MicroRNA-375 Suppresses the Tumor Aggressive Phenotypes of Clear Cell Renal Cell Carcinomas through Regulating YWHAZ.

BACKGROUND: MicroRNAs (miRNAs) are key regulators during tumor initiation and progression. MicroRNA-375 (MiR-375) has been proven to play a tumor-suppressive role in various types of human malignancies; however, its biological role in clear cell renal cell carcinoma (ccRCC) remains unclear. The purpose of this study was to explore the biologic role as well as the underlying mechanism of miR-375 in ccRCC progression. METHODS: Quantitative polymerase chain reaction (qPCR) was applied to test the expression of miR-375 in tissues and cell lines by t-test. Functional experiments were used to investigate the biological role of miR-375 utilizing a gain-of-function strategy. The target of miR-375 was investigated by bioinformatic analysis and further verified by luciferase reporter assay, qPCR, Western blotting, and functional experiments in vitro. RESULTS: Our study demonstrated that miR-375 was significantly downregulated in ccRCC tissues (cancer vs. normal, 0.804 ± 0.079 vs. 1.784 ± 0.200, t = 5.531 P < 0.0001) and cell lines, and loss of miR-375 expression significantly associated with advanced Fuhrman nuclear grades (Grade III and IV vs. Grade I and II, 1.000 ± 0.099 vs. 1.731 ± 0.189, t = 3.262 P = 0.003). Functional studies demonstrated that miR-375 suppressed ccRCC cell proliferation, migration, and invasion (all P < 0.05 in both 786-O and A498 cell lines). Multiple miRNA target prediction algorithms indicated the well-studied oncogene YWHAZ as a direct target of miR-375, which was further confirmed by the luciferase reporter assay, qPCR, and Western blotting. Moreover, restoration of YWHAZ could rescue the antiproliferation effect of miR-375. CONCLUSIONS: The data provide the solid evidence that miR-375 plays a tumor-suppressive role in ccRCC progression, partially through regulating YWHAZ. This study expands the antitumor profile of miR-375, and supports its role as a potential therapeutic target in ccRCC treatment.

The effect of gemcitabine/paclitaxel chemotherapy on the survival of patients with metastatic urothelial cancers.

BACKGROUND: To evaluate the survival benefit of gemcitabine and paclitaxel (GT) chemotherapy for patients with metastatic urothelial cancer (UC), a retrospective analysis was performed to compare the overall survival in two periods: before (group I) and after (group II) the introduction of GT chemotherapy. PATIENTS AND METHODS: Eighty-five patients with metastatic UC were treated with MEC/MVAC (methotrexate, epirubicin, and cisplatin / methotrexate, vinblastine, doxorubicin, and cisplatin) or GT between 1995 and 2007. The response rate, maintenance rate, maintenance duration of each regimen, and the survival times of responding patients in each group were evaluated retrospectively. RESULTS: The median survival of patients in group ΙI (20 months) was significantly longer than that for group I (13 months) (p = 0.03). Especially in patients with a favorable response (CR/PR) to induction chemotherapy, the median survival period was significantly different between group Ι and group II (median 15 and 28 months, respectively; p = 0.02). The rate of the shift to maintenance chemotherapy when using GT chemotherapy was significantly higher than with MEC/MVAC chemotherapy alone (p < 0.05), and the cessation rate due to adverse effects was significantly lower when using GT chemotherapy (26.1%) than MEC/MVAC in group Ι (42.1%). CONCLUSION: Our results demonstrated that the administration of GT chemotherapy may be useful to improve the survival of patients with metastatic UC. This effect was significant, especially among those who were sensitive to the induction course of first-line chemotherapy. The excellent tolerability of GT regimens mean that they may be suitable for maintenance chemotherapy.

A potent chemotherapeutic strategy in prostate cancer: S-(methoxytrityl)-L-cysteine, a novel Eg5 inhibitor.

Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 (kinesin spindle protein), which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of S-(methoxytrityl)-L-cysteine (S(MeO)TLC), a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S(MeO)TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S(MeO)TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S(MeO)TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S(MeO)TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S(MeO)TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S(MeO)TLC exhibited its significant inhibitory activity (P<0.05) on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S(MeO)TLC is a potent promising anticancer agent in prostate cancer.