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1.  MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells 
Oncotarget  2015;6(34):35851-35865.
Gliomas are the most common primary brain malignancies and are associated with a poor prognosis. Here, we showed that the PDZ domain-containing protein membrane-associated guanylate kinase inverted 3 (MAGI3) was downregulated at the both mRNA and protein levels in human glioma samples. MAGI3 inhibited proliferation, migration, and cell cycle progression of glioma cells in its overexpression and knockdown studies. By using GST pull-down and co-immunoprecipitation assays, we found that MAGI3 bound to β-catenin through its PDZ domains and the PDZ-binding motif of β-catenin. MAGI3 overexpression inhibited β-catenin transcriptional activity via its interaction with β-catenin. Consistently, MAGI3 overexpression in glioma cells C6 suppressed expression of β-catenin target genes including Cyclin D1 and Axin2, whereas MAGI3 knockdown in glioma cells U373 and LN229 enhanced their expression. MAGI3 overexpression decreased growth of C6 subcutaneous tumors in mice, and inhibited expression of β-catenin target genes in xenograft tumors. Furthermore, analysis based on the Gene Expression Omnibus (GEO) glioma dataset showed association of MAGI3 expression with overall survival and tumor grade. Finally, we demonstrated negative correlation between MAGI3 expression and activity of Wnt/β-catenin signaling through GSEA of three public glioma datasets and immunohistochemical staining of clinical glioma samples. Taken together, these results identify MAGI3 as a novel tumor suppressor and provide insight into the pathogenesis of glioma.
PMCID: PMC4742146  PMID: 26452219
glioma; β-catenin; MAGI3; PDZ; protein-protein interaction
2.  Diversity and structure of soil bacterial communities in the Fildes Region (maritime Antarctica) as revealed by 454 pyrosequencing 
This study assessed the diversity and composition of bacterial communities in four different soils (human-, penguin-, seal-colony impacted soils and pristine soil) in the Fildes Region (King George Island, Antarctica) using 454 pyrosequencing with bacterial-specific primers targeting the 16S rRNA gene. Proteobacteria, Actinobacteria, Acidobacteria, and Verrucomicrobia were abundant phyla in almost all the soil samples. The four types of soils were significantly different in geochemical properties and bacterial community structure. Thermotogae, Cyanobacteria, Fibrobacteres, Deinococcus-Thermus, and Chlorobi obviously varied in their abundance among the 4 soil types. Considering all the samples together, members of the genera Gaiella, Chloracidobacterium, Nitrospira, Polaromonas, Gemmatimonas, Sphingomonas, and Chthoniobacter were found to predominate, whereas members of the genera Chamaesiphon, Herbaspirillum, Hirschia, Nevskia, Nitrosococcus, Rhodococcus, Rhodomicrobium, and Xanthomonas varied obviously in their abundance among the four soil types. Distance-based redundancy analysis revealed that pH (p < 0.01), phosphate phosphorus (p < 0.01), organic carbon (p < 0.05), and organic nitrogen (p < 0.05) were the most significant factors that correlated with the community distribution of soil bacteria. To our knowledge, this is the first study to explore the soil bacterial communities in human-, penguin-, and seal- colony impacted soils from ice-free areas in maritime Antarctica using high-throughput pyrosequencing.
doi:10.3389/fmicb.2015.01188
PMCID: PMC4623505  PMID: 26579095
antarctica; 16S rRNA gene; bacterial communities; soil geochemical property; molecular ecology
3.  A mixed analysis comparing nine minimally invasive surgeries for unresectable hepatocellular carcinoma patients 
Oncotarget  2016;8(3):5460-5473.
Hepatocellular carcinoma (HCC) is usually managed by the transcatheter arterial chemoembolization (TACE). However, this technique has been challenged since severe complications have been observed in clinical practices. As a result, clinicians have started to seek other minimally invasive surgeries with equivalent efficacy. The corresponding surgeries were assessed by the five outcomes: complete response (CR), partial response (PR), stable disease (SD), progression disease (PD) and objective response rate (ORR). Direct meta-analysis and network meta-analysis were performed and the results were represented by odds ratios (OR), 95% confidence and credential intervals. Furthermore, the value of surface under the cumulative ranking curve (SUCRA)was calculated to provide corresponding rankings.Seventeen studies were incorporated into the network meta-analysis which indicated that TACE + external-beam radiation therapy (EBRT) and drug-eluting beads (DEB) were better than TACE at controllingPD. TACE + EBRT demonstrated their advantages compared to TARE-90Y.However, network meta-analysis comparison showed no significant difference between the corresponding eight treatments with respect to CR, PR, SD and ORR. Moreover, the SUCRA suggested that TACE+EBRT were better than other treatments at treating unresectableHCC.Based on the present results of this network meta-analysis, TACE + EBRT was more effective than the other seven minimally invasive surgeries and therefore it is considered as the optimal treatment for HCC.
doi:10.18632/oncotarget.12348
PMCID: PMC5354923  PMID: 27705924
unresectable hepatocellular carcinoma; transcatheter arterial chemoembolization; network meta-analysis
4.  Lambert-Eaton myasthenic syndrome in a patient with small-cell lung cancer: A case report 
Oncology Letters  2015;10(3):1339-1342.
Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular junction disorder characterized by fluctuating proximal limb muscle weakness, decreased deep tendon reflexes and various autonomic symptoms. LEMS is reportedly the most common neurological paraneoplastic syndrome. This is the case report of a patient with small-cell lung cancer (SCLC) who developed LEMS. A 68-year-old male patient presented with a 6-month history of progressive weakness of the proximal limbs and a 2-month history of xerostomia. The patient was admitted to the Department of Neurology of the People's Liberation Army General Hospital of Shenyang Military Region (Shenyang, China). The symptoms of the patient were not relieved with supportive therapy. Further laboratory tests, electrodiagnostic studies, chest computed tomography and immunohistochemical staining confirmed the diagnosis of LEMS in the presence of SCLC. Following administration of two cycles of rescue chemotherapy with a combination of etoposide and cisplatin, the symptoms of the patient were gradually relieved and, after six cycles of therapy, the primary malignancy completely regressed. In conclusion, a diagnosis of LEMS may lead to the timely detection of SCLC, significantly improving patient prognosis and survival.
doi:10.3892/ol.2015.3473
PMCID: PMC4533275  PMID: 26622673
Lambert-Eaton myasthenic syndrome; small-cell lung cancer; myasthenia gravis; voltage-gated calcium channel
5.  Self‐Rated Health Status and Risk of Ischemic Heart Disease in the China Kadoorie Biobank Study: A Population‐Based Cohort Study 
Dong, Wenhong | Pan, Xiong‐Fei | Yu, Canqing | Lv, Jun | Guo, Yu | Bian, Zheng | Yang, Ling | Chen, Yiping | Wu, Tangchun | Chen, Zhengming | Pan, An | Li, Liming | Chen, Junshi | Chen, Zhengming | Collins, Rory | Peto, Richard | Avery, Daniel | Boxall, Ruth | Derrick, Bennett | Chang, Yumei | Clarke, Robert | Du, Huaidong | Gilbert, Simon | Hacker, Alex | Hill, Mike | Holmes, Michael | Iona, Andri | Kartsonaki, Christiana | Kerosi, Rene | Kong, Ling | Kurmi, Om | Lancaster, Garry | Lewington, Sarah | Lin, Kuang | McDonnell, John | Millwood, Iona | Nie, Qunhua | Radhakrishnan, Jayakrishnan | Rafiq, Sajjad | Ryder, Paul | Sansome, Sam | Schmidt, Dan | Sherliker, Paul | Sohoni, Rajani | Stevens, Becky | Turnbull, Iain | Walters, Robin | Wang, Jenny | Wang, Lin | Wright, Neil | Yang, Ling | Yang, Xiaoming | Bian, Zheng | Guo, Yu | Han, Xiao | Hou, Can | Lv, Jun | Pei, Pei | Tan, Yunlong | Yu, Canqing | Pang, Zengchang | Gao, Ruqin | Li, Shanpeng | Wang, Shaojie | Liu, Yongmei | Du, Ranran | Zang, Yajing | Cheng, Liang | Tian, Xiaocao | Zhang, Hua | Zhai, Yaoming | Ning, Feng | Sun, Xiaohui | Li, Feifei | Lv, Silu | Wang, Junzheng | Hou, Wei | Zeng, Mingyuan | Jiang, Ge | Zhou, Xue | Yang, Liqiu | He, Hui | Yu, Bo | Li, Yanjie | Xu, Qinai | Kang, Quan | Guo, Ziyan | Wang, Dan | Hu, Ximin | Wang, Hongmei | Chen, Jinyan | Fu, Yan | Fu, Zhenwang | Wang, Xiaohuan | Weng, Min | Guo, Zhendong | Wu, Shukuan | Li, Yilei | Li, Huimei | Fu, Zhifang | Wu, Ming | Zhou, Yonglin | Zhou, Jinyi | Tao, Ran | Yang, Jie | Su, Jian | liu, Fang | Zhang, Jun | Hu, Yihe | Lu, Yan | Ma, Liangcai | Tang, Aiyu | Zhang, Shuo | Jin, Jianrong | Liu, Jingchao | Tang, Zhenzhu | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Pan, Rong | Jiang, Qilian | Lan, Jian | Liu, Yun | Wei, Liuping | Zhou, Liyuan | Chen, Ningyu | Wang, Ping | Meng, Fanwen | Qin, Yulu | Wang, Sisi | Wu, Xianping | Zhang, Ningmei | Chen, Xiaofang | Zhou, Weiwei | Luo, Guojin | Li, Jianguo | Chen, Xiaofang | Zhong, Xunfu | Liu, Jiaqiu | Sun, Qiang | Ge, Pengfei | Ren, Xiaolan | Dong, Caixia | Zhang, Hui | Mao, Enke | Wang, Xiaoping | Wang, Tao | zhang, Xi | Zhang, Ding | Zhou, Gang | Feng, Shixian | Chang, Liang | Fan, Lei | Gao, Yulian | He, Tianyou | Sun, Huarong | He, Pan | Hu, Chen | Zhang, Xukui | Wu, Huifang | He, Pan | Yu, Min | Hu, Ruying | Wang, Hao | Qian, Yijian | Wang, Chunmei | Xie, Kaixu | Chen, Lingli | Zhang, Yidan | Pan, Dongxia | Gu, Qijun | Huang, Yuelong | Chen, Biyun | Yin, Li | Liu, Huilin | Fu, Zhongxi | Xu, Qiaohua | Xu, Xin | Zhang, Hao | Long, Huajun | Li, Xianzhi | Zhang, Libo | Qiu, Zhe
Background
Self‐rated health (SRH) is a strong predictor of mortality in different populations. However, the associations between SRH measures and risk of ischemic heart disease (IHD) have not been extensively explored, especially in a Chinese population.
Methods and Results
More than 500 000 adults from 10 cities in China were followed from baseline (2004–2008) through December 31, 2013. Global and age‐comparative SRH were reported from baseline questionnaires. Incident IHD cases were identified through links to well‐established disease registry systems and the national health insurance system. During 3 423 542 person‐years of follow‐up, we identified 24 705 incident cases of IHD. In multivariable‐adjusted models, both global and age‐comparative SRH was significantly associated with incident IHD. Compared with excellent SRH, the hazard ratios for good, fair, and poor SRH were 1.02 (95% confidence interval [CI], 0.98–1.07), 1.32 (95% CI, 1.27–1.37), and 1.76 (95% CI, 1.68–1.85), respectively. Compared with better age‐comparative SRH, the hazard ratios for same and worse age‐comparative SRH were 1.23 (95% CI, 1.19–1.27) and 1.78 (95% CI, 1.70–1.86), respectively. The associations persisted in all subgroup analyses, although they were slightly modified by study location, education, and income levels.
