Inhibitory effects of Jasminum grandiflorum L. essential oil on lipopolysaccharide-induced microglia activation-integrated characteristic analysis of volatile compounds, network pharmacology, and BV-2 cell.

Neuroinflammation is considered to have a prominent role in the pathogenesis of Alzheimer's disease (AD). Microglia are the resident macrophages of the central nervous system, and modulating microglia activation is a promising strategy to prevent AD. Essential oil of Jasminum grandiflorum L. flowers is commonly used in folk medicine for the relief of mental pressure and disorders, and analyzing the volatile compound profiles and evaluating the inhibitory effects of J. grandiflorum L. essential oil (JGEO) on the excessive activation of microglia are valuable for its application. This study aims to explore the potential active compounds in JGEO for treating AD by inhibiting microglia activation-integrated network pharmacology, molecular docking, and the microglia model. A headspace solid-phase microextraction combined with the gas chromatography-mass spectrometry procedure was used to analyze the volatile characteristics of the compounds in J. grandiflorum L. flowers at 50°C, 70°C, 90°C, and 100°C for 50 min, respectively. A network pharmacological analysis and molecular docking were used to predict the key compounds, key targets, and binding energies based on the detected compounds in JGEO. In the lipopolysaccharide (LPS)-induced BV-2 cell model, the cells were treated with 100 ng/mL of LPS and JGEO at 7.5, 15.0, and 30 µg/mL, and then, the morphological changes, the production of nitric oxide (NO) and reactive oxygen species, and the expressions of tumor necrosis factor-α, interleukin-1ß, and ionized calcium-binding adapter molecule 1 of BV-2 cells were analyzed. A total of 34 compounds with significantly different volatilities were identified. α-Hexylcinnamaldehyde, nerolidol, hexahydrofarnesyl acetone, dodecanal, and decanal were predicted as the top five key compounds, and SRC, EGFR, VEGFA, HSP90AA1, and ESR1 were the top five key targets. In addition, the binding energies between them were less than -3.9 kcal/mol. BV-2 cells were activated by LPS with morphological changes, and JGEO not only could clearly reverse the changes but also significantly inhibited the production of NO and reactive oxygen species and suppressed the expressions of tumor necrosis factor-α, interleukin-1ß, and ionized calcium-binding adapter molecule 1. The findings indicate that JGEO could inhibit the overactivation of microglia characterized by decreasing the neuroinflammatory and oxidative stress responses through the multi-compound and multi-target action modes, which support the traditional use of JGEO in treating neuroinflammation-related disorders.

Establishment and validation of a predictive model for bone metastasis in prostate cancer patients based on multiple immune inflammatory parameters.

OBJECTIVE: This study aims to establish and validate a predictive model for bone metastasis in prostate cancer patients based on multiple immune inflammatory parameters. METHODS: In this retrospective study, 162 prostate cancer patients who met the inclusion criteria were selected by Urology Surgery, Shaanxi Provincial People's Hospital. Based on the medical record number of patients and the random number table method, 40 patients were randomly included in a validation group, and the rest were in a modeling group. The patients in the modeling group were divided into a metastatic group (n=67) and a non-metastatic group (n=55) according to the whole-body bone imaging results. RESULTS: The predictive model was established based on the results of Logistics regression analysis: Logit (P) = -5.341 + 0.930*total Gleason score + 1.426*total prostate specific antigen + 0.836*neutrophil-lymphocyte ratio + 0.896*platelet lymphocyte ratio + 0.641*lymphocyte/monocyte ratio + 0.750*albumin/globulin ratio. ROC analysis showed that the areas under the curve of the predictive model for bone metastasis in the modeling and validation groups were 0.896 and 0.870, respectively. Hosmer-Lemeshow test showed that P=0.253, indicating a high degree of the fitting. External verification results showed that the C-index for predicting prostate cancer bone metastasis in the predictive model established in this study was 0.760 (95% CI: 0.670-0.851). CONCLUSION: The bone metastasis predictive model based on the multiple immune inflammatory parameters (neutrophil-lymphocyte ratio, platelet lymphocyte ratio, lymphocyte/monocyte ratio and albumin/globulin ratio) in prostate cancer patients can reasonably predict the occurrence of bone metastasis and is well worth clinical application.

