Characterization of the immune related lncRNAs in bladder cancer to aid immunotherapy.

Bladder cancer (BLCA) is the 10th most common form of cancer worldwide. Currently, the response rate of BLCA patients to novel immunotherapy and immune checkpoint inhibitor (ICI) treatment is around 30% or less. Therefore, there is an urgent clinical demand to understand the regulation of immune function in BLCA patients. LncRNAs are known to play fundamental roles in the regulation of the immune system in the tumor microenvironment. In this report, we performed a comprehensive analysis to identify immune-related lncRNAs (IRLs) in BLCA patients using The Cancer Genome Atlas (TCGA) databases. BLCA patients were divided into five TME subtypes. Subtype HMIE was strongly related to survival and high anti-tumor activity of patients. Through a four-step analysis, we identified 34 IRLs as subtype HMIE related lncRNAs (HMIE-lncs).The correlation analysis with immune cell infiltration and target gene pathway enrichment showed that 34 HMIE-lncs were correlated with immune cell activation and tumor cell killing. Among them, 24 lncRNAs were related to good prognosis. We constructed a risk model to predict BLCA. Cross tumor validation was performed, and the results showed that the 34 HMIE-lncs identified in the BLCA patients in this study were highly expressed in the immune-favorable TME subtype (IE) in most of the other cancer types.

HN1L promotes stem cell-like properties by regulating TGF-ß signaling pathway through targeting FOXP2 in prostate cancer.

Dysregulated hematological and neurological expressed 1-like (HN1L) has been implicated in carcinogenesis of difference cancers, including hepatocellular carcinoma and breast cancer. However, the role of HN1L in the progression of prostate cancer (PCA) remains unknown. Therefore, we aimed to investigate the role of HN1L in stemness and progression of PCA. The expression of HN1L in PCA tissues and cells was determined by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blot analysis, and/or immunohistochemistry (IHC). CD133+ cells were sorted from PCA cells using magnetic fluorescence cell sorting technology and were considered as cancer stem cells (CSCs). Sphere formation assays, transwell assays, and animal experiments were conducted to assess cell stemness, migration, invasion, and in vivo tumorigenesis, respectively. The results showed that HN1L expression was higher in PCA tissues and cells as compared with normal tissues and cells, as well as in CD133+ cells as compared with CD133- cells. HN1L knockdown significantly decreased the expression levels of CSC markers including OCT4 (POU class 5 homeobox 1), CD44, and SRY-box transcription factor 2, inhibited cell migration, invasion, and tumorigenesis and decreased the number of tumor spheroids and CD133+ cell population. Furthermore, we found that HN1L could bind to forkhead box P2 (FOXP2) and positively regulated transforming growth factor-ß (TGF-ß) expression via upregulation of FOXP2. In addition, the overexpression of TGF-ß in HN1L-knockdown PCA cells increased the number of tumor spheroids and CD133+ cell population, as well as enhanced cell migration and invasion. Collectively, this study demonstrates that HN1L promotes stem cell-like properties and cancer progression by targeting FOXP2 through TGF-ß signaling pathway in PCA.

Reduced DAPK1 Expression Promotes Stem Cell-Like Characteristics of Prostate Cancer Cells by Activating ZEB1 via Hippo/YAP Signaling Pathway.

Prostate cancer (PCa) is a malignant tumor that originates in the male genitourinary system. Downregulation of death-associated protein kinase 1 (DAPK1) is closely related to PCa. Little is known about the functional role of DAPK1 in regulating cancer stem cell (CSC)-like characteristics of PCa cells, and we have conducted research on this topic. Compared with tumor-adjacent normal tissues, DAPK1 was severely downregulated in tumor tissues of PCa patients. DAPK1 expression was also reduced in PCa cell lines with respect to that in normal prostate cells. Moreover, we sorted PCa-CSCs (PCa-CD133+ cells) from PCa cells. PCa-CD133+ cells also exhibited a reduced DAPK1 level and elevated levels of stem cell markers (CD44, OCT4, and SOX2). DAPK1 knockdown promoted sphere formation and enhanced the proportions of PCa-CD133+/PCa-CD133- cells. Inhibition of DAPK1 also accelerated migration and invasion of PCa-CD133+ cells. In addition, DAPK1 interacted with zinc finger E-box-binding homeobox-1 (ZEB1) and repressed ZEB1 expression in PCa-CD133+ cells. DAPK1 suppressed Hippo/YAP signaling pathway by interacting with ZEB1. Finally, we generated a tumor xenograft model to verify the effect of PCa-CD133+ cells following DAPK1 overexpression on tumor growth of PCa. DAPK1 overexpression inhibited tumor growth of PCa and repressed the expression of ZEB1, YAP, and TAZ in the tumor tissues of PCa mice. In conclusion, reduced DAPK1 expression promoted stem cell-like characteristics of PCa cells through activating ZEB1 via Hippo/YAP signaling pathway. Taken together, this work sheds lights on the potential of DAPK1 as a target for PCa therapeutics from bench to clinic.

ß-elemene induced anticancer effect in bladder cancer through upregulation of PTEN and suppression of AKT phosphorylation.