Conclusions
A simple questionnaire for self‐assessment of health status was significantly associated with incident IHD in Chinese adults. Individuals and healthcare providers can use SRH measures as a convenient tool for assessing future IHD risk.
doi:10.1161/JAHA.117.006595
PMCID: PMC5634301  PMID: 28939702
Chinese; cohort study; ischemic heart disease; self‐rated health status; Cardiovascular Disease; Epidemiology; Risk Factors; Coronary Artery Disease
6.  Breastfeeding and the Risk of Maternal Cardiovascular Disease: A Prospective Study of 300 000 Chinese Women 
Peters, Sanne A. E. | Yang, Ling | Guo, Yu | Chen, Yiping | Bian, Zheng | Du, Jianwei | Yang, Jie | Li, Shanpeng | Li, Liming | Woodward, Mark | Chen, Zhengming | Chen, Junshi | Collins, Rory | Peto, Richard | Bennett, Derrick | Chang, Yumei | Clarke, Robert | Du, Huaidong | Fan, Xuejuan | Gilbert, Simon | Hacker, Alex | Holmes, Michael | Iona, Andri | Kartsonaki, Christiana | Kerosi, Rene | Kong, Ling | Kurmi, Om | Lancaster, Garry | Lewington, Sarah | McDonnell, John | Millwood, Iona | Nie, Qunhua | Radhakrishnan, Jayakrishnan | Rafiq, Sajjad | Ryder, Paul | Sansome, Sam | Schmidt, Dan | Sherliker, Paul | Sohoni, Rajani | Turnbull, Iain | Walters, Robin | Wang, Jenny | Wang, Lin | Yang, Xiaoming | Chen, Ge | Han, Bingyang | Hou, Can | Lv, Jun | Pei, Pei | Qu, Shuzhen | Tan, Yunlong | Yu, Canqing | Zhou, Huiyan | Pang, Zengchang | Gao, Ruqin | Wang, Shaojie | Liu, Yongmei | Du, Ranran | Zang, Yajing | Cheng, Liang | Tian, Xiaocao | Zhang, Hua | Lv, Silu | Wang, Junzheng | Hou, Wei | Yin, Jiyuan | Jiang, Ge | Liu, Shumei | Pang, Zhigang | Zhou, Xue | Yang, Liqiu | He, Hui | Yu, Bo | Li, Yanjie | Mu, Huaiyi | Xu, Qinai | Dou, Meiling | Ren, Jiaojiao | Wang, Shanqing | Hu, Ximin | Wang, Hongmei | Chen, Jinyan | Fu, Yan | Fu, Zhenwang | Wang, Xiaohuan | Dong, Hua | Weng, Min | Zheng, Xiangyang | Li, Yijun | Li, Huimei | Li, Chenglong | Wu, Ming | Zhou, Jinyi | Tao, Ran | Shen, Jie | Hu, Yihe | Lu, Yan | Gao, Yan | Ma, Liangcai | Zhou, Renxian | Tang, Aiyu | Zhang, Shuo | Jin, Jianrong | Tang, Zhenzhu | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Pan, Rong | Jiang, Qilian | Qing, Jingxin | Zhang, Weiyuan | Liu, Yun | Wei, Liuping | Zhou, Liyuan | Chen, Ningyu | Yang, Jun | Guan, Hairong | Wu, Xianping | Zhang, Ningmei | Chen, Xiaofang | Tang, Xuefeng | Luo, Guojin | Li, Jianguo | Chen, Xiaofang | Wang, Jian | Liu, Jiaqiu | Sun, Qiang | Ge, Pengfei | Ren, Xiaolan | Dong, Caixia | Zhang, Hui | Mao, Enke | Wang, Xiaoping | Wang, Tao | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Chang, Liang | Fan, Lei | Gao, Yulian | He, Tianyou | Jiang, Li | Sun, Huarong | He, Pan | Hu, Chen | Lv, Qiannan | Zhang, Xukui | Yu, Min | Hu, Ruying | Fang, Le | Wang, Hao | Qian, Yijian | Wang, Chunmei | Xie, Kaixue | Chen, Lingli | Pan, Yaxing | Pan, Dongxia | Huang, Yuelong | Chen, Biyun | Jin, Donghui | Liu, Huilin | Fu, Zhongxi | Xu, Qiaohua | Xu, Xin | g, Youping | Jia, Weifang | Li, Xianzhi | Zhang, Libo | Qiu, Zhe
Background
Breastfeeding confers substantial benefits to child health and has also been associated with lower risk of maternal cardiovascular diseases (CVDs) in later life. However, the evidence on the effects of CVD is still inconsistent, especially in East Asians, in whom the frequency and duration of breastfeeding significantly differ from those in the West.
