Chemotherapy-associated gonadotoxicity compromises Leydig cell steroidogenesis and leads to testosterone deficiency, yet repair is hindered by the testicular barrier–immune niche and by limited manufacturability of biologics. Inspired by the tubular architecture of seminiferous tubules, we develop a coaxial bioprinting–enabled encapsulation culture that generates continuous core–shell hydrogel microfibers for high-density 3D culture of human umbilical cord MSCs (hUMSCs) and continuous conditioned-medium harvesting, producing seminiferous tubule–inspired coaxial bioprinting–derived extracellular vesicles (STi-EVs). We directly benchmark STi-EVs against conventional 2D culture–derived EVs (2D-EVs) in a 4-hydroperoxycyclophosphamide (4-HC)–injured TM3 model and a cyclophosphamide-induced mouse model. Across cellular fitness, re-engagement of steroidogenic programs, aFnd testosterone output, STi-EVs consistently outperform 2D-EVs, while more effectively alleviating testicular histopathology and restoring serum testosterone in vivo. Transcriptomics prioritize Wnt signaling and nominate Wnt4; orthogonal validation and Wnt4 gain- and loss-of-function perturbations support that STi-EVs can restore steroidogenesis, at least in part, by restraining Wnt4/β-catenin signaling. Collectively, this work couples a scalable extracellular vesicles (EVs) manufacturing paradigm with a mechanism-guided repair axis for endocrine sequelae after alkylating chemotherapy.

Chemotherapy-associated gonadotoxicity compromises Leydig cell steroidogenesis and leads to testosterone deficiency, yet repair is hindered by the testicular barrier–immune niche and by limited manufacturability of biologics. Inspired by the tubular architecture of seminiferous tubules, we develop a coaxial bioprinting–enabled encapsulation culture that generates continuous core–shell hydrogel microfibers for high-density 3D culture of human umbilical cord MSCs (hUMSCs) and continuous conditioned-medium harvesting, producing seminiferous tubule–inspired coaxial bioprinting–derived extracellular vesicles (STi-EVs). We directly benchmark STi-EVs against conventional 2D culture–derived EVs (2D-EVs) in a 4-hydroperoxycyclophosphamide (4-HC)–injured TM3 model and a cyclophosphamide-induced mouse model. Across cellular fitness, re-engagement of steroidogenic programs, and testosterone output, STi-EVs consistently outperform 2D-EVs, while more effectively alleviating testicular histopathology and restoring serum testosterone in vivo. Transcriptomics prioritize Wnt signaling and nominate Wnt4; orthogonal validation and Wnt4 gain- and loss-of-function perturbations, and β-catenin stabilization experiments support that modulation of Wnt4/β-catenin signaling functionally contributes to STi-EV-mediated steroidogenic restoration. Collectively, this work couples a scalable extracellular vesicles (EV) manufacturing paradigm with a mechanism-informed repair strategy for endocrine sequelae after alkylating chemotherapy.

Urothelial bladder cancer (UBC) poses a considerable threat to public health, and its clinical management is limited by high recurrence rates and a tendency for progression. While dysregulation of the ubiquitin‒proteasome system (UPS) is a hallmark of tumorigenesis, the specific landscape of deubiquitinating enzymes (DUBs) in UBC remains largely underexplored. Multiple transcriptomic datasets were used for a comprehensive screening of ubiquitination-related genes in UBC, and ZRANB1 was identified as a potential oncogenic DUB, whose expression was validated using immunohistochemistry. High ZRANB1 expression was correlated with advanced pathological T stage, lymph node metastasis, and poor overall survival. The oncogenic role of ZRANB1 was assessed by proliferation, migration, and invasion assays in vitro, as well as in subcutaneous xenograft and lymph node metastasis models in vivo. Using immunoprecipitation coupled with mass spectrometry, we revealed that ZRNAB1 acted as a DUB to prevent the UPS-dependent degradation of SF3B3. The ZRANB1-SF3B3 axis subsequently modulates the alternative splicing of the cell cycle checkpoint kinase CHEK2, specifically inhibiting the production of the exon 4-skipped isoform (CHEK2-e4-). We demonstrated that while full-length CHEK2 is permissive for growth, the CHEK2-e4- isoform exerts a potent tumour-suppressive effect. This study reveals a novel post-translational mechanism linking the UPS to the RNA splicing machinery in UBC. ZRANB1 promotes tumorigenesis by stabilizing SF3B3 to prevent the generation of the tumour-suppressive CHEK2-e4- isoform, suggesting that ZRANB1 is a promising prognostic biomarker and therapeutic target.