Improved Lithium Storage Performance of a TiO2 Anode Material Doped by Co.

TiO2 is a promising anode material for lithium-ion batteries (LIBs) due to its low cost, suitable operating voltage, and excellent structural stability. The inherent poor electron conductivity and low ion diffusion coefficient, however, severely limit its application in lithium storage. Here, Co-doped TiO2 is synthesized by a hydrothermal method as an anode material since Co@TiO2 possesses a large specific surface area and high electronic conductivity. Thanks to the Co dopants, the ion diffusion and electron transport are both greatly improved, which is very beneficial for cycle stability, coulombic efficiency (CE), reversible capacity, and rate performance. As a result, Co@TiO2 shows a high reversible capacity of 227 mAh g-1 at 3 C, excellent rate performance, and cycling stability with a capacity of about 125 mAh g-1 at 10C after 600 cycles (1 C = 170 mA g-1).

Tenascin-C promotes bladder cancer progression and its action depends on syndecan-4 and involves NF-κB signaling activation.

BACKGROUND: Bladder Cancer (BCa) is a severe genitourinary tract disease with an uncertain pathology. Increasing evidence indicates that the tumor microenvironment plays a decisive role with respect to cancer progression, and that this is driven by tumor cell interactions with stromal components. Tenascin-C (TN-C) is an important extracellular matrix (ECM) component, which has been reported to be involved in other types of cancer, such as breast cancer. The expression of TN-C in BCa tissue has been reported to be positively associated with the BCa pathological grade, yet the presence of urine TN-C is considered as an independent risk factor for BCa. However, the role of TN-C in BCa progression is still unknow. Thus, the object of the present investigation is to determine the role of TN-C in BCa progression and the involved mechanism. METHODS: In this study, expression of TN-C in BCa tissue of Chinese local people was determined by IHC. Patients corresponding to tumor specimens were flowed up by telephone call to get their prognostic data and analyzed by using SPSS 19.0 statistic package. In vitro mechanistic investigation was demonstrated by QT-qPCR, Western Blot, Plasmid transfection to establishment of high/low TN-C-expression stable cell line, Boyden Chamber Assay, BrdU incorporation, Wound Healing, laser scanning confocal microscopy (LSCM) and ELISA. RESULTS: TN-C expression in BCa tissue increases with tumor grade and is an independent risk factor for BCa patient. The in vitro investigation suggested that TN-C enhances BCa cell migration, invasion, proliferation and contributes to the elevated expression of EMT-related markers by activating NF-κB signaling, the mechanism of which involving in syndecan-4. CONCLUSIONS: Expression of TN-C in BCa tissues of Chinese local people is increased according to tumor grade and is an independent risk factor. TN-C mediates BCa cell malignant behavior via syndecan-4 and NF-κB signaling. Although the mechanisms through which syndecan-4 is associated with the activation of NF-κB signaling are unclear, the data presented herein provide a foundation for future investigations into the role of TN-C in BCa progression.

N-myristoyltransferase-1 deficiency blocks myristoylation of LAMTOR1 and inhibits bladder cancer progression.

N-myristoyltransferase-1 (NMT1) catalyzes protein posttranslational myristoylation and functions as an oncogene in various cancers, although its roles in bladder cancer remain elusive. Here, we demonstrated that NMT1 was obviously upregulated in bladder cancer and correlated with overall survival and poor prognosis. Elevation of NMT1 promotes cancer progression and inhibits autophagy in vitro and in vivo. Furthermore, we confirm that LAMTOR1 was myristoylated by NMT1 at Gly 2, resulting in increased LAMTOR1 protein stability and lysosomal localization. Importantly, B13, an inhibitor of NMT1 enzymatic activity, exerted its anti-tumor effects against bladder cancer cells in vitro and in vivo. Taken together, these findings uncover a molecular mechanism of NMT1 in modulating bladder cancer progression and indicate that targeting NMT1 may represent a novel clinical intervention in bladder cancer.