Methods and Results
In 2004–2008, the nationwide China Kadoorie Biobank recruited 0.5 million individuals aged 30 to 79 years from 10 diverse regions across China. During 8 years of follow‐up, 16 671 incident cases of coronary heart disease and 23 983 cases of stroke were recorded among 289 573 women without prior CVD at baseline. Cox regression yielded adjusted hazard ratios (HRs) and 95% CIs for incident CVD by breastfeeding. Overall, ≈99% of women had given birth, among whom 97% reported a history of breastfeeding, with a median duration of 12 months per child. Compared with parous women who had never breastfed, ever breastfeeding was associated with a significantly lower risk of CVD, with adjusted HRs of 0.91 (95% CI, 0.84–0.99) for coronary heart disease and 0.92 (95% CI, 0.85–0.99) for stroke. Women who had breastfed for ≥24 months had an 18% (HR, 0.82; 0.77–0.87) lower risk of coronary heart disease and a 17% (HR, 0.83; 0.79–0.87) lower risk of stroke compared with women who had never breastfed. Among women who ever breastfed, each additional 6 months of breastfeeding per child was associated with an adjusted HR of 0.96 (95% CI, 0.94–0.98) for coronary heart disease and 0.97 (95% CI, 0.96–0.98) for stroke.
Conclusions
Among Chinese women, a history of breastfeeding was associated with an ≈10% lower risk of CVD in later life and the magnitude of the inverse association was stronger among those with a longer duration of breastfeeding.
doi:10.1161/JAHA.117.006081
PMCID: PMC5669201  PMID: 28637778
breastfeeding; cardiovascular disease; China; epidemiology; risk factor; women; Cardiovascular Disease; Epidemiology; Women; Risk Factors
7.  Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating Hedgehog signaling pathway in colorectal cancer 
Cell Death & Disease  2016;7(12):e2569-.
Epigenetic silencing of tumor suppressors contributes to the development and progression of colorectal cancer (CRC). We recently found that speckle-type POZ protein (SPOP) was significantly downregulated and the inactivation of SPOP promoted metastasis in CRC. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in CRC. Our results revealed that the core region of SPOP promoter was hypermethylated in CRC tissues and its methylation was correlated with poor survival. Transcription factor RXRA had a vital role in the regulation of SPOP gene. The data indicated that DNA methylation at −167 bp of the SPOP gene altered the binding affinity between transcription factor RXRA and SPOP promoter. Moreover, SPOP was found to associate with Gli2 and promoted its ubiquitination and degradation in CRC. Consequently, the expression level of Hh/Gli2 pathway-related apoptotic protein Bcl-2 was decreased and the function of resisting cell death was inhibited in CRC. It suggests that methylation status of SPOP promoter can be used as a novel epigenetic biomarker and a therapeutic target in CRC.
doi:10.1038/cddis.2016.435
PMCID: PMC5261007  PMID: 28032859
8.  NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer 
Oncotarget  2016;7(34):54983-54997.
G protein-coupled estrogen receptor (GPER) plays an important role in mediating the effects of estradiol. High levels of GPER have been implicated to associate with the malignant progress of invasive breast cancer (IBC). However, the mechanisms by which GPER protein levels were regulated remain unclear. In this study, PDZ protein Na+/H+ exchanger regulatory factor (NHERF1) was found to interact with GPER in breast cancer cells. This interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal PDZ binding motif of GPER. NHERF1 was demonstrated to facilitate GPER expression at post-transcriptional level and improve GPER protein stability by inhibiting the receptor degradation via ubiquitin-proteasome pathway in a GPER/NHERF1 interaction-dependent manner. In addition, GPER protein levels are positively associated with NHERF1 protein levels in a panel of estrogen receptor (ER)-positive breast cancer cells. Furthermore, analysis of clinical IBC data from The Cancer Genome Atlas (TCGA) showed no significant difference in GPER mRNA levels between ER-positive IBC and normal breast tissues. However, gene set enrichment analysis (GSEA) showed that GPER signaling is ultra-activated in ER-positive IBC when compared with normal and its activation is positively associated with NHERF1 mRNA levels. Taken together, our findings identify NHERF1 as a new binding partner for GPER and its overexpression promotes protein stability and activation of GPER in ER-positive IBC. Our data indicate that regulation of GPER stability by NHERF1 may contribute to GPER-mediated carcinogenesis in ER-positive IBC.
doi:10.18632/oncotarget.10713
PMCID: PMC5342396  PMID: 27448983
G protein-coupled receptor; EBP50; protein-protein interaction; protein degradation; carcinogenesis
9.  A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs 
BMC Biology  2016;14:52.
Background
Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. De novo generation of novel cis-regulatory elements (CREs) is much rarer than genomic events that alter existing CREs such as transposition, promoter switching or co-option. Only one case of de novo generation has been reported to date, in fish and without involvement of phenotype alteration. Yet, this event likely occurs in other animals and helps drive genetic/phenotypic variation.
Results
Using a porcine model of spontaneous hearing loss not previously characterized we performed gene mapping and mutation screening to determine the genetic foundation of the phenotype. We identified a mutation in the non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor (MITF) gene that generated a novel silencer. The consequent elimination of expression of the MITF-M isoform led to early degeneration of the intermediate cells of the cochlear stria vascularis and profound hearing loss, as well as depigmentation, all of which resemble the typical phenotype of Waardenburg syndrome in humans. The mutation exclusively affected MITF-M and no other isoforms. The essential function of Mitf-m in hearing development was further validated using a knock-out mouse model.
Conclusions
Elimination of the MITF-M isoform alone is sufficient to cause deafness and depigmentation. To our knowledge, this study provides the first evidence of a de novo CRE in mammals that produces a systemic functional effect.
Electronic supplementary material
The online version of this article (doi:10.1186/s12915-016-0273-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12915-016-0273-2
PMCID: PMC4922063  PMID: 27349893
De novo silencer; MITF-M; Hearing loss; Waardenburg syndrome; cis-regulatory element; Pig
10.  Expression of Notch Family Proteins in Placentas From Patients With Early-Onset Severe Preeclampsia 
Reproductive Sciences  2014;21(6):716-723.
Objectives:
This study is aimed to identify the expression of Notch family proteins in placentas from patients with early-onset severe preeclampsia.
