Publications by authors named "Shourong Wu"

23 Publications

  • Page 1 of 1

Role of Fibrinolytic Enzymes in Anti-Thrombosis Therapy.

Front Mol Biosci 2021 28;8:680397. Epub 2021 May 28.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

Thrombosis, a major cause of deaths in this modern era responsible for 31% of all global deaths reported by WHO in 2017, is due to the aggregation of fibrin in blood vessels which leads to myocardial infarction or other cardiovascular diseases (CVDs). Classical agents such as anti-platelet, anti-coagulant drugs or other enzymes used for thrombosis treatment at present could leads to unwanted side effects including bleeding complication, hemorrhage and allergy. Furthermore, their high cost is a burden for patients, especially for those from low and middle-income countries. Hence, there is an urgent need to develop novel and low-cost drugs for thrombosis treatment. Fibrinolytic enzymes, including plasmin like proteins such as proteases, nattokinase, and lumbrokinase, as well as plasminogen activators such as urokinase plasminogen activator, and tissue-type plasminogen activator, could eliminate thrombi with high efficacy rate and do not have significant drawbacks by directly degrading the fibrin. Furthermore, they could be produced with high-yield and in a cost-effective manner from microorganisms as well as other sources. Hence, they have been considered as potential compounds for thrombosis therapy. Herein, we will discuss about natural mechanism of fibrinolysis and thrombus formation, the production of fibrinolytic enzymes from different sources and their application as drugs for thrombosis therapy.
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http://dx.doi.org/10.3389/fmolb.2021.680397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194080PMC
May 2021

Biological roles of Yin Yang 2: Its implications in physiological and pathological events.

J Cell Mol Med 2020 11 23;24(22):12886-12899. Epub 2020 Sep 23.

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

Yin yang 2 (YY2) is a multifunctional zinc finger protein that belongs to the yin yang (YY) family. YY2 has dual function in regulating gene expression, as it could act either as a transcriptional activator or as a repressor of its target genes. YY2 could regulate genes that have been previously identified as targets of yin yang 1 (YY1), another member of the YY family, by binding to their common binding sequences. However, recent studies revealed that YY2 also has its own specific binding sequences, leading to its particular biological functions distinct from those of YY1. Furthermore, they have different levels or even opposite regulatory effects on common target genes, suggesting the importance of balanced YY1 and YY2 regulations in maintaining proper cellular homeostasis and biological functions. Recent studies revealed that YY2 plays crucial roles in maintaining stemness and regulating differentiation potential of embryonic stem cells, as well as in the development of the brain, nervous and cardiovascular systems. YY2 expression is also closely related to diseases, as it could act as a tumour suppressor gene that regulates tumour cell proliferation and metastasis. Moreover, YY2 is also involved in immune regulation and immune surveillance. Herein, we summarize recent perspectives regarding the regulatory functions of YY2, as well as its biological functions and relation with diseases.
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http://dx.doi.org/10.1111/jcmm.15919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754051PMC
November 2020

Dapagliflozin Promotes Neovascularization by Improving Paracrine Function of Skeletal Muscle Cells in Diabetic Hindlimb Ischemia Mice Through PHD2/HIF-1α Axis.

Front Pharmacol 2020 10;11:1104. Epub 2020 Aug 10.

