Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-κB signaling

Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-κB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-κB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo. Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression.published_or_final_versio

Targeting GRB7/ERK/FOXM1 Signaling Pathway Impairs Aggressiveness of Ovarian Cancer Cells

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Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-κB signaling

Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-κB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-κB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo. Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression.published_or_final_versio

p21-Activated Kinases 1, 2 and 4 in Endometrial Cancers: Effects on Clinical Outcomes and Cell Proliferation

p21-activated kinases (Paks) are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028) and cytoplasmic p-Pak2 (P = 0.048) expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05). Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001). On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05) while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05). Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026). Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα) and progestogen receptor (PR) expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 are involved in the pathogenesis of endometrial cancer especially in postmenopausal women. Pak1 promote endometrial cancer cell proliferation, particular in type I endometrioid carcinoma. Cytoplasmic Pak4 can be potential prognostic marker in endometrial cancer.published_or_final_versio

Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways

Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. Methods: The upstream miRNA regulators were predicted by in silico analysis. Expression of GRB7 was examined by qPCR, immunoblotting and immunohistochemical analyses, while miR-193a-3p levels were evaluated by qPCR and in situ hybridization in ovarian cancer cell lines and clinical tissue arrays. MS-PCR and pyrosequencing analyses were used to assess the methylation status of miR-193a-3p. Stable overexpression or gene knockdown and Tet-on inducible approaches, in combination with in vitro and in vivo tumorigenic assays, were employed to investigate the functions of GRB7 and miR-193a-3p in ovarian cancer cells. Results: Both miR-193a-3p and its isoform, miR-193b-3p, directly targeted the 3' UTR of GRB7. However, only miR-193a-3p showed a significantly inverse correlation with GRB7-upregulated ovarian cancers. Epigenetic studies revealed that methylation-mediated silencing of miR-193a-3p led to a stepwise decrease in miR-193a-3p expression from low to high-grade ovarian cancers. Intriguingly, miR-193a-3p not only modulated GRB7 but also ERBB4, SOS2 and KRAS in the MAPK/ERK signaling pathway to enhance the oncogenic properties of ovarian cancer cells in vitro and in vivo. Conclusion: These findings suggest that epigenetic silencing of miR-193a-3p by DNA hypermethylation is a dynamic process in ovarian cancer progression, and miR-193a-3p may be explored as a promising miRNA replacement therapy in this disease.published_or_final_versio

Infant growth disparity in the Khanh Hoa province in Vietnam: a follow-up study

<p>Abstract</p> <p>Background</p> <p>Surveys in Vietnam have indicated that wasting and stunting have been prevalent among children, but the country is undergoing rapid socio-economic changes and little has been known about the relative situation in the different areas of the country. In 2006, the WHO introduced new growth standards applicable to all infant and child populations, which facilitates for improved assessments of the prevalence of growth impairment, independent of time, place and ethnicity. The aim of our study was to assess the growth of singleton infants delivered at term in three main birth clinics in the Khanh Hoa province in Vietnam by using the new WHO standards as reference, and the association between growth and some maternal, birth and health factors.</p> <p>Methods</p> <p>A cohort of 237 singleton infants born in the period May-July 2005 in three main delivery clinics in the Khanh Hoa province were observed prospectively. Their anthropometrical measures a year later were compared to the WHO sex-specific growth standards for weight-for-age, length-for-age, weight-for-length, and BMI-for-age. These measures were analysed as dependent outcomes using multiple linear regression models including the following independent factors: urban vs. rural birth, 1-minute Apgar score, weight and length at birth, duration of lactation, ever had diarrhoea, dengue fever, pneumonia or dysentery, and maternal age, height, gestational duration and parity.</p> <p>Results</p> <p>Compared to the standard distributions, 79% were below the median for weight-for-length; 18.0% were within the 5^thpercentile for length-for-age, 9.6% for weight-for-age, 20.3% for weight-for-length, and 19.8% for BMI. A lower length- and weight-for-age were statistically associated with being born rurally.</p> <p>Conclusions</p> <p>In this delivery-clinic based sample of children in the Khanh Hoa province in Vietnam, the proportions within the WHO-standard 5^thpercentiles for length-for-age, weight-for-length and BMI in late infancy were 3-4 times higher than expected, which indicate that deficient growth is prevalent. The infants born in a rural area had a lower weight- and length-for-age than their urban counterparts, independent of diarrhoea.</p

