Expression In Prostate Cancer Tissues Research Articles

DSCAM-AS1 promotes the development of prostate cancer

PurposeThe purpose of this study was to investigate the role of lncRNA DSCAM-AS1 in prostate cancer to find new therapeutic targets and promote the research progress of prostate cancer.MethodsRT-qPCR was used to detect DSCAM-AS1 expression in prostate cancer tissues, normal tissues, human normal prostate epithelial cells (RWPE), and four prostate cancer cell lines. The clinical and prognostic role of DSCAM-AS1 was evaluated by the Kaplan–Meier curve and chi-square test. Secondly, a dual luciferase reporter gene assay was used to study the regulatory mechanism between miR-338-3p and DSCAM-AS1. Finally, the roles of DSCAM-AS1 and miR-338-3p in prostate cancer cell proliferation and metastasis were explored by CCK-8 and Transwell assays.ResultsIt was found that DSCAM-AS1 upregulation could serve as a warning of deterioration and poor prognosis in prostate cancer patients, and that knockdown of DSCAM-AS1 expression inhibited the progression of prostate cancer cells. In addition, miR-338-3p, a target of DSCAM-AS1, was found to be down-regulated in prostate cancer cells and miR-338-3p knockdown could reverse the inhibitory effect of DSCAM-AS1 silencing on prostate cancer.ConclusionDSCAM-AS1 is up-regulated in prostate cancer and regulates the progression of prostate cancer cells by targeting miR-338-3p.

Ubiquitin B, Ubiquitin C, and β-Catenin as Promising Diagnostic and Prognostic Tools in Prostate Cancer.

Prostate cancer (PC) is a major global public health concern, imposing a significant burden on men and ranking as the second most prevalent malignancy. This study delves into the intricate world of ubiquitination processes and expression regulation, with a specific focus on understanding the roles of ubiquitin B (UBB), ubiquitin C (UBC), and β-Catenin in PC development. We thoroughly analyze the expression profiles of UBB, UBC, and β-Catenin, investigating their interactions and associations with clinical and histopathological data. These findings offer valuable insights into their potential as robust prognostic markers and their significance for patient survival. Our research uncovers the upregulation of UBB and UBC expression in PC tissues, and an even more pronounced expression in lymph node metastases, highlighting their pivotal roles in PC progression. Moreover, we identify a compelling correlation between high UBB and UBC levels and diminished overall survival in PC patients, emphasizing their clinical relevance. Additionally, we observe a significant reduction in membranous β-Catenin expression in PC tissues. Importantly, abnormal β-Catenin expression is strongly associated with shorter survival in PC patients and serves as a significant, independent prognostic factor for patient outcomes. Kaplan-Meier survival analysis indicates that patients with tumors characterized by simultaneous UBB and aberrant β-Catenin expression exhibit the poorest overall survival. These collective insights underline the clinical importance of evaluating UBB, UBC, and β-Catenin as combined prognostic markers in PC.

Long Chain Non-Coding RNA MSC-AS1 Promote Invasion and Migration of Prostate Cancer Through Regulating microRNA-190a-3p

We investigated the role of the lncRNA MSC-AS1 in prostate cancer (PCa) by analyzing its expression in 56 pairs of PCa tissues and adjacent tissues. We examined the relationship between MSC-AS1 expression, clinicopathological indicators, and patient prognosis. In PCa cell lines, we overexpressed or knocked down MSC-AS1 and assessed its impact on cell function using transwell assays and wound healing tests. We explored the interaction between MSC-AS1 and miR-190a-3p using luciferase reporter assays. Our findings showed significantly higher MSC-AS1 expression in PCa tumor specimens compared to adjacent tissues. High MSC-AS1 expression correlated with increased incidence of lymph node and distant metastasis. Overexpressing MSC-AS1 reduced cell invasiveness and migration, while knocking it down enhanced these abilities. We observed decreased miR-190a-3p expression in PCa tissues, negatively correlating with MSC-AS1 expression. Modulating miR-190a-3p expression counteracted the effects of MSC-AS1 on cell invasiveness and migration. In conclusion, our study highlights the association of MSC-AS1 with metastasis and poor prognosis in PCa patients, suggesting its involvement in the malignant progression of the disease via miR-190a-3p modulation. MSC-AS1 holds potential as a prognostic biomarker for PCa and a therapeutic target for novel treatment strategies. Further research is needed to understand the underlying mechanisms and validate the clinical implications of targeting MSC-AS1 and miR-190a-3p in PCa management.

