survival of Prostate Cancer Patients Leveraging Multiple Gene Expression Profiles in Tumor Microenvironment.

Tumor-adjacent normal (TAN) tissues, which constitute tumor microenvironment and are different from healthy tissues, provide critical information at molecular levels that can be used to differentiate aggressive tumors from indolent tumors. In this study, we analyzed 52 TAN samples from the Cancer Genome Atlas (TCGA) prostate cancer patients and developed a 10-gene prognostic model that can accurately predict biochemical recurrence-free survival based on the profiles of these genes in TAN tissues. The predictive ability was validated using TAN samples from an independent cohort. These 10 prognostic genes in tumor microenvironment are different from the prognostic genes detected in tumor tissues, indicating distinct progression-related mechanisms in two tissue types. Bioinformatics analysis showed that the prognostic genes in tumor microenvironment were significantly enriched by p53 signaling pathway, which may represent the crosstalk tunnels between tumor and its microenvironment and pathways involving cell-to-cell contact and paracrine/endocrine signaling. The insight acquired by this study has advanced our knowledge of the potential role of tumor microenvironment in prostate cancer progression.

Roles of TLR7 in Schistosoma japonicum Infection-Induced Hepatic Pathological Changes in C57BL/6 Mice.

S. japonicum infection can induce granulomatous inflammation in the liver of the host. Granulomatous inflammation limits the spread of infection and plays a role in host protection. Toll-like receptor 7 (TLR7) is an endosomal TLR that recognizes single-stranded RNA (ssRNA). In this study, the role of TLR7 in S. japonicum infection-induced hepatitis was investigated in both normal and TLR7 knockout (KO) C57BL/6 mice. The results indicated that TLR7 KO could aggravate S. japonicum infection-induced damage in the body, with less granuloma formation in the tissue, lower WBCs in blood, and decreased ALT and AST in the serum. Then, the expression of TLR7 was detected in isolated hepatic lymphocytes. The results indicated that the percentage of TLR7+ cells was increased in the infected mice. Hepatic macrophages, DCs, and B cells could express TLR7, and most of the TLR7-expressing cells in the liver of infected mice were macrophages. The percentage of TLR7-expressing macrophages was also increased after infection. Moreover, macrophages, T cells, and B cells showed significant changes in the counts, activation-associated molecule expression, and cytokine secretion between S. japonicum-infected WT and TLR7 KO mice. Altogether, this study indicated that TLR7 could delay the progression of S. japonicum infection-induced hepatitis mainly through macrophages. DCs, B cells, and T cells were involved in the TLR7-mediated immune response.

Identification and Validation of a PPP1R12A-Related Five-Gene Signature Associated With Metabolism to Predict the Prognosis of Patients With Prostate Cancer.

BACKGROUND: Prostate cancer (PCa) is the most common malignant male neoplasm in the American male population. Our prior studies have demonstrated that protein phosphatase 1 regulatory subunit 12A (PPP1R12A) could be an efficient prognostic factor in patients with PCa, promoting further investigation. The present study attempted to construct a gene signature based on PPP1R12A and metabolism-related genes to predict the prognosis of PCa patients. METHODS: The mRNA expression profiles of 499 tumor and 52 normal tissues were extracted from The Cancer Genome Atlas (TCGA) database. We selected differentially expressed PPP1R12A-related genes among these mRNAs. Tandem affinity purification-mass spectrometry was used to identify the proteins that directly interact with PPP1R12A. Gene set enrichment analysis (GSEA) was used to extract metabolism-related genes. Univariate Cox regression analysis and a random survival forest algorithm were used to confirm optimal genes to build a prognostic risk model. RESULTS: We identified a five-gene signature (PPP1R12A, PTGS2, GGCT, AOX1, and NT5E) that was associated with PPP1R12A and metabolism in PCa, which effectively predicted disease-free survival (DFS) and biochemical relapse-free survival (BRFS). Moreover, the signature was validated by two internal datasets from TCGA and one external dataset from the Gene Expression Omnibus (GEO). CONCLUSION: The five-gene signature is an effective potential factor to predict the prognosis of PCa, classifying PCa patients into high- and low-risk groups, which might provide potential novel treatment strategies for these patients.

Corrigendum: TFEB Promotes Prostate Cancer Progression via Regulating ABCA2-Dependent Lysosomal Biogenesis.

[This corrects the article DOI: 10.3389/fonc.2021.632524.].

A HIF1α-GPD1 feedforward loop inhibits the progression of renal clear cell carcinoma via mitochondrial function and lipid metabolism.

BACKGROUND: Hypoxia signaling, especially the hypoxia inducible factor (HIF) pathway, is a major player in clear cell renal cell carcinoma (ccRCC), which is characterized by disorders in lipid and glycogen metabolism. However, the interaction between hypoxia and lipid metabolism in ccRCC progression is still poorly understood. METHODS: We used bioinformatic analysis and discovered that glycerol-3-phosphate dehydrogenase 1 (GPD1) may play a key role in hypoxia and lipid metabolism pathways in ccRCC. Tissue microarray, IHC staining, and survival analysis were performed to evaluate clinical function. In vitro and in vivo assays showed the biological effects of GPD1 in ccRCC progression. RESULTS: We found that the expression of GPD1 was downregulated in ccRCC tissues, and overexpression of GPD1 inhibited the progression of ccRCC both in vivo and in vitro. Furthermore, we demonstrated that hypoxia inducible factor-1α (HIF1α) directly regulates GPD1 at the transcriptional level, which leads to the inhibition of mitochondrial function and lipid metabolism. Additionally, GPD1 was shown to inhibit prolyl hydroxylase 3 (PHD3), which blocks prolyl-hydroxylation of HIF1α and subsequent proteasomal degradation, and thus reinforces the inhibition of mitochondrial function and phosphorylation of AMPK via suppressing glycerol-3-phosphate dehydrogenase 2 (GPD2). CONCLUSIONS: This study not only demonstrated that HIF1α-GPD1 forms a positive feedforward loop inhibiting mitochondrial function and lipid metabolism in ccRCC, but also discovered a new mechanism for the molecular basis of HIF1α to inhibit tumor activity, thus providing novel insights into hypoxia-lipid-mediated ccRCC therapy.