MiR-1273 g-3p Promotes Malignant Progression and has Prognostic Implications in Prostate Cancer.

Prostate cancer (PCa) is the most popular cancer of mankind. Our study aimed to provide the expression and the predictive significance of miR-1273 g-3p in PCa. Moreover, the effects on cell biological activities were also investigated. The relative expression of miR-1273 g-3p in PCa tissues and cell lines was validated by quantitative real-time PCR. Kaplan-Meier curve and Cox regression analyses were performed to indicate the prognostic value. The implications of miR-1273 g-3p on cell proliferation, migration, and invasion were validated using the CCK-8 and Transwell assay. Our results provided that the expression of miR-1273 g-3p was increased in PCa tissues and cell lines. The levels of miR-1273 g-3p were associated with Gleason score, TNM stage, clinical stage, and lymph node metastasis. Overexpression of miR-1273 g-3p indicated a promising overall survival rate. Cox regression results indicated miR-1273 g-3p might be an independent marker for PCa patients. Silenced miR-1273 g-3p inhibited PCa cell proliferation, migration, and invasion. In total, miR-1273 g-3p was increased in PCa and identified as a therapeutic target and a prognostic factor for PCa patients. Overexpression of miR-1273 g-3p might be an oncogene via accelerating cell proliferation, migration, and invasion.

Bladder cancer cells interact with vascular endothelial cells triggering EGFR signals to promote tumor progression.

Although important progress has been made in elucidating the role of the tumor microenvironment in the development of bladder cancer, little is currently known regarding the interactions with vascular endothelial cells (ECs) that promote cancer progression. In the present study, it is reported that epidermal growth factor receptor ligands induced by the upregulation of vascular endothelial growth factor (VEGF)­A and VEGF­C via the VEGF receptor (R)2/nuclear factor­κB signaling pathway in ECs, may trigger EGFR signaling in bladder cancer cells and promote bladder cancer progression. Furthermore, the interaction between bladder cancer cells and ECs enhanced EC recruitment though the CXCL1/CXCL5/CXCL8­CXCR2 pathway. Western blotting was used to evaluate the presence of VEGFR, EGFR and nuclear factor­κB, and reverse transcription­quantitative polymerase chain reaction was used to evaluate the expression of VEGFR ligands and EGFR ligands. The present results indicate the mechanism by which the indirect interplay between bladder cancer cells and vascular ECs promotes cancer progression, through the VEGFR2 signaling pathway in vascular ECs and through the EGFR signaling pathway in bladder cancer cells.

Silibinin suppresses bladder cancer cell malignancy and chemoresistance in an NF-κB signal-dependent and signal-independent manner.

Because bladder cancer (BCa) is the 9th most common malignant tumor and 13th leading cause of death due to cancer, therapeutic approaches have attracted a great deal of attention from both clinicians and BCa patients. Although the development of surgery and targeted drugs has brought new challenges for the traditional concept of BCa therapy, various types of chemotherapy remain the final treatment method for many BCa patients. However, chemoresistance inevitably appears, leading to the failure of chemotherapy. Silibinin, a polyphenolic flavonoid component isolated from the fruits or seeds of milk thistle, has been reported to play important roles in inhibiting tumor chemoresistance in breast cancer and head and neck squamous cell carcinomas. Our previous study indicated that silibinin inhibited BCa progression in some mechanisms but with no conclusion of chemoresistance inhibition. Therefore, in the present study, we dissected the role of silibinin in BCa progression and chemoresistance. Our results revealed that in BCa, chemodrug-induced chemoresistance was reversed in the presence of silibinin. Further mechanistic study indicated that silibinin suppressed chemoresistance and BCa malignancy in an NF-κB-dependent and -independent manner. In addition, all of the inhibitory effects were dose­dependent. Thus, our results provide a potential use for silibinin in BCa therapeutics.