The kinesin-14 family motor protein KIFC2 promotes prostate cancer progression by regulating p65

The kinesin-14 motor proteins play important roles in tumor development and drug resistance and have been reported as potential biomarkers or therapeutic targets for tumor treatment. However, kinesin family member C2 (KIFC2), one of the kinesin-14 motor family members, remains largely unknown in prostate cancer (PCa) progression. Here, we used the GEO and The Cancer Genome Atlas datasets, Western blotting, and immunohistochemistry analyses to detect KIFC2 expression in PCa tissues. Additionally, a series of invivo and invitro experiments were utilized to demonstrate the roles of KIFC2 in PCa cells. We found that KIFC2 was highly expressed and positively correlated with the clinicopathological characteristics in PCa. Functional experiments indicated that KIFC2 could promote PCa progression. Furthermore, we performed an analysis of the KEGG and GSEA databases, subcellular fractionation, and immunofluorescence to investigate the potential mechanisms of KIFC2 in PCa. We confirmed that KIFC2 could regulate the NF-κB pathway via mediating NF-κB p65 protein expression and nuclear translocation thereby promoting PCa progression and chemotherapeutic resistance. Together, our results suggest that KIFC2 is overexpressed in PCa. By regulating the NF-κB pathway, KIFC2 may play a crucial role in PCa.

[Mechanism of piRNA in bisphenol A-promoted invasion and migration of prostate cancer cells].

Objective: To investigate the regulatory mechanisms of piwi-interacting RNA (piRNA) in bisphenol A (BPA)-induced prostate cancer cell invasion and migration. Methods: The Cancer Genome Atlas (TCGA) data was used to analyze and screen for piRNAs with significantly increased expression in prostate cancer tissues. PC-3 cells were treated with different concentrations of BPA for 12, 24, and 48 h, respectively, and the 20% inhibitory concentration (IC20) was measured using a CCK-8 assay. The expression levels of piRNAs before and after BPA treatment were determined by reverse transcription-quantitative PCR. Target genes regulated by BPA and associated with prostate cancer were screened in the Comparative Toxicogenomics Database (CTD). Dual-luciferase reporter gene assay was performed to verify the relationship between piRNA and target genes, and the expression change of the piRNA target gene was detected by Western blotting. Cell migration and invasion assays were used to determine the effects of piRNA on the malignant phenotype of prostate cancer cells. Results: After treatment of PC-3 cells with 160 μmol/L BPA, the expression of piR-sno48 was most significantly increased (P<0.05). Transfection of piR-sno48 antagomir resulted in decreased expression of endogenous piR-sno48 and a significant increase in the expression of its target gene GSTP1 (P<0.05). However, the expression of GSTP1 did not change significantly in BPA-treated PC-3 cells after transfection with piR-sno48 antagomir (P>0.05). The dual-luciferase reporter gene confirmed that piR-sno48 inhibited the expression of GSTP1 by forming an inversely complementary sequence with the 3'-UTR of GSTP1. The Transwell assay results showed that treatment with BPA significantly increased the invasion and migration ability of prostate cancer cells (P<0.01), whereas piR-sno48 antagonists significantly inhibited the effects above (P<0.01). Conclusion: BPA promotes the invasion and migration of prostate cancer cells by upregulating the expression of piR-sno48 and suppressing the expression of GSTP1. Interfering with the expression of endogenous piR-sno48 may inhibit the malignant phenotype of prostate cancer cells caused by BPA.

Anillin actin-binding protein expression correlates with poor prognosis for prostate cancer patients