BACKGROUND:Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. METHODS:A total of 142 pairs of tumor and adjacent formalin-fixed paraf-fin-embedded tissue samples from patients with prostate cancer were collected from the Pathology Department at Sun Yat-sen Memorial Hos-pital. LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes. RESULTS:LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide. CONCLUSIONS:LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.

Tumors have a unique niche system that plays an important role in their occurrence and development. At present, there is increasing interest in the biomechanical properties of niches. The increased stemness of cancer cells is closely related to bladder cancer progression and recurrence. However, how biomechanical properties in the niche regulate bladder cancer stemness remains unclear. Here, we show that as bladder cancer progresses, matrix stiffness increases, and tumor stemness increases. Mechanistically, high matrix stiffness mediates β-catenin nuclear translocation by increasing the nuclear pore size. On the other hand, it promotes the expression of the nuclear cytoskeletal protein Lamin A/C, inhibits the nuclear export of β-catenin, and finally, it upregulates the Wnt pathway to increase the stemness of cancer cells. These findings reveal a role for matrix stiffness in the regulation of stemness in bladder cancer cells and suggest that targeting matrix stiffness may be an effective strategy to delay bladder cancer progression.

Background: Bipolar transurethral enucleation of the prostate (B-TUEP) is a well-established surgical treatment for benign prostatic hyperplasia (BPH); however, its efficacy may vary depending on patient characteristics. Magnetic resonance imaging (MRI) with radiomics analysis can offer comprehensive and quantitative information about prostate characteristics that may relate to surgical outcomes. This study aimed to explore the value of MRI and radiomics analysis in predicting the short-term efficacy of B-TUEP for BPH. Materials and methods: A total of 137 patients with BPH who underwent B-TUEP at 2 institutions were included. Radiological features were measured in the MRIs, and the radiomics score was developed from 1702 radiomics features extracted from the prostate and transitional zone regions of interest. Three prediction models were developed and validated based on clinical-radiological features, radiomic features, and their combinations. The models were evaluated using the area under the receiver operating characteristic curve, calibration curve, and decision curve analysis. Results: The combination model exhibited the highest area under curve in both the training set (0.838) and the external validation set (0.802), indicating superior predictive performance and robustness. Furthermore, the combination model demonstrated good calibration (p > 0.05) and optimal clinical utility. The combination model indicated that a higher maximum urine flow rate, lower transitional zone index, and higher radiomics score were associated with an increased risk of poor efficacy. Conclusions: Magnetic resonance imaging with radiomic analysis can offer valuable insights for predicting the short-term efficacy of B-TUEP in patients with BPH. A combination model based on clinical and radiomics features can assist urologists in making more precise clinical decisions.

Circular RNAs (circRNAs) are a family of endogenous RNAs that have become a focus of biological research in recent years. Emerging evidence has revealed that circRNAs exert biological functions by acting as transcriptional regulators, microRNA sponges, and binding partners with RNA-binding proteins. However, few studies have identified coding circRNAs, which may lead to a hidden repertoire of proteins. In this study, we unexpectedly discovered a protein-encoding circular RNA circCCDC7(15,16,17,18,19) while we were searching for prostate cancer related chimeric RNAs. circCCDC7(15,16,17,18,19) is derived from exon 19 back spliced to exon 15 of the CCDC7 gene. It is significantly downregulated in patients with high Gleason score. Prostate cancer patients with decreased circCCDC7(15,16,17,18,19) expression have a worse prognosis, while linear CCDC7 had no such association. Overexpressed circCCDC7(15,16,17,18,19) inhibited prostate cancer cell migration, invasion, and viability, supporting classification of circCCDC7(15,16,17,18,19) as a bona fide tumor suppressor gene. We provide evidence that its tumor suppressive activity is driven by the protein it encodes, and that circCCDC7(15,16,17,18,19) encodes a secretory protein. Consistently, conditioned media from circCCDC7(15,16,17,18,19) overexpressing cells has the same tumor suppressive activity. We further demonstrate that the tumor suppressive activity of circCCDC7(15,16,17,18,19) is at least partially mediated by FLRT3 , whose expression also negatively correlates with Gleason score and clinical prognosis. In conclusion, circCCDC7(15,16,17,18,19) functions as a tumor suppressor in prostate cancer cells through the circCCDC7-180aa secretory protein it encodes, and is a promising therapeutic peptide for prostate cancer.