[Knock-down of DAB2 interacting protein (DAB2IP) promotes proliferation and inhibits apoptosis of bladder cancer cells].

Objective To study the expression of DAB2 interacting protein (DAB2IP) in human bladder cancer tissues and analyze its relationship with pathological grade and clinical stage, and observe its role in drug resistance of bladder cancer cells. Methods The expression of DAB2IP in primary and recurrent bladder cancers was detected by immunohistochemical staining. RNA interference (RNAi) technique was used to down-regulate the expression of DAB2IP in 5637 and 253J bladder cancer cells. MTT assay and clone formation assay were performed to test the sensitivity of cancer cells to pirarubicin. Flow cytometry was done to detect the apoptosis rate of low-DAB2IP-expressing cells treated with pirarubicin. Results The expression of DAB2IP was negatively correlated with TNM stage, pathological grade and lymph node metastasis of bladder cancer. The expression of DAB2IP in the recurrent bladder cancer was lower than that in the primary bladder cancer. The low expression of DAB2IP in bladder carcinoma cells was related to drug resistance. Knock-down of DAB2IP enhanced the colony formation of bladder cancer cells, reduced the expressions of PARP and caspase-3, increased expressions of Bcl-2 and Mcl-1, reduced the apoptosis of cancer cells and induced chemotherapy tolerance. Conclusion Knock-down of DAB2IP can promote the proliferation and inhibit the apoptosis of bladder cancer cells, and increase the resistance to chemotherapy.

Synthesis of a cell penetrating peptide modified superparamagnetic iron oxide and MRI detection of bladder cancer.

Bladder cancer is the most common malignancy of the urinary tract for which the accurate measurement of minimal residual disease is critical to treatment and determining prognosis. Although cystoscope examination and voided urine cytology remain the current standard of care for detecting residual disease, these approaches are limited by mechanical trauma and lack sensitivity. To develop a new accurate noninvasive method, we developed a novel contrast agent where the surface of superparamagnetic iron oxide (SPIO) nanoparticles is functionalized with a bladder cancer-specific fluorescein isothiocyanate (FITC) labeled cell penetrating peptide (CPP)-polyarginine peptides (R11) for active targeting and imaging. The stable nanoparticles have an average hydrodynamic diameter of 51 nm, surface charge of -21 mV and MRI r2 relaxivity 135 mM-1s-1. In vitro cell studies demonstrated that the R11-conjugated SPIO (SPIO-R11) nanoparticles were taken up by bladder cancer cells (T24) in a dose-dependent manner, which was higher than unconjugated SPIO. TEM showed that SPIO-R11 was mainly concentrated on cell vesicle and lysosome, not in cell nucleus, and no obvious damage was seen on cell ultrastructure. Moreover, uptake of the nanoparticles showed significantly more SPIO-R11 accumulation in bladder cancer cells than in immortalized bladder epithelial cells unlike control SPIO. Further, SPIO-R11 was compatible with immortalized bladder epithelial cells at all tested concentrations up to 200 µg/mL after 72 h incubation. Moreover, SPIO-R11 decreased the magnetic resonance T2 relaxation time by 73% in tumors cells in vitro compared to 12% with SPIO. These results indicate great potential of SPIO-R11 as contrast agent to target bladder cancer for diagnostic and therapeutic applications.

Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling.

Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression.

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer.

