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Shi S.,University of Chinese Academy of Sciences | Deng Y.-Z.,University of Chinese Academy of Sciences | Zhao J.-S.,University of Chinese Academy of Sciences | Ji X.-D.,University of Chinese Academy of Sciences | And 8 more authors.
Journal of Biological Chemistry | Year: 2012

Non-small-cell lung cancer (NSCLC) is a deadly disease due to lack of effective diagnosis biomarker and therapeutic target. Much effort has been made in defining gene defects in NSCLC, but its full molecular pathogenesis remains unexplored. Here, we found RACK1 (receptor of activated kinase 1) was elevated in most NSCLC, and its expression level correlated with key pathological characteristics including tumor differentiation, stage, and metastasis. In addition, RACK1 activated sonic hedgehog signaling pathway by interacting with and activating Smoothened to mediate Gli1-dependent transcription in NSCLC cells. And silencing RACK1 dramatically inhibited in vivo tumor growth and metastasis by blocking the sonic hedgehog signaling pathway. These results suggest that RACK1 represents a new promising diagnosis biomarker and therapeutic target for NSCLC. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Cai Y.,Red Cross | Li J.,Red Cross | Lu A.,Red Cross | Zhong W.,Red Cross | And 6 more authors.
Medicine (United States) | Year: 2014

This study was aimed to investigate the roles of serum macrophage inflammatory protein-3α (MIP-3α) and cystatin A in nasopharyngeal carcinoma (NPC) prognosis. The serum levels of MIP-3α and cystatin A in 140 primary NPC patients without distant metastasis were detected by enzyme-linked immunosorbent assay before and after treatment. The results were compared with those in 100 healthy controls. The log-rank test was used to compare survival curves of the 2 groups. Multivariate analysis of prognostic factors used Cox proportional hazards regression model. Serum levels of MIP-3α and cystatin A in pretreatment patients with NPC were higher than those in healthy controls. Concentrations of these 2 factors in the majority of patients after the therapy decreased to control level. Patients with high serum level of MIP-3α and cystatin A before treatment had poorer overall survival (OS), local recurrence-free survival, and distant metastasis-free survival than the ones with low level. In addition, serum pretreatment MIP-3α and cystatin A levels were independent prognostic factors for OS and distant metastasis-free survival of NPC patients; serum posttreatment MIP-3α and cystatin A levels were independent prognostic factors of local recurrence-free survival. Our results revealed that serum MIP-3α and cystatin A may be promising candidate prognostic factors for NPC, and higher serum levels of MIP-3α and cystatin A correlate with shorter probability of OS, local recurrence, and distant metastasis. Copyright © 2014 Wolters Kluwer Health-Lippincott Williams & Wilkins. Source

Shang Y.,Beijing Normal University | Shang Y.,Tsinghua University | Xu X.,Tsinghua University | Duan X.,Second Peoples Hospital of Zhuhai | And 5 more authors.
Biochemical and Biophysical Research Communications | Year: 2014

Transforming growth factor-β (TGF-β) signaling plays an important role in regulation of a wide variety of cellular processes. Canonical TGF-β signaling is mediated by Smads which were further regulated by several factors. We previously reported that E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein, also named Stub1) controlled the sensitivity of TGF-β signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. Here, we present evidence that Hsp70 and Hsp90 regulate the complex formation of Smad3/CHIP. Furthermore, we observed that over-expressed Hsp70 or inhibition of Hsp90 by geldanamycin (GA) leads to facilitated CHIP-induced ubiquitination and degradation of Smad3, which finally enhances TGF-β signaling. In contrast, over-expressed Hsp90 antagonizes CHIP mediated Smad3 ubiquitination and degradation and desensitizes cells in response to TGF-β signaling. Taken together, our data reveal an opposite role of Hsp70 and Hsp90 in regulating TGF-β signaling by implicating CHIP-mediated Smad3 ubiquitination and degradation. This study provides a new insight into understanding the regulation of the TGF-β signaling by chaperones. © 2014 Elsevier Inc. All rights reserved. Source

Dong W.,Sun Yat Sen University | Gong M.,Sun Yat Sen University | Shi Z.,Second Peoples Hospital of Zhuhai | Xiao J.,Sun Yat Sen University | And 2 more authors.
PLoS ONE | Year: 2016

Programmed cell death-1 (PD-1) plays an important inhibitory role in anti-tumor responses, so it is considered as a powerful candidate gene for individual's genetic susceptibility to cancer. Recently, some epidemiological studies have evaluated the association between PD-1 polymorphisms and cancer risk. However, the results of the studies are conflicting. Therefore, a meta-analysis was performed. We identified all studies reporting the relationship between PD-1 polymorphisms and cancers by electronically searches. According to the inclusion criteria and the quality assessment of Newcastle-Ottawa Scale (NOS), only high quality studies were included. A total of twelve relevant studies involving 5,206 cases and 5,174 controls were recruited. For PD-1.5 (rs2227981) polymorphism, significantly decreased cancer risks were obtained among overall population, Asians subgroup and population-based subgroup both in TT vs. CC and TT vs. CT+CC genetic models. In addition, a similar result was also found in T vs. C allele for overall population. However, there were no significant associations between either PD-1.9 (rs2227982) or PD-1 rs7421861 polymorphisms and cancer risks in all genetic models and alleles. For PD-1.3 (rs11568821) polymorphism, we found different cancer susceptibilities between GA vs. GG and AA vs. AG+GG genetic models, and no associations between AA vs. GG, AA+AG vs. GG genetic models or A vs. G allele and cancer risks. In general, our results firstly indicated that PD-1.5 (rs2227981) polymorphism is associated a strongly decreased risk of cancers. Additional epidemiological studies are needed to confirm our findings. © 2016 Dong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Zhang Y.,Tsinghua University | Zhang Y.,University of Sichuan | Liu C.,Tsinghua University | Liu C.,University of Sichuan | And 13 more authors.
Journal of Biological Chemistry | Year: 2014

CREPT (cell cycle-related and expression elevated protein in tumor)/RPRD1B (regulation of nuclear pre-mRNA domain-containing protein 1B), highly expressed during tumorigenesis, was shown to enhance transcription of CCND1 and to promote cell proliferation by interacting with RNA polymerase II. However, which signaling pathway is involved in CREPT-mediated activation of gene transcription remains unclear. In this study, we reveal that CREPT participates in transcription of the Wnt/ β-catenin signaling activated genes through the β-catenin and the TCF4 complex. Our results demonstrate that CREPT interacts with both β-catenin and TCF4, and enhances the association of β-catenin with TCF4, in response to Wnt stimulation. Furthermore, CREPT was shown to occupy at TCF4 binding sites (TBS) of the promoters of Wnt-targeted genes under Wnt stimulation. Interestingly, depletion of CREPT resulted in decreased occupancy of β-catenin on TBS, and over-expression of CREPT enhances the activity of the β-catenin·TCF4 complex to initiate transcription of Wnt target genes, which results in up-regulated cell proliferation and invasion. Our study suggests that CREPT acts as an activator to promote transcriptional activity of the β-catenin·TCF4 complex in response to Wnt signaling. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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