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

Diabetes mellitus is associated with a high risk of hindlimb ischemia (HLI) progression and an inevitably poor prognosis, including worse limb salvage and mortality. Skeletal muscle cells can secrete angiogenic factors, which could promote neovascularization and blood perfusion recovery. Thus, paracrine function of skeletal muscle cells, which is aberrant in diabetic conditions, is crucial for therapeutic angiogenesis in diabetic HLI. Dapagliflozin is a well-known anti-hyperglycemia and anti-obesity drug; however, its role in therapeutic angiogenesis is unknown. Herein, we found that dapagliflozin could act as an angiogenesis stimulator in diabetic HLI. We showed that dapagliflozin enhances the viability, proliferation, and migration potentials of skeletal muscle cells and promotes the secretion of multiple angiogenic factors from skeletal muscle cells, most plausibly through PHD2/HIF-1α axis. Furthermore, we demonstrated that conditioned medium from dapagliflozin-treated skeletal muscle cells enhances the proliferation and migration potentials of vascular endothelial and smooth muscle cells, which are two fundamental cells of functional mature vessels. Finally, an study demonstrated that intramuscular administration of dapagliflozin effectively enhances the formation of mature blood vessels and, subsequently, blood perfusion recovery in diabetic HLI mice. Hence, our results suggest a novel function of dapagliflozin as a potential therapeutic angiogenesis agent for diabetic HLI.
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http://dx.doi.org/10.3389/fphar.2020.01104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424065PMC
August 2020

The biological implications of Yin Yang 1 in the hallmarks of cancer.

Theranostics 2020 4;10(9):4183-4200. Epub 2020 Mar 4.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.

Tumorigenesis is a multistep process characterized by the acquisition of genetic and epigenetic alterations. During the course of malignancy development, tumor cells acquire several features that allow them to survive and adapt to the stress-related conditions of the tumor microenvironment. These properties, which are known as hallmarks of cancer, include uncontrolled cell proliferation, metabolic reprogramming, tumor angiogenesis, metastasis, and immune system evasion. Zinc-finger protein Yin Yang 1 (YY1) regulates numerous genes involved in cell death, cell cycle, cellular metabolism, and inflammatory response. YY1 is highly expressed in many cancers, whereby it is associated with cell proliferation, survival, and metabolic reprogramming. Furthermore, recent studies also have demonstrated the important role of YY1-related non-coding RNAs in acquiring cancer-specific characteristics. Therefore, these YY1-related non-coding RNAs are also crucial for YY1-mediated tumorigenesis. Herein, we summarize recent progress with respect to YY1 and its biological implications in the context of hallmarks of cancer.
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http://dx.doi.org/10.7150/thno.43481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086370PMC
May 2021

Neurogenic differentiation factor 1 promotes colorectal cancer cell proliferation and tumorigenesis by suppressing the p53/p21 axis.

Cancer Sci 2020 Jan 10;111(1):175-185. Epub 2019 Dec 10.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

Neurogenic differentiation factor 1 (NeuroD1) is a transcription factor critical for promoting neuronal differentiation and maturation. NeuroD1 is involved in neuroblastoma and medulloblastoma; however, its molecular mechanism in promoting tumorigenesis remains unclear. Furthermore, the role of NeuroD1 in non-neural malignancies has not been widely characterized. Here, we found that NeuroD1 is highly expressed in colorectal cancer. NeuroD1-silencing induces the expression of p21, a master regulator of the cell cycle, leading to G -M phase arrest and suppression of colorectal cancer cell proliferation as well as colony formation potential. Moreover, NeuroD1-mediated regulation of p21 expression occurs in a p53-dependent manner. Through chromatin immunoprecipitation and point mutation analysis in the predicted NeuroD1 binding site of the p53 promoter, we found that NeuroD1 directly binds to the p53 promoter and suppresses its transcription, resulting in increased p53 expression in NeuroD1-silenced colorectal cancer cells. Finally, xenograft experiments demonstrated that NeuroD1-silencing suppresses colorectal cancer cell tumorigenesis potential by modulating p53 expression. These findings reveal NeuroD1 as a novel regulator of the p53/p21 axis, underscoring its importance in promoting non-neural malignancies. Furthermore, this study provides insight into the transcriptional regulation of p53.
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http://dx.doi.org/10.1111/cas.14233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942426PMC
January 2020

Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation.

Theranostics 2019 14;9(25):7599-7615. Epub 2019 Oct 14.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.