Background: Renal carcinoma is common and highly malignant, it is not sensitive to chemo-radiotherapy, leading its poor progression. Currently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in renal cancer and explore its role in cancer progression and its interaction with CD8+T cells. Methods: We analyzed the subcluster and differentiation states of monocytes and CD8+T cells in RCC and their cellchart based on integrated scRNA-seq data. S100A9 expression and percentage of CD8+T cell infiltration in RCC tissue samples from 79 patients were assessed by immunohistochemistry. Results: Monocytes were categorized into 5 clusters and S100A9 was mainly expressed by inflammatory cells on monocytes C1-1 in human RCC tissues, is a terminal status of monocytes and low expressed with immune checkpoints reported on monocytic cells. CD8+ T cells were defined into 5 clusters. Next, we identified strong interactions among Mono-C1-1 and ACT/CTL/EXT clusters with NAMPT-(IGTA5+IGTB1) and slightly interaction with VEGF pathway. Statistical analysis showed that a high percentage of S100A9 cells infiltration (> = 10%) in cancer tissues was positively correlated with poor prognosis. Further investigation found that S100A9 distribution in RCC was negatively related to CD8+ T cells infiltration. Conclusions: Our results showed S100A9 was mainly expressed in monocytes, while S100A9 in RCC is associated with poor prognosis and negatively related to CD8+ T cells infiltration by NAMPT-(IGTA5+IGTB1) and VEGF pathway.

Background:Radiologists currently accept the concept of "interfascial plane (IFP)" to understand retroperitoneal anatomy, replacing Meyers' classic tricompartmental theory. Despite much research on retroperitoneal anatomy, its anatomical structure, embryonic origin and developmental process still require further exploration to guide the optimization of surgical process. This study aims to explore the anatomical basis of IFP related to laparoscopic upper retroperitoneal surgery (LURS) and to compare the clinical outcomes of trans-interfascial plane procedures for LURS (TIFP-LURS) with conventional LURS (Con-LURS).Methods:The study consisted of two parts: cadaveric and clinical study. The cadaveric study involved dissecting and observing the retroperitoneal fasciae and IFP in 32 cadavers using gross anatomical and histological methods. This retrospective clinical study compared the perioperative data and complications of 229 patients who underwent TIFP-LURS and 121 patients who underwent Con-LURS for upper retroperitoneal lesions at our center.Results:The cadaveric study revealed that the retroperitoneal space was composed of multilaminar fasciae that formed potential bloodless spaces among them, that could be used as surgical landmarks and operating planes. The clinical study showed that TIFP-LURS had a significantly less estimated blood loss, lower intraoperative complication rate, lower postoperative complication rate, shorter hospital-stay and lower long-term postoperative complications rate than Con-LURS. Multivariate analysis indicated that the TIFP procedure was an independent protective factor for decreasing the risk of postoperative complications.Conclusions:The IFP are potential avascular spaces that can be used during laparoscopic surgery, and TIFP-LURS is a novel surgical approach that can improve the safety and efficacy of laparoscopic surgery for upper retroperitoneal lesions.

Abstract Background Currently, the potential link between aspirin use and the development of prostate cancer remains uncertain. The purpose of this study using two-sample Mendelian randomization (MR) was to elucidate the causal effect of aspirin use on prostate cancer (PCa) risk. Methods This study included pooled statistics from two Genome-Wide Association Study (GWAS), one for aspirin use (61583 cases and 50427 control) and the other for PCa of European descent (22534 cases and 270176 control). Inverse variance weighting (IVW) was used as the main method, MR-Egger method, weighted median method and weighted model method were used to evaluate the causal relationship between aspirin use and PCa risk. Cochran's Q test was used to check the heterogeneity, and the MR-Egger intercept test was used to analyze the horizontal pleotropy of the results, and a residual analysis was carried out to confirm the robustness and reliability of the results. Results Inverse variance weighting was used to infer that aspirin use had a protective effect on reducing the incidence of PCa (OR = 0.986, 95% CI = 0.978–0.994, P = 0.001). Sensitivity analysis showed that pleiotropy and heterogeneity were not observed. Furthermore, the remain-one analysis showed that the survey results were not significantly affected by any instrumental variable. Conclusion There is a causal relationship between aspirin use and the development of PCa, that is, aspirin use reduces the risk of PCa.

