Publications by authors named "Zehua Bian"

38 Publications

MG53 suppresses NF-κB activation to mitigate age-related heart failure.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Department of Surgery, Division of Cardiac Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
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http://dx.doi.org/10.1172/jci.insight.148375DOI Listing
September 2021

Dinitrophenol-mediated modulation of an anti-PD-L1 VHH for Fc-dependent effector functions and prolonged serum half-life.

Eur J Pharm Sci 2021 Oct 10;165:105941. Epub 2021 Jul 10.

Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China. Electronic address:

Single-domain antibodies, VHHs or nanobodies, represent a promising set of alternatives to conventional therapeutic antibodies, gaining substantial attention in the field of cancer immunotherapy. However, inherent drawbacks of nanobodies such as fast clearance from blood circulation and lack of immune effector functions often led to unsatisfactory therapeutic efficacy. We previously reported that dinitrophenyl modification of an anti-EGFR VHH conferred Fc-dependent immune effector functions and elongated serum half-life on it through recruiting of hapten antibodies, resulting in improved immunotherapy efficacy in vivo. In the present work, we further tested the versatility of this approach in the case of an anti-PD-L1 blockade VHH (KN035). Site-specific dinitrophenyl conjugation did not impair the binding capacity of KN035 portion to PD-L1, but indirectly restored its immune effector functions, manifested by the observed antibody dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against PD-L1 positive tumor cells. Significant delay of blood clearance of dinitrophenylated KN035 was evidenced by the prolonged half-life of ca. 22 h. This approach, using small hapten molecule conjugation, loaded additional antibody-mediated tumor killing mechanisms to PD-L1 blockade VHH and therefore improved efficacy is anticipated in the future in vivo therapeutic studies. Thus, our results underscore the power of this versatile approach for achieving desirable properties of VHH-based or similar therapeutics.
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http://dx.doi.org/10.1016/j.ejps.2021.105941DOI Listing
October 2021

Long noncoding RNA MCM3AP-AS1 enhances cell proliferation and metastasis in colorectal cancer by regulating miR-193a-5p/SENP1.

Cancer Med 2021 04 8;10(7):2470-2481. Epub 2021 Mar 8.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.

Background: Accumulating evidences have shown that long noncoding RNAs (lncRNAs) play key roles in many diseases, including cancer. Several studies reported that MCM3AP antisense RNA 1 (MCM3AP-AS1) was associated with the tumorigenesis and progression. However, the specific function and mechanism of MCM3AP-AS1 in colorectal cancer (CRC) have not been fully understood.

Methods: The expression of MCM3AP-AS1 was detected by quantitative reverse transcription PCR (RT-qPCR) in CRC tissues and matched noncancerous tissues (NCTs). CCK-8 assay, colony formation assay, transwell assay, xenograft and lung metastasis mouse models were used to examine the tumor-promoting function of MCM3AP-AS1 in vitro and in vivo. The binding relationship between MCM3AP-AS1, miR-193a-5p and sentrin-specific peptidase 1 (SENP1) were screened and identified by databases, RT-qPCR, dual luciferase reporter assay and western blot.

Results: In the present study, we got that the expression of MCM3AP-AS1 was higher in CRC tissues than in paired NCTs, and increased MCM3AP-AS1 expression was associated with adverse outcomes in CRC patients. Functional experiments in vitro revealed that silencing of MCM3AP-AS1 could inhibit the proliferation, colony formation, migratory, and invasive abilities of CRC cells. The mouse models of xenograft and lung metastasis further confirmed that in vivo silencing MCM3AP-AS1 could significantly inhibit the growth and metastasis of CRC. Further mechanism studies indicated that MCM3AP-AS1 could sponge miR-193a-5p and inhibit the activity of it. What is more, SENP1 was proved to be a novel target of miR-193a-5p and could be upregulated by MCM3AP-AS1. At last, we observed that SENP1 overexpression in CRC tissues was closely related to unfavorable prognosis.

Conclusion: Taken together, we identified in CRC the MCM3AP-AS1/miR-193a-5p/SENP1 regulatory axis, which affords a therapeutic possibility for CRC.
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http://dx.doi.org/10.1002/cam4.3830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982620PMC
April 2021

Comprehensive ceRNA network analysis and experimental studies identify an IGF2-AS/miR-150/IGF2 regulatory axis in colorectal cancer.

Pathol Res Pract 2020 Oct 16;216(10):153104. Epub 2020 Jul 16.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China; Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, China. Electronic address:

Recently, a growing body of studies has demonstrated that long non-coding RNA (lncRNA) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression and play essential roles in tumor initiation and progression. In the present study, we constructed a competitive endogenous RNA (ceRNA) network and identified potential regulatory axes in colorectal cancer (CRC) through both bioinformation and experimental validation. Firstly, we obtained differentially expressed (DE) lncRNAs, miRNAs, and mRNAs by analyzing the RNA expression profiles of CRC retrieved from The Cancer Genome Atlas (TCGA) database and CRC patients' data from affiliated Hospital of Jiangnan University, respectively. Then, we established a ceRNA regulatory network of CRC that includes 23 lncRNAs, 7 miRNAs and 244 mRNAs. To further identify these lncRNA-miRNA-mRNA regulatory axes which might play vital roles in CRC tumorigenesis and prognosis, we performed additional analyses using comprehensive bioinformatic methods. Several ceRNA regulatory axes, which consist of 2 lncRNAs, 2 miRNAs and 5 mRNAs, were obtained from the network. Finally, the interactions and correlations among these ceRNA networks were validated by experiments on CRC cell lines and clinical tumor tissues, and a potential IGF2-AS/miR-150/IGF2 axis that perfectly conform to the ceRNA theory was determined. According to the qRT-PCR results, miR-150 overexpression remarkably decreased IGF2-AS and IGF2 expression. Meanwhile, IGF2-AS expression was positively correlated with IGF2 expression in tumor tissue of CRC patients. Besides, dual luciferase reporter assays indicated that miR-150 could bound to IGF2-AS and the 3'UTR of and IGF2. In general, the constructed novel IGF2-AS/miR-150/IGF2 network might provide potential mechanisms of CRC development, and could act as a promising target for CRC treatment.
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http://dx.doi.org/10.1016/j.prp.2020.153104DOI Listing
October 2020

Exosome-mediated delivery of miR-204-5p inhibits tumor growth and chemoresistance.

Cancer Med 2020 08 2;9(16):5989-5998. Epub 2020 Jul 2.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.

Background: Nano-sized extracellular vesicles secreted by cells play key roles in intercellular crosstalk, and appear to be an excellent biocompatible material as therapeutic cargoes in vivo. Previously, we have demonstrated that miR-204-5p is a key tumor suppressor that could inhibit tumor growth, metastasis and chemoresistance.

Methods: A HEK293T cell line stably expressing miR-204-5p (293T-miR-204) was constructed by lentivirus transduction. Fluorescence real-time quantitative PCR (qPCR) was applied to measure the expression of miR-204-5p. CCK-8 and colony formation assays were used to evaluate the in vitro anticancer effects, and the flow cytometry was used to detect apoptosis. The in vivo therapeutic effects of exosomal miR-204-5p were evaluated using a xenograft mouse model. Western blots were used to detect the protein levels of CD63, Flotillin-2, RAB22A and Bcl2. The protein levels of RAB22A and Bcl2 in tumor tissues were measured by immunohistochemistry staining.

Results: MiR-204-5p was clearly upregulated in CRC cells after coculturing with 293T-miR-204 cell-derived conditioned medium (CM) or exosomes. CCK-8 and colony formation assays showed that the cell proliferation ability of CRC cells was clearly inhibited by 293T-miR-204 cell-derived CM or exosomes. The inhibitory effects of exosomal miR-204-5p on cell proliferation were further confirmed in other types of cancers. Exosomal miR-204-5p could induce apoptosis and increase the sensitivity of cancer cells to the chemotherapeutic drug-5-fluorourcil. In addition, exosomal miR-204-5p inhibited the tumor growth in mice. Western blot assay and IHC staining showed that the protein levels of miR-204-5p targets were clearly decreased in cancer cells or xenograft tissues treated with exosomal miR-204-5p.

Conclusions: In this study, we confirmed that exosomal miR-204-5p could efficiently inhibit cancer cell proliferation, induce apoptosis and increase chemosensitivity by specifically suppressing the target genes of miR-204-5p in human cancer cells.
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http://dx.doi.org/10.1002/cam4.3248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433811PMC
August 2020

MG53 Does Not Manifest the Development of Diabetes in Mice.

Diabetes 2020 05 5;69(5):1052-1064. Epub 2020 Mar 5.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH

MG53 is a member of the TRIM protein family that is predominantly expressed in striated muscles and participates in cell membrane repair. Controversy exists regarding MG53's role in insulin signaling and manifestation of diabetes. We generated mice with either whole-body ablation or sustained elevation of MG53 in the bloodstream in order to evaluate the physiological function of MG53 in diabetes. To quantify the amount of MG53 protein in circulation, we developed a monoclonal antibody against MG53 with high specificity. Western blot using this antibody revealed lower or no change of serum MG53 levels in mice or patients with diabetes compared with control subjects. Neither whole-body ablation of MG53 nor sustained elevation of MG53 in circulation altered insulin signaling and glucose handling in mice. Instead, mice with ablation of MG53 were more susceptible to streptozotocin-induced dysfunctional handling of glucose compared with the wild-type littermates. Alkaline-induced corneal injury demonstrated delayed healing in mice, which was restored by topical administration of recombinant human (rh)MG53. Daily intravenous administration of rhMG53 in rats at concentrations up to 10 mg/kg did not produce adverse effects on glucose handling. These findings challenge the hypothetical function of MG53 as a causative factor for the development of diabetes. Our data suggest that rhMG53 is a potentially safe and effective biologic to treat diabetic oculopathy in rodents.
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http://dx.doi.org/10.2337/db19-0807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171965PMC
May 2020

An Integrated Three-Long Non-coding RNA Signature Predicts Prognosis in Colorectal Cancer Patients.

Front Oncol 2019 22;9:1269. Epub 2019 Nov 22.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China.