Lipid accumulation is a driving force in tumor development, as it provides tumor cells with both energy and the building blocks of phospholipids for construction of cell membranes. Aberrant homeostasis of lipid metabolism has been observed in various tumors; however, the molecular mechanism has not been fully elucidated. Yin yang 1 (YY1) expression in hepatocellular carcinoma (HCC) was analyzed using clinical specimens, and its roles in HCC in lipid metabolism were examined using gain- and loss-of function experiments. The mechanism of YY1 regulation on peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and its downstream genes medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were investigated using molecular biology and biochemical methods. The role of YY1/ PGC-1β axis in hepatocarcinogenesis was studied using xenograft experiment. This study showed that YY1 suppresses fatty acid β-oxidation, leading to increase of cellular triglyceride level and lipid accumulation in HCC cells, and subsequently induction of the tumorigenesis potential of HCC cells. Molecular mechanistic study revealed that YY1 blocks the expression of , an activator of fatty acid β-oxidation, by directly binding to its promoter; and thus downregulates PGC-1β/MCAD and PGC1-β/LCAD axis. Importantly, we revealed that YY1 inhibition on occurs irrespective of the expression of hypoxia-inducible factor-1α (HIF1-α), enabling it to promote lipid accumulation under both normoxic and hypoxic conditions. Our study reveals the critical role of YY1/PGC-1β axis in HCC cell lipid metabolism, providing novel insight into the molecular mechanisms associated with tumor cell lipid metabolism, and a new perspective regarding the function of YY1 in tumor progression. Thus, our study provides evidences regarding the potential of YY1 as a target for lipid metabolism-based anti-tumor therapy.
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http://dx.doi.org/10.7150/thno.34931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831470PMC
September 2020

Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination.

EBioMedicine 2019 Oct 11;48:248-263. Epub 2019 Sep 11.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China; State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing 400044, China. Electronic address:

Background: Aberrant expression of p53 and its downstream gene p21 is closely related to alterations in cell cycle and cell proliferation, and is common among cancer patients. However, the underlying molecular mechanism has not been fully unravelled. ZER6 is a zinc-finger protein with two isoforms possessing different amino termini (N-termini) in their proteins, p52-ZER6 and p71-ZER6. The biological function of ZER6 isoforms, as well as their potential involvement in tumourigenesis and the regulation of p53 remain elusive.

Methods: The effect of ZER6 isoforms on p53 and p21 was determined using specific knockdown and overexpression. p52-ZER6 expression in tumours was analysed using clinical specimens, while gene modulation was used to explore p52-ZER6 roles in regulating cell proliferation and tumourigenesis. The mechanism of p52-ZER6 regulation on the p53/p21 axis was studied using molecular biology and biochemical methods.

Findings: p52-ZER6 was highly expressed in tumour tissues, and was closely related with tumour progression. Mechanistically, p52-ZER6 bound to p53 through a truncated KRAB (tKRAB) domain in its N-terminus and enhanced MDM2/p53 complex integrity, leading to increased p53 ubiquitination and degradation. p52-ZER6-silencing induced G-G phase arrest, and subsequently reduced cell proliferation and tumourigenesis. Intriguingly, this regulation on p53 was specific to p52-ZER6, whereas p71-ZER6 did not affect p53 stability, most likely due to the presence of a HUB-1 domain.

Interpretation: We identified p52-ZER6 as a novel oncogene that enhances MDM2/p53 complex integrity, and might be a potential target for anti-cancer therapy.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838388PMC
October 2019

Tyrosol Facilitates Neovascularization by Enhancing Skeletal Muscle Cells Viability and Paracrine Function in Diabetic Hindlimb Ischemia Mice.