Nanostructural Diversity of Synapses in the Mammalian Spinal Cord

This work for funded by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/M021793/1), RS MacDonald Charitable Trust, Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Engineering and Physical Sciences Research Council (EPSRC; EP/P030017/1), Welcome Trust (202932/Z/16/Z), European Research Council (ERC; 695568) and the Simons Initiative for the Developing Brain.Functionally distinct synapses exhibit diverse and complex organisation at molecular and nanoscale levels. Synaptic diversity may be dependent on developmental stage, anatomical locus and the neural circuit within which synapses reside. Furthermore, astrocytes, which align with pre and post-synaptic structures to form “tripartite synapses”, can modulate neural circuits and impact on synaptic organisation. In this study, we aimed to determine which factors impact the diversity of excitatory synapses throughout the lumbar spinal cord. We used PSD95-eGFP mice, to visualise excitatory postsynaptic densities (PSDs) using high-resolution and super-resolution microscopy. We reveal a detailed and quantitative map of the features of excitatory synapses in the lumbar spinal cord, detailing synaptic diversity that is dependent on developmental stage, anatomical region and whether associated with VGLUT1 or VGLUT2 terminals. We report that PSDs are nanostructurally distinct between spinal laminae and across age groups. PSDs receiving VGLUT1 inputs also show enhanced nanostructural complexity compared with those receiving VGLUT2 inputs, suggesting pathway-specific diversity. Finally, we show that PSDs exhibit greater nanostructural complexity when part of tripartite synapses, and we provide evidence that astrocytic activation enhances PSD95 expression. Taken together, these results provide novel insights into the regulation and diversification of synapses across functionally distinct spinal regions and advance our general understanding of the ‘rules’ governing synaptic nanostructural organisation.Publisher PDFPeer reviewe

Function and modulation of Pdcd4 in ovarian cancer

Poster Session 4 - Cytoplasmic Signal Transducers: abstract no. 1079Programmed cell death 4 (Pdcd4), a novel gene and originally identified as the neoplastic transformation inhibitor, is attenuated in various cancer types. It has been shown to have tumor suppressor properties such as inhibiting cell proliferation and inducing apoptosis. Our previous study demonstrated a continuous down-regulation of Pdcd4 expression in the sequence of normal-borderline-malignant ovarian tissue samples, and a significant correlation of Pdcd4 expression with disease-free survival. The objective of the current study is to further investigate the function and modulation of Pdcd4 in ovarian cancer cells. Our in vitro studies demonstrated that ectopic Pdcd4 expression significantly inhibited ovarian cancer cell proliferation by up-regulation of cyclin dependent kinase inhibitors of p27 and p21 and subsequently leading to cell cycle arrest at G1 stage. Unlike other cancers, Pdcd4 neither induce ovarian cancer cell apoptosis, nor promote the cellular sensitivity in response to cisplatin treatment. Pdcd4 over-expressing ovarian cancer cells exhibited elevated phosphatase and tensin homolog (PTEN) and decreased p-Akt expressions. In addition, Pdcd4 expression was up-regulated and translocated from cell nucleus to cytoplasm upon serum withdrawal treatment, but was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of Pdcd4. In conclusion, loss of Pdcd4 may result in diminished cell ability to arrest at key checkpoint, leading to tumor development. The PI3K-Akt pathway may be involved in the regulation of Pdcd4 degradation in ovarian cancer cells. In response to the stress condition, Pdcd4 expression was altered and it was translocated to cytoplasm, suggesting that Pdcd4 was able to shuttle between cell compartments to perform its diverted functions.link_to_OA_fulltextThe 102nd Annual Meeting of the American Association for Cancer Reseach (AACR 2011), Orlando, FL., 2-6 April 2011