Colorectal cancer (CRC) is one of the most common cancers worldwide, whose morbidity and mortality gradually increased. Here, we aimed to identify and access prognostic long non-coding RNAs (lncRNAs) associated with overall survival (OS) in CRC. Firstly, RNA expression profiles were obtained from The Cancer Genome Atlas (TCGA) database, and 439 CRC patients were enrolled as a training set. Univariate Cox analysis and the least absolute shrinkage and selection operator analysis (LASSO) were performed to identify the prognostic lncRNAs. Multivariable Cox regression analysis was used to establish a prognostic risk formula including three lncRNAs (AP003555.2, AP006284.1, and LINC01602). The low-risk group had a better OS than the high-risk group ( < 0.0001), and the areas under the receiver operating characteristic curve (AUCs) of 3- and 5-year OS were 0.712 and 0.674, respectively. Then, we evaluated the signature in a clinical validation set which were collected from the Affiliated Hospital of Jiangnan University. Compared with the low-risk group, patients' OS were found to be significantly worse in the high-risk group ( = 0.0057). The AUCs of 3- and 5-year OS were 0.701 and 0.694, respectively. Finally, we constructed an lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network to explore the potential function of three differentially expressed lncRNAs (DElncRNAs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these DElncRNAs were involved with several cancer-related pathways. In summary, our data provide evidence that the three-lncRNA signature could serve as an independent biomarker to predict prognosis in CRC. This study will also suggest that these three lncRNAs potentially participate in the progression of CRC.
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http://dx.doi.org/10.3389/fonc.2019.01269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883412PMC
November 2019

Sustained elevation of MG53 in the bloodstream increases tissue regenerative capacity without compromising metabolic function.

Nat Commun 2019 10 11;10(1):4659. Epub 2019 Oct 11.

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA.

MG53 is a muscle-specific TRIM-family protein that presides over the cell membrane repair response. Here, we show that MG53 present in blood circulation acts as a myokine to facilitate tissue injury-repair and regeneration. Transgenic mice with sustained elevation of MG53 in the bloodstream (tPA-MG53) have a healthier and longer life-span when compared with littermate wild type mice. The tPA-MG53 mice show normal glucose handling and insulin signaling in skeletal muscle, and sustained elevation of MG53 in the bloodstream does not have a deleterious impact on db/db mice. More importantly, the tPA-MG53 mice display remarkable dermal wound healing capacity, enhanced muscle performance, and improved injury-repair and regeneration. Recombinant human MG53 protein protects against eccentric contraction-induced acute and chronic muscle injury in mice. Our findings highlight the myokine function of MG53 in tissue protection and present MG53 as an attractive biological reagent for regenerative medicine without interference with glucose handling in the body.
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http://dx.doi.org/10.1038/s41467-019-12483-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789113PMC
October 2019

Long non-coding RNA IQCJ-SCHIP1 antisense RNA 1 is downregulated in colorectal cancer and inhibits cell proliferation.

Ann Transl Med 2019 May;7(9):198

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi 214062, China.

Background: IQCJ-SCHIP1 antisense RNA 1 (IQCJ-SCHIP1-AS1) was a functional novel long non-coding RNA (lncRNA) revealed by our previous expression profile. In this study, we aim to investigate its clinical relevance and biological significance in colorectal cancer (CRC).

Methods: We measured the expression levels of IQCJ-SCHIP1-AS1 in 86 paired CRC tissues using quantitative RT-PCR assay, and then analyzed its association with patient prognoses. Moreover, gain-of-function and loss-of-function studies were performed to examine the biological functions of IQCJ-SCHIP1-AS1. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to elucidate potential mechanisms of IQCJ-SCHIP1-AS1 in CRC.

Results: More than 2-fold decreased expression of IQCJ-SCHIP1-AS1 was found in half of CRC tissues (53.5%, 46/86). IQCJ-SCHIP1-AS1 down-regulation was correlated with poor differentiation (P=0.025), advanced depth of tumor (P=0.022), lymphatic invasion (P=0.010), advanced tumor stage (P=0.006), and poor prognosis (P=0.0027) in CRC patients. The Cox proportional hazards model demonstrated that IQCJ-SCHIP1-AS1 expression was an independent prognostic factor for CRC (HR =0.247, 95% CI: 0.081-0.752, P=0.014). Moreover, knockdown of IQCJ-SCHIP1-AS1 promoted CRC cell proliferation through increasing cell cycle progression and impairing cell apoptosis. Additionally, bioinformatics analysis showed that differential expression genes in IQCJ-SCHIP1-AS1-depleted CRC cells were enriched in the pathways of cell cycle, DNA replication, and p53.

Conclusions: Our results demonstrate that IQCJ-SCHIP1-AS1 has an indicative tumor suppressor role and appears to be a potential prognostic factor in CRC for the first time.
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http://dx.doi.org/10.21037/atm.2019.04.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545302PMC
May 2019

A panel of serum exosomal microRNAs as predictive markers for chemoresistance in advanced colorectal cancer.

Cancer Chemother Pharmacol 2019 08 14;84(2):315-325. Epub 2019 May 14.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi, 214062, Jiangsu, China.

Background: Chemoresistance is a common problem for cancer treatment worldwide. Circulating exosomal microRNAs (miRNAs) have been considered as promising biomarkers of cancers. However, few studies have assessed the relationship between serum/plasma exosomal microRNAs and chemoresistance in colorectal cancer (CRC).

Methods: Based on previous microarray analysis, we selected 30 miRNAs which are aberrantly expressed during CRC progression and then detected their expression levels in three pairs of oxaliplatin/5-fluorouracil-resistant CRC cell lines and the corresponding secreted exosomes. Six candidate exosomal miRNAs were identified for further evaluating potential value in predicting chemotherapeutic effect in advanced CRC patients. Finally, the molecular mechanisms of these miRNAs in drug resistance were explored by bioinformatics preliminarily.