Bladder cancer (BCa) is the 9th most common malignant tumor and the 13th leading cause of death due to cancer. The development of surgery and target drugs bring new challenges for the traditional concept for BCa therapy, and chemotherapy is still the final option for many BCa patients, and cisplatin-containing regimen the most effective one. However, the ubiquitous application of cisplatin-containing regimen in BCa results in the cisplatin-resistance, in addition, the cisplatin­resistant BCa manifests enhanced malignant behavior, the mechanism of which is unclear. In the present study, we used BCa cell lines to to clarify this point. BCa cell lines T24/J82 were pretreated with cisplatin >3 months to construct stable cisplatin-resistant cell lines (tagged T24(Cis-R) and J82(Cis-R)), which manifested as enhanced capacity of proliferation and malignant behavior in vivo and in vitro, accompanied by cisplatin, and even doxorubicin resistance. The following mechanism dissection revealed that prolonged treatment time of T24/J82 cells led to elevated expression of HIF-1α, which targeted the increased expression of MDR1 on the one hand, and contributed to BCa cell proliferation, migration/invasion on the other hand. Finally, IHC staining of human BCa tissue supported our conclusion that the expression of HIF-1α and MDR1 was higher in chemoresistant tissue vs. chemosensitive tissue. Our results provided a new view of HIF-1α in chemotherapy.

NF-κB signaling plays irreplaceable roles in cisplatin-induced bladder cancer chemoresistance and tumor progression.

Bladder cancer (BCa) is the most vital urogenital malignant disease worldwide, bringing huge economic and social burden every year. Clinically, BCa is subdivided into superficial type and invasive type according to clinic-pathology, accompanied with different strategy of therapy. Number of reports indicate that 10-30% of superficial BCa will inevitable progress into invasive type, manifesting enhanced malignant behavior compared to original invasive type. Regardless of the original being an original invasive type or invasive type that progressed from superficial type of BCa, chemotherapy (including adjuvant or neo-adjuvant chemotherapy) in line with radiotherapy is the final regimen for BCa patients. Previous reports pointed out the high efficiency of cisplatin-containing chemotherapeutic regimen for BCa patients, leading to wide use of this regimen in BCa therapeutics. However, cisplatin-resistance inevitably appear, resulting in the failure of the BCa chemotherapy, the mechanism of which is still unknown. In the present study, parental BCa cell lines T24/J82 were used to obtain stable-cisplatin-resistance cell lines T24R/J82R, which showed enhanced capacity of malignancy, tumorigenesis and drug resistance, accompanied by elevated expression of EMT markers. The further mechanism investigation suggested that prolonged time of cisplatin-treatment contributed to the activation of the NF-κB signal, resulting in the upregulation of EMT markers, the maintenance of stem cell marker and the elevated expression of ABCB1. Thus, our study provides us a new view of the role of NF-κB signaling in BCa therapeutics.

Inhibiting bladder tumor growth with a cell penetrating R11 peptide derived from the p53 C-terminus.

Urothelial carcinoma of the bladder (UCB) is the most common malignancy of the urinary tract, nearly half of which contains a mutation in TP53 gene. Hence, therapeutic approach by restoring functional p53 protein in cancer cells will be beneficial. Recent studies have demonstrated the inhibition of cancer cell growth by p53 reactivation using a peptide derived from the p53 C-terminus (p53C). However, the outcome of reactivating p53 in controlling bladder cancer development is limited by its efficiency and specificity of peptide delivery, especially in metastatic animal models. Herein, we report that the cell penetrating peptide (polyarginine, R11)-conjugated p53C can exhibit a preferential uptake and growth inhibit of UCB cells expressing either mutant or wild-type TP53 by the activation of p53-dependent pathway. R11-p53C peptide treatment of preclinical orthotopic and metastatic bladder cancer models significantly decreased the tumor burden and increased the lifespan without a significant cytotoxicity. Based on these results, we believe that R11-p53C peptide has therapeutic potential for primary and metastatic bladder cancer, and R11-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to tumor cells in vitro and in vivo.

G9a Inhibition Induces Autophagic Cell Death via AMPK/mTOR Pathway in Bladder Transitional Cell Carcinoma.