Front Pharmacol 2019 14;10:909. Epub 2019 Aug 14.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

As one of the most severe manifestations of diabetes, vascular complications are the main causes of diabetes-related morbidity and mortality. Hyperglycemia induces systemic abnormalities, including impaired angiogenesis, causing diabetic patients to be highly susceptible in suffering hindlimb ischemia (HLI). Despite its severe prognosis, there is currently no effective treatment for diabetic HLI. Skeletal muscle cells secrete multiple angiogenic factors, hence, recently are reported to be critical for angiogenesis; however, hyperglycemia disrupted the paracrine function in skeletal muscle cells, leading to the impaired angiogenesis potential observed in diabetic patients. The present study showed that tyrosol, a phenylethanoid compound, suppresses accumulation of intracellular reactive oxygen species (ROS) caused by hyperglycemia, most plausibly by promoting heme oxygenase-1 (HO-1) expression in skeletal muscle cells. Consequently, tyrosol exerts cytoprotective function against hyperglycemia-induced oxidative stress in skeletal muscle cells, increases their proliferation vigorously, and simultaneously suppresses apoptosis. Furthermore, tyrosol grossly increases the secretion of vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) from skeletal muscle cells. This leads to enhanced proliferation and migration capabilities of vascular endothelial and smooth muscle cells, two types of cells that are responsible in forming blood vessels, through cell-cell communication. Finally, experiment using the diabetic HLI mouse model showed that tyrosol injection into the gastrocnemius muscle of the ischemic hindlimb significantly enhances the formation of functional blood vessels and subsequently leads to significant recovery of blood perfusion. Overall, our findings highlight the potential of the pharmacological application of tyrosol as a small molecule drug for therapeutic angiogenesis in diabetic HLI patients.
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http://dx.doi.org/10.3389/fphar.2019.00909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702659PMC
August 2019

Salidroside-Pretreated Mesenchymal Stem Cells Enhance Diabetic Wound Healing by Promoting Paracrine Function and Survival of Mesenchymal Stem Cells Under Hyperglycemia.

Stem Cells Transl Med 2019 04 9;8(4):404-414. Epub 2019 Jan 9.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People's Republic of China.

Systemic abnormalities cause several complications in diabetes patients. Impaired wound healing is a serious complication that leads to severe foot ulcer and amputation. Mesenchymal stem cells (MSCs) have been considered a promising strategy for promoting wound healing due to their paracrine function. However, their poor survival after transplantation limits their therapeutic effect and applications. Salidroside, a glucopyranoside, has been reported to exert cytoprotective effects. Our previous study revealed that salidroside could promote the paracrine function of skeletal muscle cells. However, whether salidroside could improve MSCs survival under hyperglycemic condition and, subsequently, promote wound healing in diabetic model mice remains unknown. Here, we found that salidroside pretreatment effectively reversed the hyperglycemia-induced suppression of the expression of crucial wound healing factors in MSCs, such as heme oxygenase-1 (HO-1), fibroblast growth factor 2 (FGF2), and hepatocyte growth factor (HGF). Salidroside pretreatment also suppressed the hyperglycemia-induced intracellular reactive oxygen species (ROS) levels in MSCs, thereby lowering the apoptosis rate and enhancing MSCs survival rate. Furthermore, salidroside improved the MSCs migration potential that was impaired under hyperglycemia. in vivo experiments revealed that salidroside pretreatment prior to transplantation significantly enhanced the effect of MSCs in promoting wound closure in diabetic mice. Collectively, our results suggest that pretreatment with salidroside could be an effective strategy to enhance the survival rate and the therapeutic effect of MSCs. Thus, our article suggested a novel, potential MSC-based strategy for diabetic wound healing. Stem Cells Translational Medicine 2019;8:404-414.
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http://dx.doi.org/10.1002/sctm.18-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431607PMC
April 2019

XBP1-s promotes colorectal cancer cell proliferation by inhibiting TAp73 transcriptional activity.