ObjectiveOctamer transcription factor 1 (OCT1), a transcription factor that interacts with androgen receptor, is involved in prostate cancer (PCa) progression. The OCT1 target gene, anillin actin-binding protein (ANLN), is highly expressed in castration-resistant PCa tissue; however, it remains unclear whether ANLN expression in hormone-sensitive PCa tissue could be used as a predictive biomarker for poor prognosis of patients. We investigated ANLN expression in PCa tissue obtained via radical prostatectomy. MethodsImmunohistochemical staining for ANLN was performed on 86 PCa specimens, followed by evaluation using immunoreactivity (IR) scores. Prognosis was analyzed by the log-rank test using the Kaplan-Meier method to generate a cancer-specific survival curve. The correlations between ANLN IR and clinical parameters as well as OCT1 IR were analyzed using the Chi-squared test. ResultsThe median IR score was 0 for ANLN. Accordingly, given the low median IR score, an IR score of ≥3 was defined as positive. There were 17 (19.8%) ANLN-positive cases, and these cases had a significantly poorer prognosis. Multivariate analysis revealed that the Gleason score, pathologic T and N stages, and positive ANLN IR were significant predictors of poor prognosis. Notably, patients with both positive ANLN and high OCT1 expression had a significantly decreased overall survival (p=0.01). ConclusionANLN, which is a OCT1 target gene especially in castration-resistant PCa, is expressed in a small number of hormone-sensitive PCa cases. Both positive ANLN expression and a high IR score for OCT1 are significantly correlated with poor prognosis for PCa patients.

Exportin XPO7 acts as an oncogenic factor in prostate cancer via upregulation of TCF3.

As a nuclear transport protein, XPO7 has been observed to show abnormal expression in various types of human cancers. However, the role of XPO7 in PCa remains elusive. Here, in this study, immunohistochemistry and bioinformatics were used to determine the expression pattern and prognostic significance of XPO7. To investigate the functions ofXPO7 in vitro and in vivo, we knocked down XPO7 in PCa cell lines and established xenograft mice models. Then, we used multiple experiments to determine the cell proliferation, migration, invasion, cell cycle and EMT in PCa cells after XPO7 modulation. Mechanistically, we conducted RNA-seq and identified the regulating effect of XPO7 on cell cycle-related and PI3K-AKT pathways. Furthermore, we assessed the regulating correlation between XPO7 and TCF3 and verified by a series of rescue experiments. We found a higher XPO7 expression in prostate cancer tissues and predicted a poorer prognosis of prostate cancer. Then, we further revealed that the ectopic expression of XPO7 in PCa cells facilitated cells proliferation, migration, cell cycle progression and EMT in vitro and promoted tumor growth in vivo. Mechanistically, we conducted RNA-seq and identified the regulating effect of XPO7 on cell cycle-related and PI3K-AKT pathways. Furthermore, a significantly positive correlation was discovered between the expression of XPO7 and TCF3. In addition, XPO7 may regulate PCa through mediating TCF3 expression. TCF3 depletion could alleviate the influence of XPO7 overexpression on malignant phenotypesof PCa cells. These findings indicate that XPO7 promotes PCa initiation and progression and that targeting XPO7 might be therapeutically beneficial to patients with PCa.

Circular RNA LPAR3 targets JPT1 via microRNA-513b-5p to facilitate glycolytic activation but repress prostate cancer radiosensitivity

A great many circular RNAs (circRNAs) are considered key modulators of human malignancies. However, the function of circRNA lysophosphatidic acid receptor 3 (LPAR3) in the radioresistance of prostate cancer (PCa) cells is still uncertain. circLPAR3, microRNA (miR)-329-3p, and JPT1 expression in PCa tissues and cells were detected by real-time quantitative PCR or western blot. Cell proliferation was detected by CCK-8 (cell proliferation assay) and colony formation assay, apoptosis was by flow cytometry, and migration and invasion ability were by Transwell assay. Cell glycolysis was analyzed by glucose uptake, lactate production, and ATP metabolism. Under different doses of radiation, the radiosensitivity of PCa cells was detected by colony formation assay. The relationship between circLPAR3, miR-513b-5p, and JPT1 was confirmed by dual luciferase reporter gene detection and RIP assay. The data presented that circLPAR3 and JPT1 expression was elevated in PCa, while miR-513b-5p expression was reduced. Repression of circLPAR3 depressed cell advancement, and restrained glycolysis, but enhanced the radiosensitivity of PCa cells. CircLPAR3's target miRNA was miR-513b-5p which targeted JPT1. Elevated JPT1 reversed the repressive effects of circLPAR3 knockdown or miR-513b-5p overexpression on PCa advancement, glycolysis, and radiosensitivity. In summary, the knockdown of circLPAR3 reduces glycolysis, but promotes PCa radiosensitivity via the miR-513b-5p/JPT1 axis, discovering a novel mechanism in PCa progression.