Study Design:
The expression of Notch family proteins in placentas was investigated by immunohistochemistry, Western blotting, and real-time reverse transcription–polymerase chain reaction (RT-PCR).
Results:
The profile of distribution of all Notch family proteins in placentas from patients with early-onset severe preeclampsia is similar to that in normal placentas. All Notch family proteins are expressed in placental trophoblasts. Moreover, Notch1 and Jagged1 (Jag1) are detected in placental endothelial cells. Real-time RT-PCR showed that messenger RNA levels of Notch2 and Delta-like4 (Dll4) in placentas from patients with early-onset severe preeclampsia are lower than that of normal placentas. Western blotting showed a significant increase in Notch3 expression and a significant decrease in Notch2 expression in placentas from patients with early-onset severe preeclampsia relative to those in normal placentas.
Conclusion:
The results suggest that Notch2 and Notch3 may play some roles in the pathogenesis of preeclampsia.
doi:10.1177/1933719113512530
PMCID: PMC4016722  PMID: 24336671
Notch proteins; placenta; severe preeclampsia; early onset
11.  Effects of Notch2 and Notch3 on Cell Proliferation and Apoptosis of Trophoblast Cell Lines 
Aims: To investigate the effect of Notch2 and Notch3 on cell proliferation and apoptosis of two trophoblast cell lines, BeWo and JAR.
Methods: Notch2 and Notch3 expression in BeWo and JAR cells was upregulated or downregulated using lentivirus-mediated overexpression or RNA interference. The effect of Notch2 and Notch3 on cell proliferation was assessed by the CCK-8 assay. The effect of Notch2 and Notch3 on the apoptosis of BeWo and JAR cells was evaluated by flow cytometry using the Annexin V-PE Apoptosis kit. Lentivirus-based overexpression vectors were constructed by cloning the full-length coding sequences of human Notch2 and Notch3 C-terminally tagged with GFP or GFP alone (control) into a lentivirus-based expression vector. Lentivirus-based gene silencing vectors were prepared by cloning small interfering sequences targeting human Notch2 and Notch3 and scrambled control RNA sequence into a lentivirus-based gene knockdown vector. The effect of Notch2 and Notch3 on cell proliferation was assessed by the CCK-8 assay. And the effect of Notch2 and Notch3 on the apoptosis of BeWo and JAR cells was evaluated by flow cytometry using the Annexin V PE Apoptosis kit.
Results: We found that the downregulation of Notch2 and Notch3 gene expression in BeWo and JAR cells resulted in an increase in cell proliferation, while upregulation of Notch3 and Notch2 expression led to a decrease in cell proliferation. Moreover, the overexpression of Notch3 and Notch2 in BeWo and JAR cells reduced apoptosis in these trophoblast cell lines, whereas apoptosis was increased in the cells in which the expression of Notch3 and Notch2 was downregulated.
Conclusions: Notch2 and Notch3 inhibited both cell proliferation and cell apoptosis in BeWo and JAR trophoblast cell lines.
doi:10.7150/ijms.12935
PMCID: PMC4643077  PMID: 26640406
BeWo; JAR; Notch2; Notch3; proliferation; apoptosis
12.  Fatigue-Induced Damage in Zr-Based Bulk Metallic Glasses 
Scientific Reports  2013;3:2578.
In the present work, we investigate the effect of “fatigue” on the fatigue behavior and atomic structure of Zr-based BMGs. Fatigue experiments on the failed-by-fatigue samples indicate that the remnants generally have similar or longer fatigue life than the as-cast samples. Meanwhile, the pair-distribution-function (PDF) analysis of the as-cast and post-fatigue samples showed very small changes of local atomic structures. These observations suggest that the fatigue life of the 6-mm in-diameter Zr-based BMG is dominated by the number of pre-existing crack-initiation sites in the sample. Once the crack initiates in the specimen, the fatigue-induced damage is accumulated locally on these initiated sites, while the rest of the region deforms elastically. The results suggest that the fatigue failure of BMGs under compression-compression fatigue experiments is a defect-controlled process. The present work indicates the significance of the improved fatigue resistance with decreasing the sample size.
doi:10.1038/srep02578
PMCID: PMC3759835  PMID: 23999496
13.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
doi:10.1093/hmg/dds029
PMCID: PMC3315211  PMID: 22323360
14.  Kinematics of hip, knee, ankle of the young and elderly Chinese people during kneeling activity*  
Objective: The purpose of this study was to measure the kinematics of the lower limbs of Chinese people during normal kneeling activity, as such data could be valuable in designing joint prosthesis and arthroplasty that meet the needs of Chinese citizens’ daily activities. Methods: Thirty young and twenty elderly Chinese participants with no personal history of joint diseases were recruited, and matched by age (average age: 23.8 years for the young group, 60.8 years for the elderly group). Each participant performed six trials during which three-dimensional (3D) kinematics data were collected and the means of the 3D angles of the ankle, knee, and hip joints of two groups were calculated. Results: There were no obvious differences between the two groups in the knee and ankle joints. The mean range of knee flexion was 139.6° for the young group and 140.9° for the elderly group. The mean range of ankle flexion was 35.7° for the young group and 37.6° for the elderly group. The maximal eccentric flexion at the hip joint was 67.5° for the young group compared to 100.5° for the elderly group. Conclusions: The elderly uses more hip flexion angles than the young when assuming the kneeling posture. The ranges of motion obtained during kneeling activity are greater than the reported mean ranges of motion achieved following joint arthroplasty. The data could be valuable in establishing criteria for lower limb prosthetics and rehabilitation protocol for the Chinese population.
doi:10.1631/jzus.B1100355
PMCID: PMC3468826  PMID: 23024050
Joint angle; Kneeling; Kinematics; Chinese people
15.  Top–down fabrication of sub-nanometre semiconducting nanoribbons derived from molybdenum disulfide sheets 
Nature Communications  2013;4:1776-.