Results: We observed that the expression of 14 miRNAs was significantly higher in three drug-resistant CRC cells comparing with their parental cells. Among these miRNAs, miR-21-5p, miR-1246, miR-1229-5p, miR-135b, miR-425 and miR-96-5p are also up-regulated in exosomes from culture media of resistant cells. Clinical sample analysis confirmed that the expression levels of miR-21-5p, miR-1246, miR-1229-5p and miR-96-5p in serum exosomes were significantly higher in chemoresistant patients in contrast with chemosensitive controls. ROC curve showed that the combination of the four miRNAs had an area of under the curve (AUC) of 0.804 (P < 0.05). In addition, GO analysis and KEGG pathway analysis revealed that these miRNAs were enriched in PI3K-Akt signaling pathway, FoxO signaling pathway and autophagy pathway.

Conclusions: Our study demonstrates that a panel of serum exosomal miRNAs containing miR-21-5p, miR-1246, miR-1229-5p and miR-96-5p could significantly distinguish the chemotherapy-resistant group from advanced colorectal cancer patients. Targeting these miRNAs may promote chemosensitivity to oxaliplatin and 5-fluorouracil, and might be promising strategy for CRC treatment.
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http://dx.doi.org/10.1007/s00280-019-03867-6DOI Listing
August 2019

LncRNA-SNHG15 enhances cell proliferation in colorectal cancer by inhibiting miR-338-3p.

Cancer Med 2019 05 3;8(5):2404-2413. Epub 2019 Apr 3.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.

The incidence and death rate of colorectal cancer (CRC) is very high, which brings great need to understand the early molecular events of CRC. These studies demonstrate that long noncoding RNA (lncRNA) plays an important role in the occurrence and development of human cancer. Small nucleolar RNA host gene 15 (SNHG15) was recently identified as a cancer-related lncRNA. In this study, we aimed to evaluate the function and mechanism of SNHG15 in CRC. The expression of SNHG15 was detected by quantitative RT-PCR (qRT-PCR) in CRC tissues and matched noncancerous tissues (NCTs). CCK-8 assay, colony formation assay, flow cytometric analysis, and nude mouse xenograft mode were used to examine the tumor-promoting function of SNHG15 in vitro and in vivo. The binding relationship between SNHG15, miR-338-3p and the target genes of miR-338-3p were screened and identified by databases, qRT-PCR, dual luciferase reporter assay and western blot. Our results showed that SNHG15 was up-regulated in CRC tissues compared with paired NCTs (P < 0.0001). High level of SNHG15 expression predicted poor prognosis of CRC (P = 0.0051). SNHG15 overexpression could promote cell proliferation and inhibit cell apoptosis. Animal experiments showed that up-regulation of SNHG15 promoted tumor growth in vivo. The results of mechanism experiments showed that SNHG15 could bind to miR-338-3p and block its inhibition on the expression and activity of FOS or RAB14. In conclusion SNHG15 promotes cell proliferation through SNHG15/miR-338-3p/FOS-RAB14 axis in CRC.
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http://dx.doi.org/10.1002/cam4.2105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536931PMC
May 2019

Correction: Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR-139-5p.

Oncogenesis 2018 08 16;7(8):63. Epub 2018 Aug 16.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.

This article was originally published under Nature Research's License to Publish, but now has been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41389-018-0067-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095883PMC
August 2018

LncRNA-FEZF1-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling.

Clin Cancer Res 2018 10 18;24(19):4808-4819. Epub 2018 Jun 18.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.

Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, FEZF1-AS1, a highly overexpressed lncRNA in colorectal cancer, was identified by lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of FEZF1-AS1 in colorectal cancer. LncRNA expression in colorectal cancer tissues was measured by lncRNA microarray and qRT-PCR. The functional roles of FEZF1-AS1 in colorectal cancer were demonstrated by a series of and experiments. RNA pull-down, RNA immunoprecipitation and luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1. We identified a series of differentially expressed lncRNAs in colorectal cancer using lncRNA microarrays, and revealed that FEZF1-AS1 is one of the most overexpressed. Further validation in two expanded colorectal cancer cohorts confirmed the upregulation of FEZF1-AS1 in colorectal cancer, and revealed that increased FEZF1-AS1 expression is associated with poor survival. Functional assays revealed that FEZF1-AS1 promotes colorectal cancer cell proliferation and metastasis. Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling. In addition, PKM2 was upregulated in colorectal cancer tissues and correlated with FEZF1-AS1 expression and patient survival. Together, these data provide mechanistic insights into the regulation of FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2967DOI Listing
October 2018

Up-regulated expression of SNHG6 predicts poor prognosis in colorectal cancer.