Biochem Biophys Res Commun 2019 01 23;508(1):203-209. Epub 2018 Nov 23.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China; State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, 400044, China. Electronic address:

Endoplasmic reticulum (ER) stress activation could be found in a wide range of human tumors. ER stress induces the splicing of X-box binding protein 1 (XBP1) to form its splicing variant XBP1-s, which in turn activates various ER stress-related genes. XBP1-s is highly expressed in various tumors; however, its role in tumorigenesis is still largely unknown. Herein we showed that XBP1-s suppresses the expression of tumor suppressor TAp73, a member of p53 family with high homology with p53, by directly binds to TAp73 promoter and suppresses its transcriptional activity. We also found that overexpression of TAp73 cancelled the effect of XPB1-s on enhancing colorectal cancer cells proliferation and colony formation potential, indicating that TAp73 is critical for XBP1-s-induced tumorigenesis. Together, our findings not only reveal a novel mechanism of TAp73 aberrant regulation in tumor cells, but also link up tumor cells ER stress with tumor suppressive activity of TAp73.
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http://dx.doi.org/10.1016/j.bbrc.2018.11.112DOI Listing
January 2019

Transcription Factor YY1 Promotes Cell Proliferation by Directly Activating the Pentose Phosphate Pathway.

Cancer Res 2018 08 19;78(16):4549-4562. Epub 2018 Jun 19.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

Tumor cells alter their metabolism to meet their demand for macromolecules and support a high rate of proliferation as well as cope with oxidative stress. The transcription factor yin yang 1 (YY1) is upregulated in various types of tumors and is crucial for tumor cell proliferation and metastasis. However, its role in tumor cell metabolic reprogramming is poorly understood. Here, we show that YY1 alters tumor cell metabolism by activating glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway. By stimulating the pentose phosphate pathway, YY1 enhanced production of nucleotides and DNA synthesis, decreased intracellular reactive oxygen species levels, and promoted antioxidant defense by supplying increased reducing power in the form of NADPH. Importantly, YY1-mediated regulation of the pentose phosphate pathway in tumor cells occurred not through p53, but rather through direct activation of G6PD transcription by YY1. Regulation of pentose phosphate pathway activity through G6PD was strongly related to YY1-induced proliferation of tumor cells and tumorigenesis. Together, our results describe a novel role for YY1 in regulating G6PD in a p53-independent manner, which links its function in tumorigenesis to metabolic reprogramming in tumor cells. This study reveals a novel role for YY1 in regulating G6PD and activating the pentose phosphate pathway, linking its function in tumorigenesis to metabolic reprogramming. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-4047DOI Listing
August 2018

Yin Yang 1 promotes the Warburg effect and tumorigenesis via glucose transporter GLUT3.

Cancer Sci 2018 Aug 12;109(8):2423-2434. Epub 2018 Jul 12.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

Cancer cells typically shift their metabolism to aerobic glycolysis to fulfill the demand of energy and macromolecules to support their proliferation. Glucose transporter (GLUT) family-mediated glucose transport is the pacesetter of aerobic glycolysis and, thus, is critical for tumor cell metabolism. Yin Yang 1 (YY1) is an oncogene crucial for tumorigenesis; however, its role in tumor cell glucose metabolism remains unclear. Here, we revealed that YY1 activates GLUT3 transcription by directly binding to its promoter and, concomitantly, enhances tumor cell aerobic glycolysis. This regulatory effect of YY1 on glucose entry into the cells is critical for YY1-induced tumor cell proliferation and tumorigenesis. Intriguingly, YY1 regulation of GLUT3 expression, and, subsequently, of tumor cell aerobic glycolysis and tumorigenesis, occurs p53-independently. Our results also showed that clinical drug oxaliplatin suppresses colon carcinoma cell proliferation by inhibiting the YY1/GLUT3 axis. Together, these results link YY1's tumorigenic potential with the critical first step of aerobic glycolysis. Thus, our novel findings not only provide new insights into the complex role of YY1 in tumorigenesis but also indicate the potential of YY1 as a target for cancer therapy irrespective of the p53 status.
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http://dx.doi.org/10.1111/cas.13662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113438PMC
August 2018

Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library.

Sci Adv 2017 10 18;3(10):e1701383. Epub 2017 Oct 18.

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.