Developments in semiconductor technology are propelling the dimensions of devices down to 10 nm, but facing great challenges in manufacture at the sub-10 nm scale. Nanotechnology can fabricate nanoribbons from two-dimensional atomic crystals, such as graphene, with widths below the 10 nm threshold, but their geometries and properties have been hard to control at this scale. Here we find that robust ultrafine molybdenum-sulfide ribbons with a uniform width of 0.35 nm can be widely formed between holes created in a MoS2 sheet under electron irradiation. In situ high-resolution transmission electron microscope characterization, combined with first-principles calculations, identifies the sub-1 nm ribbon as a Mo5S4 crystal derived from MoS2, through a spontaneous phase transition. Further first-principles investigations show that the Mo5S4 ribbon has a band gap of 0.77 eV, a Young’s modulus of 300GPa and can demonstrate 9% tensile strain before fracture. The results show a novel top–down route for controllable fabrication of functional building blocks for sub-nanometre electronics.
Fabricating semiconductor devices with dimensions below 10 nm presents significant challenges. Here, Liu et al. use controlled electron irradiation to remove atoms in an MoS2 sheet, creating Mo5S4 nanoribbons with a uniform width of 0.35 nm and a theoretical band gap of 0.77 eV.
doi:10.1038/ncomms2803
PMCID: PMC3644098  PMID: 23653188
16.  Protective Effects of Leukemia Inhibitory Factor on Retinal Vasculature and Cells in Streptozotocin-induced Diabetic Mice 
Chinese Medical Journal  2018;131(1):75-81.
Background:
Leukemia inhibitory factor (LIF) has been reported to possess various pharmacological effects, including displaying vascular and neuroprotective properties, during retinal disease. The aim of this study was to investigate the vascular and structural changes in the retina of diabetic mice and to explore whether LIF prevents experimental diabetes-induced retinal injury in the early stages.
Methods:
Diabetes was induced in C57Bl/6J mice with streptozotocin (STZ) injections. Successful diabetic animal models were randomly separated into two groups: the diabetic group (n = 15) and the LIF-treated group (n = 15). Normal C57BL/6 mice served as the normal control group (n = 14). Recombinant human LIF was intravitreally injected 8 weeks after the diabetic model was successfully established. Retinas were collected and evaluated using histological and immunohistochemical techniques, and flat-mounted retinas and Western blotting were performed at 18 weeks after the induction of diabetes and 2 days after the intravitreal injection of LIF. The analysis of variance test were used.
Results:
Histological analysis showed that there were fewer retinal ganglion cells (RGCs) and the inner nuclear layer (INL) became thinner in the diabetic model group (RGC 21.8 ± 4.0 and INL 120.2 ± 4.6 μm) compared with the normal control group (RGC 29.0 ± 6.7, t = −3.02, P = 0.007; INL 150.7 ± 10.6 μm, t = −8.88, P < 0.001, respectively). After LIF treatment, the number of RGCs (26.9 ± 5.3) was significantly increased (t = 3.39, P = 0.030) and the INL (134.5 ± 14.2 μm) was thicker compared to the diabetic group (t = 2.75, P = 0.013). In the anti-Brn-3a-labeled retinas, the number of RGCs in the LIF-treated group (3926.0 ± 143.9) was obviously increased compared to the diabetic group (3507.7 ± 286.1, t = 2.38, P = 0.030), while no significance was found between the LIF-treated group and the control group (4188.3 ± 114.7, t = −2.47, P = 0.069). Flat-mounted retinas demonstrated that a disorganized, dense distribution of the vessel was prominent in the diabetic model group. Vessel distribution in the LIF-treated mouse group was typical and the thickness was uniform. The levels of phosphosignal transducer and activator of transcription 3 activation were obviously higher in the LIF-injected retinas than those in the diabetic control group (t = 3.85, P = 0.019) and the normal control (t = −3.20, P = 0.019).
Conclusion:
The present study provides evidence that LIF treatment protects the integrity of the vasculature and prevents retinal injury in the early stages of diabetic retinopathy in STZ-induced diabetic models.
doi:10.4103/0366-6999.221263
PMCID: PMC5754962  PMID: 29271384
Diabetic Retinopathy; Leukemia Inhibitory Factor; Streptozotocin-induced Diabetic Mice
17.  Outcomes of Coronary Artery Bypass Graft Surgery Versus Percutaneous Coronary Intervention in Patients Aged 18–45 Years with Diabetes Mellitus 
Chinese Medical Journal  2017;130(24):2906-2915.
Background:
Debate on treatment for young patients with coronary artery disease still exists. This study aimed to investigate the intermediate- and long-term outcomes between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients aged 18–45 years with diabetes mellitus (DM).
Methods:
Between January 2006 and March 2016, a total of 2018 DM patients aged 18–45 years including 517 cases of CABG and 1501 cases of PCI were enrolled in the study. Using propensity score matching (PSM), 406 patients were matched from each group. The intermediate- and long-term data were collected. The primary end point of this study was long-term death. The secondary end points included long-term major adverse cardiovascular and cerebrovascular events (MACCEs), stroke, angina, myocardial infarction (MI), and repeat revascularization.
