Low-dose hexavalent chromium(VI) exposure promotes prostate cancer cell proliferation by activating MAGEB2-AR signal pathway.

Hexavalent chromium [Cr(VI)], one common environmental contaminant, has long been recognized as a carcinogen associated with several malignancies, such as lung cancer, but little information was available about the effects of its low-dose environmental exposure in prostate cancer. Our previous study has shown that low-dose Cr(VI) exposure could promote prostate cancer(PCa) cell growth in vitro and in vivo. In the present study, we furthermore found that low-dose Cr(VI) exposure could induce DNA demethylation in PCa cells. Based on our transcriptome sequencing data and DNA methylation database, we further identified MAGEB2 as a potential effector target that contributed to tumor-promoting effect of low-dose Cr(VI) exposure in PCa. In addition, we demonstrated that MAGEB2 was upregulated in PCa and its knockdown restrained PCa cell proliferation and tumor growth in vitro and in vivo. Moreover, Co-IP and point mutation experiments confirmed that MAGEB2 could bind to the NH2-terminal NTD domain of AR through the F-box in the MAGE homology domain, and then activated AR through up-regulating its downstream targets PSA and NX3.1. Together, low-dose Cr(VI) exposure can induce DNA demethylation in prostate cancer cells, and promote cell proliferation via activating MAGEB2-AR signaling pathway. Thus, inhibition of MAGEB2-AR signaling is a novel and promising strategy to reverse low-dose Cr(VI) exposure-induced prostate tumor progression, also as effective adjuvant therapy for AR signaling-dependent PCa.

RAB38 promotes bladder cancer growth by promoting cell proliferation and motility.

BACKGROUND: Bladder cancer is the most common malignancy of urinary system with high morbidity and mortality. In general, the development and progression of bladder cancer are complicated pathological processes, and the treatment methods mainly include surgical resection, radiotherapy, chemotherapy, and combined therapy. In recent years, targeted therapy has made progress in the treatment of bladder cancer. Therefore, to improve survival rates of patients with advanced bladder cancer, novel therapeutic targets are still urgently needed. METHODS AND RESULTS: In this study, we found that RAB38 expressed in tumor tissues of patients with bladder cancer was linked to clinical features including pTNM stage and tumor recurrence, and positively correlated with the poor prognosis of bladder cancer. Notably, further results indicated that depletion of RAB38 could significantly inhibit the proliferation and motility of two types of human bladder cancer cells, T24 and 5637 cells. In addition, RAB38 ablation obviously blocked tumor growth and development in mice compared with control. CONCLUSION: In conclusion, this study provides significant evidence that RAB38 promotes the development of bladder cancer and provides a novel therapeutic target of bladder cancer.

Selective Actionable and Druggable Protein Kinases Drive the Progression of Neuroendocrine Prostate Cancer.

Current clinical anti-androgen therapies in advanced prostate cancer (PCa) are driving an increased incidence of neuroendocrine prostate cancer (NEPC), a histological variant exhibiting reduced androgen receptor levels and expression of neuroendocrine markers. The mechanisms underlying the development of NEPC are poorly understood. A set of available data from a well-validated xenograft model of NEPC was used to analyze the exact role of protein kinase (PK) played in the development of NEPC. Fifty-four actionable and druggable PKs, mainly enriched in PI3K-Akt, mTOR, and MAPK signaling pathways, were screened out from the drastically changed PKs during NEPC transdifferentiation. Further analysis based on the crosstalk of these above signaling pathways finally singled out 10 PKs considered drivers and therapeutic targets in the development and treatment of NEPC. In vitro, the variation trend of PK expression observed during NEPC transdifferentiation could be recapitulated in PCa cell lines with different malignant degree. The predicted kinase targets exhibited different sensibilities in the restriction of PC3 cell growth. Selective actionable and druggable PKs may act as drivers in the progression of NEPC, and most of them can be used as potential therapeutic targets in clinical practice.

Evidences for B6C3-Tg (APPswe/PSEN1dE9) double-transgenic mice between 3 and 10 months as an age-related Alzheimer's disease model.

Transgenic mouse has shown great advantages in the study of Alzheimer's disease (AD) and drug screening as AD develops rapidly resent years, while more detail information of these transgenic mice and experience of application are needed. To obtain the basic background information of the B6C3-Tg (APPswe/PSEN1dE9) double-transgenic mouse, which was reported with early onset AD, three- to ten-month-old B6C3-Tg AD mice and normal C57BL/6 mice were selected randomly to test the ability of learning memory by Morris water maze, the brain acetylcholinesterase (AChE) activity by AChE kit, and beta amyloid protein level by immunohistochemistry staining. Compared with the control group, the escape latency time of B6C3-Tg AD mice at 9 and 10 months of age is significantly longer (P < 0.05) in Morris maze test, and the activity of brain AChE is higher. ß-Amyloid plaques were observed at 3 months of age and developed rapidly. Statistical analysis showed a positive correlation between the area of these plaques and the ages of B6C3-Tg AD mouse (y = 0.0355e(0.5557x), R = 0.9557). The model's behavior is conformed to simulate behaviors of human Alzheimer's disease at the early stage and may provide detail background information a new choice when transgenic mice are needed in the research of AD.

Toxicity of trimethyltin and dimethyltin in rats and mice.

Extensive uses of methyltin compounds in polyvinyl chloride (PVC) production have led to a dramatic increase of occupational-related methyltin poisoning accidents and the widespread contamination of methyltins in various environmental media. Here, we conducted studies to compare the acute toxicity induced by trimethyltin (TMT) and dimethyltin (DMT), and investigated the cumulative toxic effects of TMT in rats and mice. Neurobehavioral changes were observed in rats and mice treated with either DMT or TMT, but we also observed that both TMT and DMT exposure in rats significantly lowered the blood potassium level. Moreover, the cumulative toxic coefficient factor of TMT was 1.7 in rats versus 3.8 in mice, suggesting a high cumulative risk for rats and a moderate risk for mice. In summary, we demonstrated that acute and chronic exposure to methyltin compounds induced neurotoxicity and hypokalemia. Moreover, our study suggests that TMT can accumulate in the body and pose a risk for workers chronically exposed to a low dose of TMT.