Traditional therapies such as surgery and endocrine therapy no longer meet the clinical needs in prostate cancer treatment, and more effective treatments are urgently required. Recent studies have reported that targeted inhibition of the transcription factor cyclin dependent kinase 7 (CDK7) could effectively suppress prostate cancer progression. However, the toxicity of CDK7 inhibitors such as THZ1 is the main limitation of the clinical application. In this work, we synthesized Cys8E nanoparticles (NPs) loaded with THZ1 (C8E@THZ1), a novel GSH-targeting and stimuli-responsive nano-delivery platform, and investigated its anti-tumor potential and biosafety properties. In vitro, C8E@THZ1 potently inhibited the proliferation and promoted the apoptosis of prostate cancer cells. On tumor-bearing mice, C8E@THZ1 inhibited tumors by up to 85%, while the damage of THZ1 to liver function was effectively avoided. These results confirmed that inhibition of CDK7 can effectively block the progression of prostate cancer, and that Cys8E NPs is a highly prospective delivery platform to promote the clinical application of CDK7 inhibitors.

BACKGROUND:Metastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa.METHODS:Transcriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2.RESULTS:We discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2.CONCLUSIONS:Overall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.

Objective:To investigate the effect of glioma tumor suppressor candidate region gene 1 (GLTSCR1) on the progression of prostate cancer.Methods:DU145 and LNCaP cells were transfected with blank vectoror or short hairpin RNA (shRNA) of GLTSCR1. Proliferation was detected by cell count kit, migration was detected by wound-scratch assays, and the effect of GLTSCR1 on prostate cancer in vivo was detected through cell derived xenograft (CDX) model with DU145. T test was used to evaluate the difference between the two groups. Results:The proliferation of DU145 cells [absorbance ( A), (1.223±0.015, 2.142±0.018, 2.576±0.036) vs. (1.754±0.009, 2.307±0.001, 2.641±0.016), t=51.360, P<0.05; t=15.590, P<0.05; t=2.868, P<0.05] and LNCaP cells [ A: (0.3221±0.002, 0.480±0.003, 1.175±0.003) vs. (0.359±0.001, 0.655±0.014, 1.473±0.022), t=15.480, 12.060, 13.600, all P<0.01] was suppressed in sh-GLTSCR1 group at 24, 48 and 72 h. The migration index in DU145-sh-GLTSCR1 group [(0.446±0.030) vs. (0.543±0.053), t=3.915, P<0.01] and LNCaP-sh-GLTSCR1 group [(0.410±0.060) vs. (0.583±0.083), t=2.927, P<0.05] was lower than in control group. CDX model suggested that the tumor burden in the sh-GLTSCR1 group was lower than in control group [(0.033±0.012) g vs. (0.083±0.022) g, t=1.987, P<0.05]. Conclusion:GLTSCR1 enhances the proliferation and migration of prostate cancer.

Immunotherapy is gradually emerging in the field of tumor treatment. However, because of the complexity of the tumor microenvironment (TME), some patients cannot benefit from immunotherapy. Therefore, we comprehensively analyzed the TME and gene mutations of ccRCC to identify a comprehensive index that could more accurately guide the immunotherapy of patients with ccRCC. We divided ccRCC patients into two groups based on immune infiltration activity. Next, we investigated the differentially expressed genes (DEGs) and constructed a prognostic immune score using univariate Cox regression analysis, unsupervised cluster analysis, and principal component analysis (PCA) and validated its predictive power in both internal and total sets. Subsequently, the gene mutations in the groups were investigated, and patients suitable for immunotherapy were selected in combination with the immune score. The prognosis of the immune score-low group was significantly worse than that of the immune score-high group. The patients with BRCA1-associated protein 1 (BAP1) mutation had a poor prognosis. Thus, this study indicated that establishing an immune score model combined with BAP1 mutation can better predict the prognosis of patients, screen suitable ccRCC patients for immunotherapy, and select more appropriate drug combinations.

BACKGROUND:Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs).METHODS:The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry.RESULTS:The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity.CONCLUSIONS:The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.