The Circular RNA Circ_0085494 Regulates Prostate Cancer Progression Through NRBP1/miR-497-5p Axis.

Aberrant expression of circular RNA (circRNA) is closely linked to the progression of various human cancers, including prostate cancer (PCa). In this research, we aimed to investigate the biological role of and mechanisms of circ_0085494 in PCa. The quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect circ_0085494, miR-497-5p, and nuclear receptor binding protein 1 (NRBP1) mRNA expression in PCa tissues and cell lines. Subsequently, colony formation, cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays were performed to evaluate PCa cell proliferation, migration, and invasion. Western blot assay was applied for assessing the protein levels. Dual-luciferase reporter and RNA pull-down assays were implemented for verifying the association between miR-497-5p and circ_0085494 or NRBP1. The role of circ_0085494 in vivo was measured by establishing a mice xenograft model. Circ_0085494 was highly expressed in PCa tissues and cells, and its absence suppressed PCa cell proliferation, migration, and invasion. Circ_0085494 impacts NRBP1 content by adsorbing miR-497-5p. Meanwhile, the repression of circ_0085494 absence on tumor growth in vivo was validated. Our finding revealed that circ_0085494 downregulation might repress PCa tumor progression through in part regulating the miR-497-5p/NRBP1 pathway.

Quantitative In Vivo Imaging of the Androgen Receptor Axis Reveals Degree of Prostate Cancer Radiotherapy Response.

hK2 expression in prostate cancer tissue is a proxy of EBRT-induced AR activity that can noninvasively be detected using [89Zr]11B6-PET; further clinical evaluation of hK2-PET for monitoring response and development of resistance to EBRT in real time is warranted.

Expression of nectin-4 in prostate cancer.

Nectin-4 is a transmembrane protein belonging to the nectin family of immunoglobulin-like molecules which is found in the placenta and trachea under physiological conditions and its expression has been shown in many cancer types. We aimed to investigate for the 1st time nectin-4 expression in human prostate cancer tissues. We retrospectively analyzed the prostate pathology specimens of 82 patients who underwent initial transrectal ultrasound-guided prostate biopsy or transurethral prostate resection and were found to have atypical small acinar proliferation (ASAP) and incidentally prostate cancer. Tissue samples with prostatic cancer were used as a control for alpha-methylacyl-CoA racemase (AMACR), and benign prostatic glands in the same tissue provided the negative control. The intensity and extent of nectin-4 expression were determined microscopically using the histochemical scoring system which was defined as the product of the staining intensity (score: 0-3) and percentage of stained cells (0-100) at a given intensity. We conducted immunohistochemical analysis of nectin-4 and AMACR expression in all 82 samples. While AMACR expression was positive in prostate cancer tissues with a GS of <7 (n=24, 100%), 7 (n=18, 100%), and ≥8 (n=15, 100%), it was negative in all ASAP samples (n=25, 100%) (p<0.001). Nectin-4 expression was not detected in any of the GS <7, GS 7, or GS ≥8 samples but was found in benign prostatic gland tissues and all 25 (100%) ASAP samples (p<0.001). We found that nectin-4 was not expressed in prostate cancer tissues but was expressed in ASAP-and benign prostate gland containing tissues. We believe that prospective studies with more patients and samples including radical prostatectomy materials will reveal the relationship between nectin-4 and prostate cancer more clearly.

Hypermethylation in the promoter region inhibits AJAP1 expression and activates the JAK/STAT pathway to promote prostate cancer cell migration and stem cell sphere formation