Human bladder cancer is one of the most aggressive tumours known and has shown resistance to traditional chemotherapy, which depends heavily on DNA-damaging drugs. ß-elemene is one of the least cytotoxic antitumor agents that are extracted from Curcuma aromatica salisb and it exhibits antitumor effects in many carcinomas. ß-elemene has attracted the attention of clinicians and scientists worldwide due to its few side effects and limited effect on the bone marrow. However, the antitumor mechanism of ß-elemene remains largely unstudied. In the present study, the expression of the AKT serine/threonine kinase (AKT) signaling pathway in bladder cancer and normal bladder tissue was investigated, and the influence of ß-elemene on bladder cancer cells and the mechanisms involved were assessed. The results showed that phosphatase and tensin homolog deleted on chromosome ten (PTEN) was downregulated and phosphorylated-AKT (pAKT) was overexpressed in human bladder cancer. ß-elemene significantly suppressed the viability of bladder cancer cells, while leaving normal bladder cells unaffected. In addition, there was an increased number of apoptotic bladder cancer cells following ß-elemene treatment, and a significant reduction in cell invasion and migration. Subsequent western blot analyses revealed that bladder cancer cells treated with ß-elemene had increased PTEN expression and decreased expression of pAKT. Taken together, these results suggest that ß-elemene has an antitumor effect in bladder cancer cells through the upregulation of PTEN and suppression of AKT phosphorylation.

[Predictive factors for clinically significant elevation of post-prostatectomy Gleason score in patients with biopsy Gleason score ≤7].

OBJECTIVE: To investigate the prognostic factors for clinically significant increase in post-prostatectomy Gleason score (pGS) in patients with biopsy Gleason score (bGS) ≤7. METHODS: This retrospective study included 170 cases of prostate cancer treated by radical prostatectomy in our hospital from January 2010 to December 2017. We analyzed the clinical and pathological data on the patients, including the age, preoperative serum tPSA, fPSA, fPSA / tPSA, prostate volume, PSA density (PSAD), and positive puncture rate of the patients with clinically significant elevation of pGS, as well as the possible factors for clinically significant pGS increase in patients with bGS = 7 and those with bGS ≤ 6. RESULTS: The pGS was found consistent with the bGS in 95 (55.9%) of the 170 patients, decreased in 11 (6.5%) and increased in 64 (37.6%). Among those with elevated pGS, 55 (32.4%) were shown with and the other 9 (5.3%) without clinical significance. Clinically significant escalation of pGS was markedly correlated with the positive puncture rate in the patients with bGS = 7 (P = 0.021) and with the age (P = 0.018) and PSAD (P = 0.033) of those with bGS ≤ 6. ROC curve analysis further showed the positive puncture rate > 0.528 in the patients with bGS = 7 and a higher risk of clinically significant pGS increase in those aged > 64.5 years with bGS ≤ 6 and PSAD > 0.267 µg/(L·g). CONCLUSIONS: Clinically significant elevation of pGS is correlated with the rate of positive punctures in prostate cancer patients with bGS = 7 and with age and PSAD in those with bGS ≤ 6.

Breviscapine (BVP) inhibits prostate cancer progression through damaging DNA by minichromosome maintenance protein-7 (MCM-7) modulation.

Naturally occurring compounds are reported as effective candidates for prevention and treatment of various cancers. Breviscapine (BVP) is a mixture of flavonoid glycosides, derived from the Chinese herbs. Previous researches have indicated that BVP has comprehensive pharmacological functions. However, little is known about whether BVP has preventive effects on human prostate cancer. Here, we attempted to explore if BVP inhibits human prostate cancer in vitro and in vivo in a comprehensive manner. We found that BVP triggered cytotoxicity in prostate cancer cell lines dose-dependently. BVP-induced DNA damage caused the cell cycle arrest and apoptosis and further induced cell death. High expression of MCM-7 was reduced in BVP-treated cancer cells and tumor tissues, and also the DNA damage response marker of γH2AX is down-regulated by BVP, associated with MCM-7 expression through regulating retinoblastoma protein (Rb) and checkpoint control proteins expression. Additionally, BVP induced apoptotic response in prostate cancer cells and tumors via activating Caspase-3 and PARP. In vivo studies indicated that BVP impeded tumor growth in xenograft animal models. In conclusion, our data indicates that breviscapine (BVP) can be further explored for its potential, which might be used in human prostate cancer therapeutics.

Association of microRNA-21 expression with clinicopathological characteristics and the risk of progression in advanced prostate cancer patients receiving androgen deprivation therapy.