Pathol Res Pract 2018 May 3;214(5):784-789. Epub 2018 Jan 3.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China; Cancer Epigenetics Program, Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, China. Electronic address:

Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumor formation and development. Small nucleolar RNA host gene 6 (SNHG6) is a recently identified cancer-related lncRNA, and its role in colorectal cancer (CRC) remains to be explored. The aim of this study was to evaluate the expression and function of SNHG6 in CRC. The expression of SNHG6 was detected by real time quantitative RT-PCR (qRT-PCR) in 74 CRC tissues and matched noncancerous tissues (NCTs). Relationships between the expression levels of SNHG6 and various clinicopathological features were analyzed by Chi-square test. The Kaplan-Meier method and log-rank test were applied to compare the survival distribution between different groups. CCK8 assay and colony formation assay were used to measure the effect of SNGH6 on cell proliferation. Flow cytometric analysis was performed to measure the effect of SNHG6 on cell cycle and apoptosis. Our results showed that SNHG6 was up-regulated more than 1.5-fold in 50.0% (37/74) of CRC tissues compared with paired NCTs (P < 0.0001). High level of SNHG6 expression was strongly associated with advanced tumor stage (P = 0.026) and predicted poor prognosis of CRC (P = 0.0215). The Cox proportional hazards model demonstrated that SNHG6 expression was an independent prognostic factor for CRC (HR, 2.568; 95% CI, 1.055-6.252; P = 0.038). Furthermore, SNHG6 knockdown by siRNA could inhibit cell proliferation, cell cycle progression, and induce apoptosis. Taken together, SNHG6 functions as an oncogene in CRC and appears as a novel prognositic factor for CRC patients.
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http://dx.doi.org/10.1016/j.prp.2017.12.014DOI Listing
May 2018

Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR-139-5p.

Oncogenesis 2017 Nov 28;6(11):395. Epub 2017 Nov 28.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.

Long intergenic non-coding RNA 152 (LINC00152) is a recently identified tumor-promoting long non-coding RNA. However, the biological functions of LINC00152 in colorectal cancer (CRC) remain unclear and require further research. The aim of the present study is to explore the roles of LINC00152 in cellular function and its possible molecular mechanism. In this study, we discovered that LINC00152 was overexpressed in CRC tissues and negatively related to the survival time of CRC patients. Functional analyses revealed that LINC00152 could promote cell proliferation. Furthermore, LINC00152 could increase the resistance of CRC cells to 5-fluorouracil (5-FU) by suppressing apoptosis. We also discovered that LINC00152 could enhance cell migration and invasion. Mechanistic studies demonstrated that LINC00152 could regulate the expression of NOTCH1 through sponging miR-139-5p and inhibiting its activity from promoting CRC progression and development. Altogether, our work points out a novel LINC00152/miR-139-5p/NOTCH1 regulatory axis in CRC progression and development.
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http://dx.doi.org/10.1038/s41389-017-0008-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868057PMC
November 2017

The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6.

Clin Cancer Res 2017 Dec 19;23(23):7375-7387. Epub 2017 Sep 19.

Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China.

Tumor-associated macrophages (TAMs) are frequently associated with poor prognosis in human cancers. However, the effects of TAMs in colorectal cancer are contradictory. We therefore investigated the functions, mechanisms, and clinical significance of TAMs in colorectal cancer. We measured the macrophage infiltration (CD68), P-gp, and Bcl2 expression in colorectal cancer tissues using IHC staining. Coculture of TAMs and colorectal cancer cells both and models was used to evaluate the effects of TAMs on colorectal cancer chemoresistance. Cytokine antibody arrays, ELISA, neutralizing antibody, and luciferase reporter assay were performed to uncover the underlying mechanism. TAM infiltration was associated with chemoresistance in patients with colorectal cancer. Colorectal cancer-conditioned macrophages increased colorectal cancer chemoresistance and reduced drug-induced apoptosis by secreting IL6, which could be blocked by a neutralizing anti-IL6 antibody. Macrophage-derived IL6 activated the IL6R/STAT3 pathway in colorectal cancer cells, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-204-5p. Rescue experiment confirmed that miR-204-5p is a functional target mediating the TAM-induced colorectal cancer chemoresistance. miR-155-5p, a key miRNA regulating C/EBPβ, was frequently downregulated in TAMs, resulting in increased C/EBPβ expression. C/EBPβ transcriptionally activated IL6 in TAMs, and TAM-secreted IL6 then induced chemoresistance by activating the IL6R/STAT3/miR-204-5p pathway in colorectal cancer cells. Our data indicate that the maladjusted miR-155-5p/C/EBPβ/IL6 signaling in TAMs could induce chemoresistance in colorectal cancer cells by regulating the IL6R/STAT3/miR-204-5p axis, revealing a new cross-talk between immune cells and tumor cells in colorectal cancer microenvironment. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1283DOI Listing
December 2017

miR-139-5p sensitizes colorectal cancer cells to 5-fluorouracil by targeting NOTCH-1.

Pathol Res Pract 2016 Jul 3;212(7):643-9. Epub 2016 May 3.

Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China. Electronic address:

Multidrug resistance (MDR), a phenomenon that often occurs with drug treatment and is characterized by relapse or attenuation of drug efficacy, is almost unavoidable in colorectal cancer (CRC) patients receiving 5-fluorouracil (5-FU)-based chemotherapy. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression. Our previous study has identified miR-139-5p as a potential tumor suppressor in CRC, but its role in chemoresistance of CRC has not been elucidated. In this study, we demonstrated that miR-139-5p was down-regulated either in CRC tumors receiving chemotherapy or in 5-FU-resistant CRC cell lines (HCT-8/5-FU and HCT-116/5-FU). Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells. Taken together, our data indicate a new role of miR-139-5p/NOTCH-1 pathway in the drug resistance of CRC cells to 5-FU, which may be a promising therapeutic target for the anti-MDR treatment of CRC.
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http://dx.doi.org/10.1016/j.prp.2016.04.011DOI Listing
July 2016

LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.