G9a has been reported to highly express in bladder transitional cell carcinoma (TCC) and G9a inhibition significantly attenuates cell proliferation, but the underlying mechanism is not fully understood. The present study aimed at examining the potential role of autophagy in the anti-proliferation effect of G9a inhibition on TCC T24 and UMUC-3 cell lines in vitro. We found that both pharmaceutical and genetical G9a inhibition significantly attenuated cell proliferation by MTT assay, Brdu incorporation assay and colony formation assay. G9a inhibition induced autophagy like morphology as determined by transmission electron microscope and LC-3 fluorescence assay. In addition, autophagy flux was induced by G9a inhibition in TCC cells, as determined by p62 turnover assay and LC-3 turnover assay. The autophagy induced positively contributed to the inhibition of cell proliferation because the growth attenuation capacity of G9a inhibition was reversed by autophagy inhibitors 3-MA. Mechanically, AMPK/mTOR pathway was identified to be involved in the regulation of G9a inhibition induced autophagy. Intensively activating mTOR by Rheb overexpression attenuated autophagy and autophagic cell death induced by G9a inhibition. In addition, pre-inhibiting AMPK by Compound C attenuated autophagy together with the anti-proliferation effect induced by G9a inhibition while pre-activating AMPK by AICAR enhanced them. In conclusion, our results indicate that G9a inhibition induces autophagy through activating AMPK/mTOR pathway and the autophagy induced positively contributes to the inhibition of cell proliferation in TCC cells. These findings shed some light on the functional role of G9a in cell metabolism and suggest that G9a might be a therapeutic target in bladder TCC in the future.

CXCL5/CXCR2 axis promotes bladder cancer cell migration and invasion by activating PI3K/AKT-induced upregulation of MMP2/MMP9.

Bladder cancer (BCa) is the most common malignant disease of the urinary tract system, yet the etiology is still poorly understood. Clinically, the majority of BCa patients progress to invasive disease at the final stage, leading to death. Previous investigations have demonstrated that matrix metal-loproteinases (MMPs) play irreplaceable roles in tumor cell extravasation and implantation. In addition, increasing numbers of reports provide evidence that MMPs, especially MMP2 and MMP9 are monitored by various signal transduction pathways targeting tumor metastasis. Seed-and-soil theory has called to attention the importance of the tumor microenvironment in disease progression. To that end, we previously reported the key role of hypoxia in BCa progression. Herein, we report the role of chemokines, specifically CXCL5, is involved in BCa development. Though it has been reported that CXCL5 promotes BCa metastasis and progression, the exact mechanisms are still unknown, necessitating the need for further investigation into the role of CXCL5 in BCa. In this study, IHC staining of BCa tumor sections showed elevated expression of CXCL5 in BCa, which correlated with disease stage. Our mechanistic studies show that CXCL5 contributes to BCa migration and invasion by binding to its receptor, CXCR2, leading to the upregulation of MMP2/MMP9 by activating PI3K/AKT signaling. This study offers vital evidence of how CXCL5 promotes BCa metastasis, and thus may potentially be used as a therapeutic target against BCa.

Autophagy induction by silibinin positively contributes to its anti-metastatic capacity via AMPK/mTOR pathway in renal cell carcinoma.

Silibinin, a dietary cancer chemopreventive flavonoid from the seeds of milk thistle, has been reported to exhibit anti-metastatic effects on renal cell carcinoma (RCC), but the mechanism underlying this phenomenon is not fully understood. The present study aimed at examining the potential role of autophagy in regulating silibinin-induced anti-metastatic effects on RCC cells. Using RCC ACHN and 786-O cells as a model system in vitro, we found that silibinin treatment increased the expression of LC3-II, resulted in the formation of autophagolysosome vacuoles, and caused a punctate fluorescence pattern with the monomeric red fluorescence protein-enhanced green fluorescence protein-LC3 (mRFP-EGFP-LC3) protein, which all are markers for cellular autophagy. Autophagy flux was induced by silibinin in RCC cells, as determined by LC3 turnover assay. Mechanically, the adenosine 5'-monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was identified as involved in regulation of silibinin-induced autophagy. Furthermore, autophagy induction was demonstrated to positively contribute to silibinin-induced anti-metastatic effects on RCC cells in vitro. Activation of autophagy enhanced silibinin-induced inhibition of migration and invasion of RCC cells, while inhibition of autophagy attenuated it. These findings thus provide new information about the potential link between autophagy and metastasis inhibition induced by silibinin, and the induction of autophagy may shed some light into future treatment strategies for metastatic RCC.