Results:
Before PSM, the in-hospital mortality was 1.2% in the CABG group and 0.1% in the PCI group, with statistically significant difference (P < 0.0001). The 10-year follow-up outcomes including long-term survival rate and freedom from MACCEs were better in the CABG group than those in the PCI group (97.3% vs. 94.5%, P = 0.0072; 93.2% vs. 86.3%, P < 0.0001), but CABG group was associated with lower freedom from stoke compared to PCI group (94.2% vs. 97.5%, P = 0.0059). After propensity score-matched analysis, these findings at 10-year follow-up were also confirmed. Freedom from MACCEs was higher in CABG group compared to PCI group, but no significant difference was observed (93.1% vs. 89.2%, P = 0.0720). The freedom from recurrent MI was significantly higher in CABG patients compared with PCI patients (95.6% vs. 92.5%, P = 0.0260). Furthermore, CABG was associated with a higher rate of long-term survival rate than PCI (97.5% vs. 94.6%, P = 0.0403). There was no significant difference in the freedom from stroke between CABG and PCI groups (95.3% vs. 97.3%, P = 0.9385). The hospital cost was greater for CABG (13,936 ± 4480 US dollars vs. 10,926 ± 7376 US dollars, P < 0.0001).
Conclusions:
In DM patients aged 18–45 years, the cumulative survival rate, and freedom from MI and repeat revascularization for CABG were superior to those of PCI. However, a better trend to avoid stroke was observed with PCI.
doi:10.4103/0366-6999.220305
PMCID: PMC5742917  PMID: 29237922
Coronary Artery Bypass Grafting; Coronary Artery Disease; Diabetes Mellitus; Percutaneous Coronary Intervention
18.  Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci 
Human Molecular Genetics  2016;25(24):5500-5512.
Abstract
Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.
doi:10.1093/hmg/ddw358
PMCID: PMC5721937  PMID: 28426890
19.  A novel dynamic model for predicting outcome in patients with hepatitis B virus related acute-on-chronic liver failure 
Oncotarget  2017;8(65):108970-108980.
Aim
It is challenging to predict the outcome of patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) through existing prognostic models. Our aim was to establish a novel dynamic model to improve the predictive efficiency of 30-day mortality in HBV-ACLF patients.
Methods
305 patients who were diagnosed as HBV-ACLF (derivation cohort, n=211; validation cohort, n=94) were included in this study. The HBV-ACLF dynamic (HBV-ACLFD) model was constructed based on the daily levels of predictive variables in 7 days after diagnosis combined with baseline risk factors by multivariate logistic regression analysis. The HBV-ACLFD model was compared with the Child-Turcotte-Pugh (CTP) score, end-stage liver disease (MELD) score, and MELD within corporation of serum sodium (MELD-Na) score by the area under the receiver-operating characteristic curves (AUROC).
Results
The HBV-ACLFD model demonstrated excellent discrimination with AUROC of 0.848 in the derivation cohort and of 0.813 in the validation cohort (p=0.620). The performance of the HBV-ACLFD model appeared to be superior to MELD score, MELD-Na score and CTP score (P<0.0001).
Conclusion
The HBV-ACLFD model can accurately predict 30-day mortality in patients with HBV-ACLF, which is helpful to select appropriate clinical procedures, so as to relieve the social and economic burden.
doi:10.18632/oncotarget.22447
PMCID: PMC5752496
acute-on-chronic liver failure; hepatitis B; prognostic model
20.  A precise and consistent assay for major wall polymer features that distinctively determine biomass saccharification in transgenic rice by near-infrared spectroscopy 
Background
The genetic modification of plant cell walls has been considered to reduce lignocellulose recalcitrance in bioenergy crops. As a result, it is important to develop a precise and rapid assay for the major wall polymer features that affect biomass saccharification in a large population of transgenic plants. In this study, we collected a total of 246 transgenic rice plants that, respectively, over-expressed and RNAi silenced 12 genes of the OsGH9 and OsGH10 family that are closely associated with cellulose and hemicellulose modification. We examined the wall polymer features and biomass saccharification among 246 transgenic plants and one wild-type plant. The samples presented a normal distribution applicable for statistical analysis and NIRS modeling.
Results
Among the 246 transgenic rice plants, we determined largely varied wall polymer features and the biomass enzymatic saccharification after alkali pretreatment in rice straws, particularly for the fermentable hexoses, ranging from 52.8 to 95.9%. Correlation analysis indicated that crystalline cellulose and lignin levels negatively affected the hexose and total sugar yields released from pretreatment and enzymatic hydrolysis in the transgenic rice plants, whereas the arabinose levels and arabinose substitution degree (reverse xylose/arabinose ratio) exhibited positive impacts on the hexose and total sugars yields. Notably, near-infrared spectroscopy (NIRS) was applied to obtain ten equations for predicting biomass enzymatic saccharification and seven equations for distinguishing major wall polymer features. Most of the equations exhibited high R 2/R 2 cv/R 2 ev and RPD values for a perfect prediction capacity.
Conclusions
Due to large generated populations of transgenic rice lines, this study has not only examined the key wall polymer features that distinctively affect biomass enzymatic saccharification in rice but has also established optimal NIRS models for a rapid and precise screening of major wall polymer features and lignocellulose saccharification in biomass samples. Importantly, this study has briefly explored the potential roles of a total of 12 OsGH9 and OsGH10 genes in cellulose and hemicellulose modification and cell wall remodeling in transgenic rice lines. Hence, it provides a strategy for genetic modification of plant cell walls by expressing the desired OsGH9 and OsGH10 genes that could greatly improve biomass enzymatic digestibility in rice.
Electronic supplementary material
The online version of this article (10.1186/s13068-017-0983-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-017-0983-x
PMCID: PMC5719720
Transgenic plant; Rice; Biomass saccharification; Plant cell wall; Near infrared spectroscopy; Bioenergy
21.  Identification, expression and functional characterization of M4L, a muscarinic acetylcholine M4 receptor splice variant 
PLoS ONE  2017;12(12):e0188330.