Sci Rep 2016 Apr 5;6:23892. Epub 2016 Apr 5.

Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.

Recent preliminary studies reported the in vitro tumor-promoting effects of long non-coding RNA urothelial carcinoma associated 1 (UCA1) in colorectal cancer (CRC). However, the in vivo functions and molecular mechanism of UCA1 in CRC remain unclear. Therefore, we investigated the detailed role and mechanism of UCA1 in CRC. We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Functional assays revealed the in vitro and in vivo growth-promoting function of UCA1 and revealed that UCA1 can decrease the sensitivity of CRC cells to 5-FU by attenuating apoptosis. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.
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http://dx.doi.org/10.1038/srep23892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820696PMC
April 2016

MG53 permeates through blood-brain barrier to protect ischemic brain injury.

Oncotarget 2016 Apr;7(16):22474-85

Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing Institute of Cardiology, Chongqing, P.R. China.

Ischemic injury to neurons represents the underlying cause of stroke to the brain. Our previous studies identified MG53 as an essential component of the cell membrane repair machinery. Here we show that the recombinant human (rh)MG53 protein facilitates repair of ischemia-reperfusion (IR) injury to the brain. MG53 rapidly moves to acute injury sites on neuronal cells to form a membrane repair patch. IR-induced brain injury increases permeability of the blood-brain-barrier, providing access of MG53 from blood circulation to target the injured brain tissues. Exogenous rhMG53 protein can protect cultured neurons against hypoxia/reoxygenation-induced damages. Transgenic mice with increased levels of MG53 in the bloodstream are resistant to IR-induced brain injury. Intravenous administration of rhMG53, either prior to or after ischemia, can effectively alleviate brain injuries in rats. rhMG53-mediated neuroprotection involves suppression of apoptotic neuronal cell death, as well as activation of the pro-survival RISK signaling pathway. Our data indicate a physiological function for MG53 in the brain and suggest that targeting membrane repair or RISK signaling may be an effective means to treat ischemic brain injury.
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http://dx.doi.org/10.18632/oncotarget.7965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008374PMC
April 2016

Sundew-Inspired Adhesive Hydrogels Combined with Adipose-Derived Stem Cells for Wound Healing.

ACS Appl Mater Interfaces 2016 Jan 12;8(3):2423-34. Epub 2016 Jan 12.

711th Human Performance Wing, Air Force Research Laboratory , Wright-Patterson AFB, Ohio 45433-7901, United States.

The potential to harness the unique physical, chemical, and biological properties of the sundew (Drosera) plant's adhesive hydrogels has long intrigued researchers searching for novel wound-healing applications. However, the ability to collect sufficient quantities of the sundew plant's adhesive hydrogels is problematic and has eclipsed their therapeutic promise. Inspired by these natural hydrogels, we asked if sundew-inspired adhesive hydrogels could overcome the drawbacks associated with natural sundew hydrogels and be used in combination with stem-cell-based therapy to enhance wound-healing therapeutics. Using a bioinspired approach, we synthesized adhesive hydrogels comprised of sodium alginate, gum arabic, and calcium ions to mimic the properties of the natural sundew-derived adhesive hydrogels. We then characterized and showed that these sundew-inspired hydrogels promote wound healing through their superior adhesive strength, nanostructure, and resistance to shearing when compared to other hydrogels in vitro. In vivo, sundew-inspired hydrogels promoted a "suturing" effect to wound sites, which was demonstrated by enhanced wound closure following topical application of the hydrogels. In combination with mouse adipose-derived stem cells (ADSCs) and compared to other therapeutic biomaterials, the sundew-inspired hydrogels demonstrated superior wound-healing capabilities. Collectively, our studies show that sundew-inspired hydrogels contain ideal properties that promote wound healing and suggest that sundew-inspired-ADSCs combination therapy is an efficacious approach for treating wounds without eliciting noticeable toxicity or inflammation.
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http://dx.doi.org/10.1021/acsami.5b11811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139680PMC
January 2016

Systematic analysis of key miRNAs and related signaling pathways in colorectal tumorigenesis.

Gene 2016 Mar 9;578(2):177-84. Epub 2015 Dec 9.

Wuxi Oncology Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China. Electronic address:

The development of colorectal cancers (CRC) is accompanied with the acquisition and maintenance of specific genomic alterations. These alterations can emerge in premalignant adenomas and faithfully maintained in highly advanced tumors. miRNAs are a class of small non-coding RNAs that are frequently deregulated in human cancers and negatively regulate a wide variety of protein coding genes. To identify the sequential alterations of miRNAs and its regulatory networks during CRC development and progression, we detected the miRNA expression profiles of tissue samples from normal colon, colorectal adenoma and CRC using miRNA microarray. qRT-PCR assay was used to validate and select the miRNAs with differential expression among the three groups, and the computer-aided algorithms of TargetScan, miRanda, miRwalk, RNAhybrid and PicTar were used to search for the possible targets of the selected 8 miRNAs (miR-18a, miR-18b, miR-31, miR-142-5p, miR-145, miR-212, miR-451, and miR-638) with continuous alterated expression. These potential target genes were enriched in several key signal transduction pathways (KEGG pathway analysis), which have been proved to be closely related to colorectal tumorigenesis. To confirm the reliability of the analyses, we identified that the metastasis-related gene ZO-1 is a certain target of miR-212 in CRC and keeps declining during CRC progression. By following these analyses, we might gain an in-depth understanding of the molecular regulatory networks of colorectal tumorigenesis and provide new potential targets for the diagnostic and therapeutic interventions of this disease.
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http://dx.doi.org/10.1016/j.gene.2015.12.015DOI Listing
March 2016

Down-regulation of SNX1 predicts poor prognosis and contributes to drug resistance in colorectal cancer.