[DAB2IP expression in bladder transitional cell carcinoma and its correlation with clinical outcome].

OBJECTIVE: To investigate the expression of DAB2IP in bladder transitional cell carcinoma (BTCC) and its correlation with clinical characteristics and prognosis of BTCC patients. METHODS: Immunohistochemical staining was applied to detect DAB2IP protein level in 79 cases of TCCB tissues and 11 cases of normal bladder tissues, and the relationships of the staining results with pathological grade, stage, lymph node metastasis, gender, age and the 3-year survival rate of the patients were analyzed. RESULTS: The expression of DAB2IP in BTCC tissues was significantly lower than that in normal bladder epithelium, and the expression score and rate of DAB2IP in the high-grade, invasive and metastatic BTCC were significantly lower than those in low-grade, superficial and non-metastatic BTCC (P < 0.05). The 3-year survival rate of the patients with high DAB2IP expression was significantly higher than that of the patients with low DAB2IP expression. CONCLUSION: DAB2IP may be one of the important inhibitory factors during the occurrence and progression of BTCC.

ASC-J9 suppresses renal cell carcinoma progression by targeting an androgen receptor-dependent HIF2α/VEGF signaling pathway.

Males have a higher incidence of renal cell carcinoma (RCC) than females, but the reason for this gender difference is unknown. Addressing this question, we report the discovery of an androgen receptor (AR)-induced HIF2α/VEGF signal that drives RCC progression. AR attenuation or augmentation in RCC cells altered their proliferation, migration, and invasion in multiple models in vitro and in vivo. Mechanistic investigations revealed that AR targeting inhibited RCC cell migration and invasion by modulating HIF2α/VEGF signals at the level of mRNA and protein expression. Interrupting HIF2α/VEGF signals with inhibitors of either HIF2α or VEGF was sufficient to suppress RCC progression. Similarly, the specific AR degradation enhancer ASC-J9 was sufficient to suppress AR-induced HIF2α/VEGF signaling and RCC progression in multiple models in vitro and in vivo. Taken together, our results revealed a novel role for AR in RCC initiation and progression with implications for novel therapeutic strategies.

Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo.

Although neo-adjuvant radiotherapy is generally successful in treatment of advanced prostate cancer, radioresistance is still a major therapeutic problem in many patients. In the current study, we investigated the effects of metformin (1,1-dimethylbiguanide hydrochloride), a widely used antidiabetic drug, on tumor cell radiosensitivity in prostate cancer. Through clonogenic survival assays, we found that metformin treatment enhanced radiosensitivity of prostate cancer cells with a dose enhancement factor. Moreover, irradiation of subcutaneous C4-2 tumors in mice treated with metformin resulted in an increase in radiation-induced tumor growth delay (17.3 days to 29.5 days, P < 0.01), which indicates that the tumor radiosensitivity increased by metformin in vivo. We also measured the sublethal damage repair and analyzed double-strand breaks (DSBs) in X-irradiated cells. γ-H2AX, as an indicator of DSBs, had significantly more foci per cell in the group treated with metformin and radiation compared to groups treated with metformin or irradiation, respectively. Moreover, mice with subcutaneous tumor implants lived longer after a combined treatment of metformin and radiation. In addition, the reduced phosphorylation of DNA-PKcs caused by EGFR/PI3K/Akt down-regulation is essential for metformin to induce radiosensitivity in prostate cancer cells. Our results indicate that metformin enhances prostate cancer cell radiosensitivity in vitro and in vivo. Exposure to metformin before radiation therapy could be a beneficial option for the treatment of prostate cancer.