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Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial to mesenchymal transition (EMT) in tumor cells and their achievement of stem cell traits. Curcumin has recently been found to possess anticancer activities via its effect on a variety of biological pathways involved in cancer progression. In this study, we found that CAFs could induce prostate cancer cell EMT and invasion through a monoamine oxidase A (MAOA)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway, which exploits reactive oxygen species (ROS) to drive a migratory and aggressive phenotype of prostate carcinoma cells. Moreover, CAFs was able to increase CXC chemokine receptor 4 (CXCR4) and interleukin-6 (IL-6) receptor expression in prostate cancer cells. However, curcumin abrogated CAF-induced invasion and EMT, and inhibited ROS production and CXCR4 and IL-6 receptor expression in prostate cancer cells through inhibiting MAOA/mTOR/HIF-1α signaling, thereby supporting the therapeutic effect of curcumin in prostate cancer.

BackgroundRobot-assisted radical prostatectomy (RARP) is increasingly used worldwide, but comparisons of perioperative, functional, and oncologic outcomes among RARP, laparoscopic radical prostatectomy (LRP), and open radical prostatectomy (ORP) remain inconsistent.Material/MethodsSystematic literature searches were conducted using EMBASE, PubMed, the Cochrane Library, CNKI, and Science Direct/Elsevier up to April 2017. A meta-analysis was conducted using Review Manager and Stata software.ResultsWe included 33 studies. Meta-analysis revealed that blood loss, transfusion rate, and positive surgical margin (PSM) rate were significantly lower following RARP compared with LRP (SMD (95% confidence interval [CI]) 0.31 [0.01, 0.61]; combined ORs (95% CI) 5.32 [1.29, 21.98]; 1.27 [1.10, 1.46]) and ORP (SMD (95% CI) 0.75 [0.30, 1.21]; and combined ORs (95% CI) 3.44 [1.21, 9.79]); positive surgical margin (PSM) rates were significantly lower following RARP compared with LRP (combined ORs (95% CI) 1.27 [1.10, 1.46]), but not ORP. Operation time was also shorter for RARP than for LRP. The rates of nerve-sparing, recovery of complete urinary continence, and recovery of erectile function were significantly higher following RARP compared with LRP (combined ORs (95% CI) 0.55 [0.31, 0.95]; 0.66 [0.55, 0.78]; 0.46 [0.30, 0.71]) and ORP (combined ORs (95% CI) 0.36 [0.21, 0.63]; 0.33 [0.15, 0.74]; 0.65 [0.37, 1.14]).ConclusionsThis meta-analysis demonstrates that RARP results in better overall outcomes than LRP and ORP in terms of blood loss, transfusion rate, nerve sparing, urinary continence and erectile dysfunction recovery, and suggests that RARP offers better results than LRP and ORP in treatment of prostate cancer. However, studies with larger sample sizes and long-term results are needed.

MicroRNAs, a kind of small non-coding RNAs, can regulate gene expression by targeting mRNAs for translational repression or degradation. Much evidence has suggested that miR-218 was a tumor suppressor in many human cancers including prostate cancer. However, the underlying role of miR-218 in tumor angiogenesis and the mechanisms in PCa and other cancers remains to be unclear. Here in this present study, we demonstrated that miR-218 inhibited the tumor angiogenesis of PCa cells in vitro and in vivo. RICTOR, the mTOR component 2, was a direct target of miR-218 and miR218-RICTOR-VEGFA axis was the mechanism inhibiting the tumor angiogenesis of PCa cells. RICTOR knockdown phenocopied miR-218 overexpression in inhibiting prostate cancer angiogenesis. Altogether, our findings indicate that down-regulation of miR-218 contributes to tumor angiogenesis through RICTOR/VEGFA axis in PCa, providing new insights into the potential mechanisms of PCa oncogenesis and revealing the potential of miR-218 as a useful serum biomarker and a new therapeutic target for human PCa.

Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.

Stromal cell-derived factor-1 (SDF-1)/CXCR4 pathway has been shown to play an important role in prostate cancer (PCa) metastasis and siRNA expression using cell-specific promoters has been demonstrated to be a potential tool for targeted gene therapy. Here, we illustrate that human telomerase reverse transcriptase (hTERT) promoter-induced CXCR4 knockdown inhibits PCa bone metastasis. We first investigated CXCR4 expressions and interactions of CXCR4/SDF-1 in PCa cells, developed a retrovirus system that could stably express CXCR4 small hairpin RNA driven by hTERT promoter and then determined the inhibitory effects of cell-specific blockade of CXCR4/SDF-1 pathway on PCa metastasis. It was shown that both PCa tissues and cell lines expressed CXCR4 and the expression in PCa tissue had a positive correlation to clinical stages while not to Gleason scores or serum PSA level. PCa metastases most presenting human tissues expressed high levels of SDF-1. Exogenous SDF-1 enhanced in vitro adhesion, migration and invasion of PCa cells and these bioeffects were repressed by hTERT promoter-induced CXCR4-shRNA expression. This CXCR4 knockdown was also found to significantly inhibit bone metastasis in vivo. We conclude that CXCR4/SDF-1 pathway plays an important role in PCa bone metastasis. hTERT promoter-induced tumor cell-specific CXCR4 gene silencing may prevent in vitro invasiveness and in vivo bone metastasis of PCa. These findings may enable new avenues of prevention and treatment for PCa metastasis.

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Renal cell carcinoma (RCC) ranks among the most chemoresistant tumors, and P-glycoprotein (P-gp) predominates multidrug resistance mechanisms by reducing the accumulation of intracellular chemotherapy drugs such as vinblastine (VBL), which is considered the most effective chemotherapeutic agent for this neoplasia. Unfortunately, the mechanism by which the expression of P-gp is regulated and the ways to inhibit the function of P-gp are poorly understood. Our study was carried out to determine the possible role of CCN1 in P-pg-mediated drug resistance on the basis of the validated function of CCN1, an extracellular matrix protein, in promoting chemoresistance. As expected, CCN1 was overexpressed in VBL-resistant cell lines (ACHN/VBL, A498/VBL, Caki-1/VBL, and Caki-2/VBL) as measured by enzyme-linked immunosorbent assay. We then transfected non-VBL-resistant cell lines with Ad-CCN1 and observed that the IC50 of VBL increased by about 3-5 times. Furthermore, both CCN1 antibody neutralization and αvβ3 integrin antibody blockade decreased the IC50 of VBL, which showed that CCN1 and αvβ3 are associated with resistance to VBL in RCC. Simultaneously, the enhanced expression of CCN1 triggered the intracellular PI3K/Akt pathway by binding αvβ3 integrin, as shown by western blot. P-gp expression was augmented in response to activation of the PI3K/Akt pathway, which could be modified by PI3K inhibitor LY294002 or multidrug resistance siRNA transfection. Therefore, targeted restraint of CCN1 or αvβ3 integrin in combination with the administration of VBL may be beneficial in the treatment of primary and metastatic RCC.