Tumour Biol 2016 May 7;37(5):6619-25. Epub 2015 Dec 7.

Wuxi Oncology Institute, The Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi, Jiangsu, 214062, China.

As a potential tumor suppressor, the detailed clinical application value of sorting nexin 1 (SNX1) has not been elucidated in colorectal cancer (CRC). The aim of the present study was to evaluate the expression of SNX1 in CRC tissues and to determine its correlation with clinicopathologic characteristics and its impact on patient's prognosis. We detected the expression of SNX1 mRNA in 72 CRC patients and SNX1 protein in 237 CRC patients by real-time polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. Relationship between the expression of SNX1 and various clinicopathological features in these patients was evaluated. Both the mRNA and protein expression of SNX1 were remarkably decreased in CRC tissues compared with paired non-cancerous tissues, and the down-regulation of SNX1 protein was strongly associated with poor differentiation and poor overall survival (OS) rate of CRC patients. Ectopic SNX1 expression repressed CRC cell growth and promoted tumor sensitivity to most commonly used chemotherapeutic drugs (oxaliplatin and 5-Fluorouracil). In conclusion, overexpression of SNX1 may serve as a new therapeutic strategy for CRC.
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http://dx.doi.org/10.1007/s13277-015-3814-3DOI Listing
May 2016

Prion Protein Protects against Renal Ischemia/Reperfusion Injury.

PLoS One 2015 1;10(9):e0136923. Epub 2015 Sep 1.

Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Department of Urology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province, The People's Republic of China; National Prion Disease Pathology Surveillance Center, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; Department of Neurology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; National Center for Regenerative Medicine, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, United States of America; State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, The People's Republic of China.

The cellular prion protein (PrPC), a protein most noted for its link to prion diseases, has been found to play a protective role in ischemic brain injury. To investigate the role of PrPC in the kidney, an organ highly prone to ischemia/reperfusion (IR) injury, we examined wild-type (WT) and PrPC knockout (KO) mice that were subjected to 30-min of renal ischemia followed by 1, 2, or 3 days of reperfusion. Renal dysfunction and structural damage was more severe in KO than in WT mice. While PrP was undetectable in KO kidneys, Western blotting revealed an increase in PrP in IR-injured WT kidneys compared to sham-treated kidneys. Compared to WT, KO kidneys exhibited increases in oxidative stress markers heme oxygenase-1, nitrotyrosine, and Nε-(carboxymethyl)lysine, and decreases in mitochondrial complexes I and III. Notably, phosphorylated extracellular signal-regulated kinase (pERK) staining was predominantly observed in tubular cells from KO mice following 2 days of reperfusion, a time at which significant differences in renal dysfunction, histological changes, oxidative stress, and mitochondrial complexes between WT and KO mice were observed. Our study provides the first evidence that PrPC may play a protective role in renal IR injury, likely through its effects on mitochondria and ERK signaling pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136923PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556704PMC
May 2016

MicroRNA-638 inhibits cell proliferation by targeting phospholipase D1 in human gastric carcinoma.

Protein Cell 2015 Sep 7;6(9):680-688. Epub 2015 Aug 7.

Wuxi Oncology Institute, The Affiliated Hospital of Jiangnan University, Wuxi, 214062 China.

MicroRNAs (miRNAs) are a type of small non-coding RNAs that are often play important roles in carcinogenesis, but the carcinogenic mechanism of miRNAs is still unclear. This study will investigate the function and the mechanism of miR-638 in carcinoma (GC). The expression of miR-638 in GC and the DNA copy number of miR-638 were detected by real-time PCR. The effect of miR-638 on cell proliferation was measured by counting kit-8 assay. Different assays, including bioinformatics algorithms (TargetScan and miRanda), luciferase report assay and Western blotting, were used to identify the target gene of miR-638 in GC. The expression of miR-638 target gene in clinical CRC tissues was also validated by immunohistochemical assay. From this research, we found that miR-638 was downregulated in GC tissues compared with corresponding noncancerous tissues (NCTs), and the DNA copy number of miR-638 was lower in GC than NCTs, which may induce the corresponding downregulation of miR-638 in GC. Ectopic expression of miR-638 inhibited GC cell growth in vitro. Subsequently, we identified that PLD1 is the target gene of miR-638 in GC, and silencing PLD1 expression phenocopied the inhibitory effect of miR-638 on GC cell proliferation. Furthermore, we observed that PLD1 was overexpressed in GC tissues, and high expression of PLD1 in GC predicted poor overall survival. In summary, we revealed that miR-638 functions as a tumor suppressor in GC through inhibiting PLD1.
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http://dx.doi.org/10.1007/s13238-015-0187-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537476PMC
September 2015

Effect of metabolic syndrome on mitsugumin 53 expression and function.