Metastasis is the major cause of prostate cancer (PCa)-related mortality. Epithelial-mesenchymal transition (EMT) is a vital characteristic feature that empowers cancer cells to adapt and survive at the beginning of metastasis. Therefore, it is essential to identify the regulatory mechanism of EMT in metastatic prostate cancer (mPCa) and to develop a novel therapy to block PCa metastasis. Here, we discovered a novel PCa metastasis oncogene, DEP domain containing 1B (DEPDC1B), which was positively correlated with the metastasis status, high Gleason score, advanced tumor stage, and poor prognosis. Functional assays revealed that DEPDC1B enhanced the migration, invasion, and proliferation of PCa cells in vitro and promoted tumor metastasis and growth in vivo. Mechanistic investigations clarified that DEPDC1B induced EMT and enhanced proliferation by binding to Rac1 and enhancing the Rac1-PAK1 pathway. This DEPDC1B-mediated oncogenic effect was reversed by a Rac1-GTP inhibitor or Rac1 knockdown. In conclusion, we discover that the DEPDC1B-Rac1-PAK1 signaling pathway may serve as a multipotent target for clinical intervention in mPCa.

Immune checkpoint inhibitors (ICIs) treatment is becoming a new hope for cancer treatment. However, most prostate cancer (PCa) patients do not benefit from it. In order to achieve the accuracy of ICIs treatment in PCa and reduce unnecessary costs for patients, we have analyzed the data from TCGA database to find a indicator that can assist the choice of treatment. By analyzing the data of PCa patients with TMB analysis and immune infiltration analysis, we found the expression of immune cells in different immune infiltration groups. Commonly used markers of ICIs, expressed on CD8+ T cell, were highly expressed in the high immune group. Then we used the forimmune cytolytic activity (CYT) to determine its relationship with the target of ICIs treatment. Through the analysis of CYT score and the ligands of immune checkpoints, we found that there was a significant correlation between them. With the increase of CYT score, the expression of CD80/86, PD-L1/L2, TNFSF14, and LGALS9 also increased gradually. Similarly, CD8+ T cells were significantly increased in the CYT high group compared with the CYT low group in PRAD. The present research provides novel insights into the immune microenvironment of PRAD and potential immunotherapies. The proposed CYT score is a clinically promising indicator that can serve as a marker to assist anti-PD-L1 or other ICIs treatment. At the same time, it also provides a basis for the selection of other immune checkpoint drugs.

DNA damage response (DDR) plays an important role in the progression of cancers, including prostate cancer (PCa). Topoisomerase II-binding protein 1 (TopBP1) is an essential promotor of ATR-mediated DDR. Herein, we investigated the association between TopBP1 and PCa and determined its effect on the progression of PCa. The expression and clinical features of TopBP1 were analyzed using large-scale cohort of tissue microarray analyses and The Cancer Genome Atlas database, which indicated that TopBP1 was positively correlated with high Gleason Score, advanced clinical and pathological stages, the metastasis status. Multivariate analysis revealed that the upregulation of TopBP1 was an independent predictor for a worse biochemical recurrence-free survival (BCR-free survival). Furthermore, we discovered that downregulation of TopBP1 significantly suppressed the growth and migration ability of PCa lines by loss-of-function assays in vitro. Further mechanistic investigations clarified that TopBP1 promoted proliferation and migration by activating ATR-Chk1 signaling pathway.

PLC-L2, whose related members of its family facilitate in the differentiation of T cells, is a potential epigenetic marker for PCa. The density of tumor-infiltrating CD8(+) T cells in PCa is associated with a better prognosis. It remains unclear how PLC-L2 affects the TIL and PCa. A human tissue microarray (TMA) and PCa patients from the Cancer Genome Atlas were used to address the correlations between PLC-L2 and the infiltrated immune cells and to evaluate the relationship between PLC-L2 and prognosis of PCa patients. More advanced PCa expressed less PLC-L2 than less advanced PCa, in terms of pathological grade, clinical stage, and the presence of lymph node and distant metastasis. Besides, the expression of PLC-L2 had positive correlations with CD8(+) T cells and antigen-presenting cells such as macrophage and dendritic cells. PLC-L2 expression was also positively correlated with local immune cytolytic ability, TNF-alpha, IFN-gamma, IL-12A, IL-12B, and IL-18. Furthermore, PLC-L2 expression was an independent factor of a favorable prognosis in PCa patients. This study reveals that PLC-L2 might recruit CD8(+) T cells and promote their cytolytic ability in PCa. PLC-L2 accompanied by CD8(+) cytotoxic T cells could suppress the development of PCa and subsequently increase prognosis in PCa patients.