AJAP1 is down-regulated in multiple cancer types and plays a suppressive role in cancer progression. However, its molecular regulatory mechanism in prostate cancer has not been reported. Bioinformatics methods were employed to analyze AJAP1 expression in prostate cancer tissues and its association with TNM staging. MSP and qRT-PCR were used to quantify promoter methylation and AJAP1 expression after 5-aza-20-deoxycytidine (5-AzaC) treatment. Scratch healing assay and Transwell method were adopted to analyze the effects of aberrant AJAP1 expression, 5-AzaC and AG490 on cell migration and invasion. The levels of AJAP1 protein, EMT-related and JAK/STAT pathway-related proteins were determined by Western blot. The effects of AJAP1 aberrant expression and AG490 treatment on the sphere forming ability of prostate cancer cells were analyzed by sphere formation assay. This study confirmed the significant down-regulation of AJAP1 expression in prostate cancer tissues and cells, and its negative correlation with TNM staging. 5-AzaC treatment led to a significant reduction of AJAP1 methylation level and a significant upregulation of AJAP1 expression, indicating that the methylation level of AJAP1 promoter may affect the expression of AJAP1. Cell function experiments found that overexpression or decreased methylation of AJAP1 inhibited epithelial mesenchymal transition (EMT), migration, and invasion, while silencing or increased methylation of AJAP1 had the opposite functions. JAK2/STAT3 pathway inhibiting assay found that inhibition of JAK2/STAT3 pathway significantly reduced EMT, cell migration, and stem cell sphere formation in prostate cancer. Therefore, investigating the influence of aberrant AJAP1 expression on functions of prostate cancer cells is conducive to our in-depth understanding of the mechanism of prostate cancer genesis and development.

H19 in Serum Extracellular Vesicles Reflects Resistance to AR Axis-targeted Therapy Among CRPC Patients.

We aimed to evaluate the changes of androgen receptor (AR) signaling-related long non-coding RNAs (lncRNAs) in serum extracellular vesicles (EVs) from prostate cancer (PC) patients, in order to identify novel biomarkers for AR axis-targeted therapy (ARAT)-resistance among castration-resistant PC (CRPC) patients. EVs were isolated from 2 patients before and after acquiring ARAT-resistance. RNA profiling of EVs was performed by RNA-sequencing. The expression levels of selected lncRNAs in EVs were analyzed by digital droplet PCR (ddPCR) in 58 localized and 14 metastatic PC patients at diagnosis, 7 ARAT-naïve and 6 ARAT-resistant CRPC patients. LncRNA H19 expression in PC tissue was examined using published data. In order to analyze the role of H19, the prognosis was analyzed in PC patients and proteomic analysis was performed in 22Rv1 PC cells. RNA-sequencing revealed that AR-regulated RNAs were most enriched in EVs after acquiring ARAT-resistance. Among them, up-regulation of AR signaling-related lncRNAs (PCAT1, H19, HOXA-11AS, ZEB1-AS1, ARLNC1, PART1, CTBP1-AS and PCA3) was confirmed by ddPCR. H19 contained in EVs (EV-H19) was significantly increased among ARAT-resistant patients compared to ARAT-naïve CRPC or metastatic PC patients. In PC tissue, H19 was negatively correlated with AR protein and AR-activity score and up-regulated in neuroendocrine CRPC tissue with low AR expression. Furthermore, EV-H19 expression was significantly associated with worse outcome to androgen-deprivation therapy. Proteomic analysis demonstrated that H19 knockdown enhanced PC-related protein expression. EV-H19 may negatively correlate with AR-signaling activity and could be a marker to diagnose ARAT-resistance among CRPC patients.

Exosome-derived circTFDP2 promotes prostate cancer progression by preventing PARP1 from caspase-3-dependent cleavage.

Circular RNAs (circRNAs) have been reported to play a significant role in tumorigenesis. However, the detailed function of circRNA in prostate cancer (PCa) is still largely unknown. We quantified circTFDP2 expression in PCa tissues and adjacent normal tissues using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Colony formation, Cell Counting Kit-8 (CCK-8), flow cytometry, transwell, and in vivo progression and metastasis assays were applied to reveal the proliferation and metastatic abilities of circTFDP2 in PCa cells. Mass spectrometry, RNA pulldown, RNA-immunoprecipitation (RIP), western blotting and immunofluorescence were used for the mechanistic studies. qRT-PCR and RIP assays were used to explore the regulatory role of eIF4A3 in the biogenesis of circTFDP2. Finally, functional assays showed the effect of circTFDP2-containing exosomes on PCa cell progression. circTFDP2 was upregulated in PCa tissues compared with adjacent normal tissues. Furthermore, high circTFDP2 expression was positively correlated with the Gleason score. Functionally, circTFDP2 promoted PCa cell proliferation and metastasis both in vivo and in vitro. Mechanistically, circTFDP2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) protein in its DNA-binding domain to prevent it from active caspase-3-dependent cleavage, and finally relieved PCa cells from DNA damage. In addition, RNA-binding protein eIF4A3 can interact with the flanking region of circTFDP2 and promote the biogenesis of circTFDP2. Moreover, exosome-derived circTFDP2 promoted PCa cell progression. In general, our study demonstrated that circTFDP2 promoted PCa cell progression through the PARP1/DNA damage axis, which may be a promising therapeutic target for PCa.