PLoS One 2015 7;10(5):e0124128. Epub 2015 May 7.

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.

Metabolic syndrome is a cluster of risk factors, such as obesity, insulin resistance, and hyperlipidemia that increases the individual's likelihood of developing cardiovascular diseases. Patients inflicted with metabolic disorders also suffer from tissue repair defect. Mitsugumin 53 (MG53) is a protein essential to cellular membrane repair. It facilitates the nucleation of intracellular vesicles to sites of membrane disruption to create repair patches, contributing to the regenerative capacity of skeletal and cardiac muscle tissues upon injury. Since individuals suffering from metabolic syndrome possess tissue regeneration deficiency and MG53 plays a crucial role in restoring membrane integrity, we studied MG53 activity in mice models exhibiting metabolic disorders induced by a 6 month high-fat diet (HFD) feeding. Western blotting showed that MG53 expression is not altered within the skeletal and cardiac muscles of mice with metabolic syndrome. Rather, we found that MG53 levels in blood circulation were actually reduced. This data directly contradicts findings presented by Song et. al that indict MG53 as a causative factor for metabolic syndrome (Nature 494, 375-379). The diminished MG53 serum level observed may contribute to the inadequate tissue repair aptitude exhibited by diabetic patients. Furthermore, immunohistochemical analyses reveal that skeletal muscle fibers of mice with metabolic disorders experience localization of subcellular MG53 around mitochondria. This clustering may represent an adaptive response to oxidative stress resulting from HFD feeding and may implicate MG53 as a guardian to protect damaged mitochondria. Therapeutic approaches that elevate MG53 expression in serum circulation may be a novel method to treat the degenerative tissue repair function of diabetic patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124128PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423930PMC
February 2016

RPL13A as a reference gene for normalizing mRNA transcription of ovarian cancer cells with paclitaxel and 10-hydroxycamptothecin treatments.

Mol Med Rep 2015 Apr 17;11(4):3188-94. Epub 2014 Dec 17.

Laboratory of Medical Genetics, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.

Gene transcription analysis is important in cancer research, and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) has been demonstrated to be an effective method to evaluate gene transcription in cancer. RT‑qPCR requires an internal reference gene with a consistent level of mRNA transcription across various experimental conditions. However, it has been suggested that different treatments, including anticancer therapy, may influence the transcriptional stability of internal reference genes. Paclitaxel (PTX) and 10‑hydroxycamptothecin (HCPT) are widely used to treat various types of cancer, and a suitable internal reference gene is required in order to analyze the transcription profiles of the cells following treatment. In the current study, the transcriptional stability of 30 candidate reference genes was investigated in cancer cells following treatment with PTX and HCPT. The two ovarian cancer cell lines, UACC‑1598 and SKOV3, were treated with PTX and HCPT for 24 and 48 h, and the transcriptional levels of the candidate reference genes were subsequently evaluated by RT‑qPCR analysis. The transcriptional stability of the selected genes was then analyzed using qbase+ and NormFinder software. A total of 9 genes were demonstrated to exhibit high transcriptional stability and one of these genes, ribosomal protein L13a (RPL13A), was identified to exhibit high transcriptional stability in every group. The current study identified various reference genes suitable under different circumstances, while RPL13A was indicated to be the most suitable reference gene for analyzing the transcription profile of ovarian cancer cells following treatment with PTX and HCPT.
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http://dx.doi.org/10.3892/mmr.2014.3108DOI Listing
April 2015

A treadmill exercise reactivates the signaling of the mammalian target of rapamycin (mTor) in the skeletal muscles of starved mice.

Biochem Biophys Res Commun 2015 Jan 6;456(1):519-26. Epub 2014 Dec 6.

Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan; Translational Research Center, Fukushima Medical University, Fukushima 960-1295, Japan. Electronic address:

It has been well established that a starvation-induced decrease in insulin/IGF-I and serum amino acids effectively suppresses the mammalian target of rapamycin (mTor) signaling to induce autophagy, which is a major degradative cellular pathway in skeletal muscles. In this study, we investigated the systematic effects of exercise on the mTor signaling of skeletal muscles. Wild type C57BL/6J mice were starved for 24h under synchronous autophagy induction conditions. Under these conditions, endogenous LC3-II increased, while both S6-kinse and S6 ribosomal protein were dephosphorylated in the skeletal muscles, which indicated mTor inactivation. Using GFP-LC3 transgenic mice, it was also confirmed that fluorescent GFP-LC3 dots in the skeletal muscles increased, including soleus, plantaris, and gastrocnemius, which clearly showed autophagosomal induction. These starved mice were then subjected to a single bout of running on a treadmill (12m/min, 2h, with a lean of 10 degrees). Surprisingly, biochemical analyses revealed that the exercise elicited a decrease in the LC3-II/LC3-I ratio as well as an inversion from the dephosphorylated state to the rephosphorylated state of S6-kinase and ribosomal S6 in these skeletal muscles. Consistently, the GFP-LC3 dots of the skeletal muscles were diminished immediately after the exercise. These results indicated that exercise suppressed starvation-induced autophagy through a reactivation of mTor signaling in the skeletal muscles of these starved mice.
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http://dx.doi.org/10.1016/j.bbrc.2014.11.118DOI Listing
January 2015
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