Cancer on motors: How kinesins drive prostate cancer progression?

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.

Discovery of indoline derivatives that inhibit esophageal squamous cell carcinoma growth by Noxa mediated apoptosis.

A series of novel indoline derivatives were synthesized and evaluated for antiproliferative activity against four selected cancer cell lines (Hela, A549, HepG2 and KYSE30). Among them, compound 20 displayed the potent inhibition activity against esophageal cancer cells (Kyse30, Kyse450, Kyse510 and EC109). Cellular mechanism studies in esophageal squamous cell carcinoma (ESCC) cells elucidated compound 20 inhibited cell growths in vitro and in vivo, reduced colony formation, arrested cell cycle at M phase, and induced Noxa-dependent apoptosis in ESCC. Importantly, compound 20 was identified as a novel Noxa mediated apoptosis inducer. These results suggested that compound 20 might be a promising anticancer agent with potential for development of further clinical applications.

Regulation of UGT1A expression by miR-298 in human livers from the Han Chinese population and in human cell lines.

AIM: This study aimed to investigate the role of miRNAs in UGT1A regulation. MATERIALS & METHODS: Based on bioinformatic prediction results, luciferase reporter assay and cell-transfection experiments were performed to study effects of miR-298 on UGT1A expression. Correlation study was conducted in human livers. RESULTS: miR-298 overexpression reduced mRNA level of UGT1A1 and UGT1A4 in HepG2 and LS174T cells, and that of UGT1A3 and UGT1A9 in LS174T cells. miR-298 repression increased mRNA level of UGT1A4 in HepG2 and LS174T cells, and that of UGT1A1 and UGT1A3 in LS174T cells. Inverse correlations between miR-298, as well as miR-491-3p, and UGT1A3 and 1A4 mRNA levels were observed in livers. CONCLUSION: The study demonstrates that miR-298 and miR-491-3p downregulates UGT1A expression.

Apigenin inhibits renal cell carcinoma cell proliferation.

Apigenin, a natural flavonoid found in vegetables and fruits, has antitumor activity in several cancer types. The present study evaluated the effects and mechanism of action of apigenin in renal cell carcinoma (RCC) cells. We found that apigenin suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in a dose- and time-dependent manner. A comet assay suggested that apigenin caused DNA damage in ACHN cells, especially at higher doses, and induced G2/M phase cell cycle arrest through ATM signal modulation. Small interfering RNA (siRNA)-mediated p53 knockdown showed that apigenin-induced apoptosis was likely p53 dependent. Apigenin anti-proliferative effects were confirmed in an ACHN cell xenograft mouse model. Apigenin treatment reduced tumor growth and volume in vivo, and immunohistochemical staining revealed lower Ki-67 indices in tumors derived from apigenin-treated mice. These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN RCC cell proliferation in vitro and in vivo. Given its antitumor effects and low in vivo toxicity, apigenin is a highly promising agent for treatment of RCC.

Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population.

PURPOSE: Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. METHODS: Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms. RESULTS: UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. CONCLUSIONS: Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.

Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population.

CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.

[Spatio-temporal dynamics of ecosystem service value in Wuhan Urban Agglomeration].

Based on the land use vector data of Wuhan Urban Agglomeration in the years 1990, 2000 and 2009, this paper used Costanza' s evaluation formula to estimate the ecosystem service value (ESV) of the study area according to "equivalent value per unit area of ecosystem services in China" and analyze its spatio-temporal characteristics. Then the correlation analysis was applied to explore the association between the ESV evolution and the land use changes. The results showed that due to the substantial growth of water area, the ESV of Wuhan Urban Agglomeration increased by 9.5% during the study period, which showed an overall rising trend. The ESV of water regulation and waste treatment increased obviously. Furthermore, the ESV changes showed obvious regional differences, which were most significant in Xiantao, Xinzhou and Yunmeng. The ESV was higher in the southeast and lower in the northwest. Over time, a Wuhan-centered "low-high-low" hierarchically distributed structure of ESV was formed in the eastern, western and northern parts. The ecologic dominance of the northern mountainous and hilly region was gradually abated, while a structural expansion with a high-ESV cluster had taken place in the southern part of the region in 2009. During the research period, the temporal change of ESV in Wuhan Urban Agglomeration was positively correlated with the area changes of forestland, water, grassland and cultivated land. However, the spatially balanced distribution of ESV was negatively correlated with the dispersion degrees of the cultivated land and unused land.

[Strategies for sustainable development of Hong Kong Global Geopark].

Hong Kong has a limited area of 1108 km2 but remarkably rich geodiversity and diversified geology, landforms, and assemblages of associated features and processes. Some of the geological features can even be considered as world-class, which deserves more attention. Over the years, Hong Kong has allocated a lot of resources in biodiversity conservation, but the geodiversity conservation has been a missing piece in the initiatives of biocentric conversation for decades. The National Geopark in Hong Kong was eventually established in 2009, and listed as a Global Geopark by UNESCO in September 2011. This Geopark not only aims at the protection of natural environment, but also provides the public with opportunities of recreation and education. While these objectives seem to be conflicting, the conflicts can be solved by balancing the orientation first, and then, according to the real situation, implementing proper design, planning, and management.

[Land layout for lake tourism based on ecological restraint].

To avoid the decrease and deterioration of lake wetlands and the other ecological issues such as lake water pollution that were caused by the unreasonable exploration of lake tourism, a land layout for the tourism development of Liangzi Lake with the priority of ecological security pattern was proposed, based on the minimal cumulative resistance model and by using GIS technology. The study area was divided into four ecological function zones, i. e., core protection zone, ecological buffer zone, ecotone zone, and human activity zone. The core protection zone was the landscape region of ecological source. In the protection zone, new tourism land was forbidden to be increased, and some of the existing fundamental tourism facilities should be removed while some of them should be upgraded. The ecological buffer zone was the landscape region with resistance value ranged from 0 to 4562. In the buffer zone, expansion of tourism land should be forbidden, the existing tourism land should be downsized, and human activities should be isolated from ecological source by converting the human environment to the natural environment as far as possible. The ecotone zone was the landscape region with resistance value ranged from 4562 to 30797. In this zone, the existing tourism land was distributed in patches, tourism land could be expanded properly, and the lake forestry ecological tourism should be developed widely. The human activity zone was the landscape region with resistance value ranged from 30797 to 97334, which would be the key area for the land layout of lake tourism. It was suggested that the land layout for tourism with the priority of landscape ecological security pattern would be the best choice for the lake sustainable development.