Autophagy inhibition and reactive oxygen species elimination by acetyl-CoA acetyltransferase 1 through fused in sarcoma protein to promote prostate cancer

BackgroundProstate cancer is a major health issue affecting the male population worldwide, and its etiology remains relatively unknown. As presented on the Gene Expression Profiling Interactive Analysis database, acetyl-CoA acetyltransferase 1 (ACAT1) acts as a prostate cancer-promoting factor. ACAT1 expression in prostate cancer tissues is considerably higher than that in normal tissues, leading to a poor prognosis in patients with prostate cancer. Here, we aimed to study the role of the ACAT1-fused in sarcoma (FUS) complex in prostate cancer and identify new targets for the diagnosis and treatment of the disease.MethodsWe conducted immunohistochemical analysis of 57 clinical samples and in vitro and in vivo experiments using a mouse model and plasmid constructs to determine the expression of ACAT1 in prostate cancer.ResultsThe relationship between the expression of ACAT1 and the Gleason score was significant. The expression of ACAT1 was higher in tissues with a Gleason score of > 7 than in tissues with a Gleason score of ≤7 (P = 0.0011). In addition, we revealed that ACAT1 can interact with the FUS protein.ConclusionsIn prostate cancer, ACAT1 promotes the expression of P62 and Nrf2 through FUS and affects reactive oxygen species scavenging. These effects are due to the inhibition of autophagy by ACAT1. That is, ACAT1 promotes prostate cancer by inhibiting autophagy and eliminating active oxygen species. The expression of ACAT1 is related to prostate cancer. Studying the underlying mechanism may provide a new perspective on the treatment of prostate cancer.

HSPB8 facilitates prostate cancer progression via activating the JAK/STAT3 signaling pathway.

Prostate cancer (PC) is a clinically and biologically heterogeneous disease that lacks effective treatment. Heat shock protein B8 (HSPB8) is an important factor in the progression of various types of cancer. However, the clinical significance and biological role of HSPB8 in PC are still unclear. In this study, we determined HSPB8 expression in PC tissues by immunohistochemical staining and explored the in vitro functions of HSPB8 using HSPB8 knockdown DU145 and LNcap PC cell lines. The in vivo effect of HSPB8 was explored by a subcutaneous xenograft mice model. The human phospho-kinase array and signal transducer and activator of transcription (STAT) 3 activator were utilized to explore the potential mechanism of HSPB8-induced PC progression. As a result, we found that HSPB8 was abundantly expressed in PC tissues and cell lines. HSPB8 knockdown inhibited cell proliferation and migration, promoted apoptosis and cycle repression, as well as weakened tumorigenesis ability. Mechanistically, we demonstrated that HSPB8 facilitates the malignant phenotypes of PC by activating the Janus kinase/STAT3 signaling pathway. These results proposed that HSPB8 seems to be an attractive therapeutic target for PC patients.

HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer

Prostate cancer (PCa) is one of the most prevalent malignancies in adult males. However, PCa is resistant to multi-kinase inhibitors-based anti-angiogenic therapies, and the mechanism and effective targeting thereof remains unclear. In this study, single-cell and bulk-transcriptomic datasets analysis revealed that KIAA1199, a hyaluronic acid (HA) binding protein, was involved in glycolysis, hypoxia and angiogenesis pathways. Moreover, boosted KIAA1199 expression in PCa tissues was positively correlated with tumor stage, hypoxia-inducible factor (HIF)-1α overexpression, as well as angiogenesis markers. Tube formation, Western blot, enzyme-linked immunosorbent assay, and in vivo tumorigenesis results demonstrated that KIAA1199 silencing significantly inhibited angiogenesis and vasculogenic mimicry (VM), both in vitro and in vivo, by increasing semaphoring 3A (sema3A) expression while decreasing expressions of VEGFA, VE-cadherin, phosphorylated EphA2, and depolymerized HA levels. KIAA1199 overexpression was also found to promote angiogenesis and VM via increasing secretory VEGFA, however, this activity could be reversed by the HA biosynthesis inhibitor 4-methylumbelliferone (4MU). Furthermore, dual-luciferase and ChIP-PCR revealed that HIF1α is the transcriptional enhancer of KIAA1199, while lactate imported to PCa cells by monocarboxylate transporter 1 (MCT1) stabilizes HIF1α under normoxia via HIF1α lactylation. Our findings may provide a better understanding of angiogenesis and a promising therapeutic target of PCa.