Rodent genomic alignment sequences support a 2-exon model for muscarinic M4 receptor. Using this model a novel N-terminal extension was discovered in the human muscarinic acetylcholine M4 receptor. An open reading frame was discovered in the human, mouse and rat with a common ATG (methionine start codon) that extended the N-terminus of the muscarinic acetylcholine M4 receptor subtype by 155 amino acids resulting in a longer variant. Transcriptional evidence for this splice variant was confirmed by RNA-Seq and RT-PCR experiments performed from human donor brain prefrontal cortices. We detected a human upstream exon indicating the translation of the mature longer M4 receptor transcript. The predicted size for the longer two-exon M4 receptor splice variant with the additional 155 amino acid N-terminal extension, designated M4L is 69.7 kDa compared to the 53 kDa canonical single exon M4 receptor (M4S). Western blot analysis from a mammalian overexpression system, and saturation radioligand binding with [3H]-NMS (N-methyl-scopolamine) demonstrated the expression of this new splice variant. Comparative pharmacological characterization between the M4L and M4S receptors revealed that both the orthosteric and allosteric binding sites for both receptors were very similar despite the addition of an N-terminal extension.
doi:10.1371/journal.pone.0188330
PMCID: PMC5718406  PMID: 29211764
22.  Insulin-like growth factor-I induces chemoresistence to docetaxel by inhibiting miR-143 in human prostate cancer 
Oncotarget  2017;8(63):107157-107166.
Elevated levels of insulin-like growth factor-I (IGF-I) are associated with carcinogenesis and cancer progression. However, the molecular mechanisms by which IGF-I promotes prostate cancer development remain to be elucidated. Docetaxel chemotherapy is an important therapeutic strategy in many types of human cancers including prostate cancer. In this study, we showed that IGF-I rendered PC-3 and DU145 cells more resistant to docetaxel treatment. IGF-I treatment decreased miR-143 expression, but increased the expression levels of IGF-I receptor (IGF-IR) and insulin receptor substrate 1 (IRS1), direct targets of miR-143. Overexpression of miR-143 abolished IGF-I-induced chemoresistance to docetaxel treatment, decreased expression levels of IGF-I, IRS1, and vascular endothelial growth factor (VEGF) in prostate cancer cell lines. Furthermore, docetaxel treatment significantly inhibited VEGF transcriptional activation, whereas IGF-I treatment induced VEGF transcriptional activation in a dose-dependent manner. Forced expression of IGF-IR and IRS1 cDNAs without the 3’ UTR regions restored miR-143-inhibited VEGF transcriptional activation. Finally, miR-143 inhibited tumor growth and made cells more sensitive to docetaxel treatment for decreasing tumor growth in vivo. Taken together, our data demonstrates that IGF-I induces docetaxel resistance and upregulates IGF-IR and IRS1 expression through miR-143 downregulation, whereas miR-143 acts as a tumor suppressor by targeting its targets IGF-IR and IRS1.
doi:10.18632/oncotarget.22362
PMCID: PMC5739804
prostate cancer; docetaxel; miR-143; IGF-I; tumor growth
23.  miR-449a inhibits colorectal cancer progression by targeting SATB2 
Oncotarget  2016;8(60):100975-100988.
miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells in vitro and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR-449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development.
doi:10.18632/oncotarget.10900
PMCID: PMC5731849
colorectal cancer; miR-449a; SATB2; tumorigenesis
24.  IGF-1-mediated PKM2/β-catenin/miR-152 regulatory circuit in breast cancer 
Scientific Reports  2017;7:15897.
Dysregulation of miRNAs is important in breast cancer initiation and malignant progression. Recently we showed that miR-152 downregulation is associated with breast cancer development, yet the underlying mechanism of miR-152 remains to be well elucidated. In this study, we identified β-catenin as a new direct target of miR-152. MiR-152 inhibited cell proliferation by targeting and inhibiting both β-catenin and PKM2 expression. We found that miR-152 expression sensitized the breast cancer cells to paclitaxel treatment by inhibiting β-catenin and PKM2 expression. Intriguingly, IGF-1 induced β-catenin and PKM2 expression and enhanced β-catenin and PKM2 interaction. Subsequently, IGF-1-induced β-catenin and PKM2 complex translocated into the nucleus, which in turn activated expression of miR-152. These results suggested a regulatory circuit between miR-152, β-catenin and PKM2 in breast cancer. By using human clinical specimens, we also showed that miR-152 expression levels were negatively correlated with β-catenin and PKM2 levels in breast cancer tissues. Our findings provide new insights into a mechanism of miR-152 involved in β-catenin and PKM2 inhibition which would have clinical implication for the cancer development and new treatment option in the future.
doi:10.1038/s41598-017-15607-y
PMCID: PMC5698474  PMID: 29162853
25.  Identification of selection signals by large-scale whole-genome resequencing of cashmere goats 
Scientific Reports  2017;7:15142.
Inner Mongolia and Liaoning cashmere goats are two outstanding Chinese multipurpose breeds that adapt well to the semi-arid temperate grassland. These two breeds are characterized by their soft cashmere fibers, thus making them great models to identify genomic regions that are associated with cashmere fiber traits. Whole-genome sequencing of 70 cashmere goats produced more than 5.52 million single-nucleotide polymorphisms and 710,600 short insertions and deletions. Further analysis of these genetic variants showed some population-specific molecular markers for the two cashmere goat breeds that are otherwise phenotypically similar. By analyzing F ST and θπ outlier values, we identified 135 genomic regions that were associated with cashmere fiber traits within the cashmere goat populations. These selected genomic regions contained genes, which are potential involved in the production of cashmere fiber, such as FGF5, SGK3, IGFBP7, OXTR, and ROCK1. Gene ontology enrichment analysis of identified short insertions and deletions also showed enrichment in keratinocyte differentiation and epidermal cell differentiation. These findings demonstrate that this genomic resource will facilitate the breeding of cashmere goat and other Capra species in future.
doi:10.1038/s41598-017-15516-0
PMCID: PMC5680388  PMID: 29123196

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