BACKGROUND: Despite androgen deprivation therapy (ADT) remains the mainstay therapy for advanced prostate cancer (PCa), the patients have widely variable durations of response to ADT. Unfortunately, there is limited knowledge of pre-treatment prognostic factors for response to ADT. Recently, microRNA-21 (miR-21) has been reported to play an important role in development of castration resistance of CaP. However, little is known about the expression of miR-21 in advanced PCa biopsy tissues, and data on its potential predictive value in advanced PCa are completely lacking. METHODS: In this study, paraffin-embedded prostate carcinoma tissues obtained by needle biopsy from 85 advanced PCa patients were evaluated for the expression levels of miR-21 by quantitative real-time PCR (qRT-PCR). In situ hybridization (ISH) analysis was performed to further confirm the qRT-PCR results. Kaplan-Meier analysis and Cox proportional hazards regression models were performed to investigate the correlation between miR-21 expression and time to progression of advanced PCa patients. RESULTS: Compared with adjacent non-cancerous prostate tissues, the expression level of miR-21 was significantly increased in PCa tissues (PCa vs. non-cancerous prostate: 1.3273 ± 0.3207 vs. 0.9970 ± 0.2054, P < 0.001). By and large, in ISH analysis miR-21 was expressed at a higher level in tumor areas than in adjacent non-cancerous areas. Additionally, PCa patients with higher expression of miR-21 were significantly more likely to be of high Gleason score and high clinical stage (P < 0.05). There was no significant association between miR-21 expression and the initial prostate-specific antigen (PSA) level or age at diagnosis. Moreover, Kaplan-Meier survival analysis found that PCa patients with high miR-21 expression have shorter progression-free survival than those with low miR-21 expression. Furthermore, Multivariate Cox analysis revealed both miR-21 expression status (P = 0.040) and clinical stage (P = 0.042) were all independent predictive factor for progression-free survival for advanced PCa. CONCLUSION: These findings suggest for the first time that the up-regulation of miR-21 may serve as an independent predictor of progress-free survival in patients with advanced PCa. Prostate 76:986-993, 2016. © 2016 Wiley Periodicals, Inc.

[Adenovirus-mediated combined gene therapy of interleukin-18 and interleukin-12 for prostate cancer: an experimental study].

OBJECTIVE: To explore the therapeutic regimens of metastatic prostate cancer so as to provide the experimental rationales for its gene therapy. METHODS: The adenoviral vectors expressing cytokines interleukin-18 (IL-18) and interleukin-12 (IL-12) were used to induce tumor regression in a C57BL/6 murine model of prostate cancer (n = 110). RESULTS: Adenoviral vectors could express IL-18 and IL-12 effectively. The rates of tumorigenesis were 10/10, 10/10, 4/10, 5/10 and 2/10, the durations of tumor growth (12.3 ± 1.5), (12.8 ± 1.0), (15.4 ± 1.3), (14.8 ± 0.8), (24.5 ± 2.2) days and the diameters of tumor nodule after inoculation 30 days (37.0 ± 3.0), (35.0 ± 4.6), (25.0 ± 2.0), (27.0 ± 4.1) and (9.5 ± 3.2) mm respectively in inoculation wild-type, AdLacZ, AdmIL-18, AdhIL-12, AdmIL-18 and AdhIL-12 of RM-1 cell. Compared to the other four groups, AdmIL-18 and AdhIL-12 developed smaller and delayed tumors (P < 0.01). Intratumoral injection of Adm IL-18 and AdhIL-12 could not only regress the established tumors, but also reduce the number of distal lung metastases (P < 0.01). CONCLUSION: Adenovirus-mediated delivery of IL-18 and IL-12 locally by intratumoral injection is highly effective in inducing specific antitumor immune responses.

Two novel hydroperoxylated products of 20(S)-protopanaxadiol produced by Mucor racemosus and their cytotoxic activities against human prostate cancer cells.

Microbial transformation of 20(S)-protopanaxadiol (1) by Mucor racemosus AS 3.205 yielded two novel hydroperoxylated metabolites and three known hydroxylated metabolites. The structures of the metabolites were identified as 26-hydroxyl-20(S)-protopanaxadiol (2), 23,24-en-25-hydroxyl-20(S)-protopanaxadiol (3), 25,26-en-24(R)-hydroperoxyl-20(S)-protopanaxadiol (4), 23,24-en-25-hydroperoxyl-20(S)-protopanaxadiol (5), and 25-hydroxyl-20(S)-protopanaxadiol (6). 4 and 5 are new compounds. Metabolites 2, 4, and 5 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.

Microbial transformation of 20(S)-protopanaxadiol by Absidia corymbifera. Cytotoxic activity of the metabolites against human prostate cancer cells.

Biotransformation of 20(S)-protopanaxadiol (1) by the fungus Absidia corymbifera AS 3.3387 yielded five metabolites (2-6). On the basis of spectroscopic data analyses, the metabolites were identified as 26-hydroxyl-20(S)-protopanaxadiol (2), 23, 24-en-25-hydroxyl-20(S)-protopanaxadiol (3), 25-hydroxyl-20(S)-protopanaxadiol (4), 7ß-hydroxyl-20(S)-protopanaxatriol (5), and 7-oxo-20(S)-protopanaxatriol (6), respectively. Among them, 5 and 6 are new compounds. These results indicated that A. corymbifera AS 3.3387 could catalyze the side-chain oxidation-reduction, 7ß hydroxylation, and the specific C-7 dehydrogenation of derivatives of 20(S)-protopanaxadiol. The metabolites 2, 5, and 6 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.