Tissue expression of the antiapoptotic protein survinin as a potential biomarker of prostate cancer

Background. Excessive expression of survivin is associated with inhibition of cell death, activated by extrinsic or intrinsic apoptotic pathways. The survininin overexpression has been shown in various malignancies, including lung cancer, pancreatic and breast cancer, colon cancer, oral squamous cell carcinoma and high grade non-Hodgkin lymphomas.Aim. To investigate the level of survivin expression in prostate cancer tissues, and evaluate it as a diagnostic marker of prostate cancer.Materials and methods. The level of survivin expression and its subcellular localization were assessed immunohistochemically in patients with prostate cancer (n = 64) and benign prostatic hyperplasia (n = 33). Tissue samples obtained at transrectal biopsy were used for analysis. Prostate cancer samples obtained after cystprostatectomy in patients with normal prostate specific antigen level and normal ultrasound findings (n = 36) were considered control tissue (norm).Results. In prostate cancer group 3+ samples with a high level of survivin expression were present in 48.4 % of cases. In benign prostatic hyperplasia group the majority of samples were assessed as 2+, while 9.1 % of samples were negatively stained. 100 % of normal epithelium samples were negative. In patients with Gleason score &lt;7 a survivin expression level was less than 3+ in 62.5 % of cases, and in patients with Gleason score &gt;7 a highly positive reaction was detected in 68.8 % of cases. A high level of survivin expression was found in the large proportion of tissue samples at prostate specific antigen levels &gt;10 ng/ml. Almost 50 % of highly positive cells were detected at a prostate health index (PHI) value of ≥60. The largest percentage of negative staining for surviving was common with PHI value &lt;25. The degrees of staining for survining 1+ and 2+ prevailed in patients with prostate health index density (DPHI) &lt;0.8, while a high level of prostate cells staining 3+ was observed at &gt;0.8. As a Gleason score increase we observe the change of staining type for nucleocytoplasmic, and the largest number of samples has a staining degree of 2+ at a score GG4–5 (≥4 + 4). The type and frequency of prostate tissue samples staining were not differ depending on the initial prostate specific antigen level.Conclusion. Immunohistochemical assessment of the survivin level, including its subcellular localization, could be considered as tumor-associated and a potential biomarker for differential diagnosis and prediction of prostate cancer course.

MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels.

CircSCAF8 promotes growth and metastasis of prostate cancer through the circSCAF8-miR-140-3p/miR-335-LIF pathway

Circular RNAs (circRNAs) have been increasingly linked to cancer progression. However, the detailed biological functions of circRNAs in prostate cancer (PCa) remain unclear. Using high-throughput circRNA sequencing, we previously identified 18 urine extracellular vesicle circRNAs that were increased in patients with PCa compared with those with benign prostatic hyperplasia. Spearman correlation analysis of the expression levels of the 18 circRNAs between the tumor tissue and matched urine extracellular vesicles in 30 PCa patients showed that circSCAF8 had the highest R2 (R2 = 0.635, P < 0.001). The Cox proportional hazards regression model was used to estimate the effect of circSCAF8 on progression-free survival. The in vitro and in vivo functional experiments were implemented to investigate the effects of circSCAF8 on the phenotype of PCa. We found that the knockdown of circSCAF8 in PCa cells suppressed the proliferation, migration, and invasion ability, while overexpression of circSCAF8 had the opposite effects. Similar results were observed in vivo. In a cohort of 85 patients who had undergone radical prostatectomy, circSCAF8 expression in PCa tissues was a powerful predictor of progression-free survival (HR = 2.14, P = 0.022). Mechanistically, circSCAF8 can function by binding to both miR-140-3p and miR-335 to regulate LIF expression and activate the LIF-STAT3 pathway that leads to the growth and metastasis of PCa. Collectively, our findings demonstrate that circSCAF8 contributes to PCa progression through the circSCAF8-miR-140-3p/miR-335-LIF pathway.