Cell cycle progression is a tightly controlled fundamental process in living cells, with any defects being closely linked to various abnormalities. The tumor suppressor p53/p21 axis is a core pathway controlling cell cycle progression; however, its regulatory mechanism has not been fully elucidated. In an effort to unravel this crucial network, we screened a short hairpin RNA expression vector library and identified unspliced X-box binding protein 1 (XBP1-u) as a novel and critical regulator of the p53/p21 axis. Specifically, XBP1-u negatively regulates the p53/p21 axis by enhancing p53 ubiquitination, which in turn down-regulates p21 expression. We show that XBP1-u suppression induces G-G phase arrest and represses cell proliferation. We further report that the carboxyl terminus of XBP1-u, which differs from that of its spliced form (XBP1-s) due to a codon shift, binds and stabilizes mouse double minute homolog 2 (MDM2) protein, a negative regulator of p53, by inhibiting its self-ubiquitination. Concomitantly, XBP-u overexpression enhances tumorigenesis by positively regulating MDM2. Together, our findings suggest that XBP1-u functions far beyond being merely a precursor of XBP1-s and, instead, is involved in fundamental biological processes. Furthermore, this study provides new insights regarding the regulation of the MDM2/p53/p21 axis.
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http://dx.doi.org/10.1126/sciadv.1701383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647124PMC
October 2017

Prolyl hydroxylase domain-2 silencing induced by hydrodynamic limb vein injection enhances vascular regeneration in critical limb ischemia mice through activation of multiple genes.

Curr Gene Ther 2015 ;15(3):313-25

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, 174 Shazheng Street, Shapingba, Chongqing 400044, China.

Therapeutic revascularization had been considered as the most potential strategy for treating ischemic diseases. Reconstruction of mature blood vessels, which is the key for functional revascularization, is a complex process involving multiple angiogenesis factors. Attempts had been made to promote functional revascularization by delivering vectors or other macromolecules that could positively regulate angiogenesis; however, the delivery method of these therapeutic angiogenesis factors had been mostly limited to direct intramuscular injection. In this study, we showed that compared to intramuscular injection, the hydrodynamic limb vein (HLV) injection of naked short-hairpin RNA expression plasmid targeting PHD2 (shPHD2) into critical himblimb ischemia mice could increase not only the expressions of HIF-dependent and HIF-independent angiogenic factors, but also tissue protective factors involved in various endogenous pathways more efficiently. We also found that PHD2-silencing enhanced innate endogenous recovery mechanism, as the expression levels of these factors had been slightly upregulated merely by the ischemic condition. Finally, we showed that HLV injection of shPHD2 promoted the formation of mature and functional vessels, and thus, enhances the recovery of ischemic hindlimbs more efficiently. These results suggest that HLV delivery of shPHD2 might become a promising treatment strategy to promote vascular regeneration in critical limb ischemia disease via enhancing innate endogenous pathways.
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http://dx.doi.org/10.2174/156652321503150329003735DOI Listing
January 2016

Synergistic cooperation of MDM2 and E2F1 contributes to TAp73 transcriptional activity.

Biochem Biophys Res Commun 2014 Jul 15;449(3):319-26. Epub 2014 May 15.

The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing 400044, China. Electronic address:

TAp73, a structural homologue of p53, plays an important role in tumorigenesis. E2F1 had been reported as a transcriptional regulator of TAp73, however, the detailed mechanism remains to be elucidated. Here we reported that MDM2-silencing reduced the activities of the TAp73 promoters and the endogenous TAp73 expression level significantly; while MDM2 overexpression upregulated them. We further revealed that the regulation of TAp73 transcriptional activity occurs as a synergistic effect of MDM2 and E2F1, most probably through their physical interaction in the nuclei. Furthermore, we also suggested that MDM2 might be involved in DNA damage-induced TAp73 transcriptional activity. Finally, we elucidated that MDM2-silencing reduced the proliferation rate of colon carcinoma cells regardless of the p53 status. Our data show a synergistic effect of MDM2 and E2F1 on TAp73 transcriptional activity, suggesting a novel regulation pathway of TAp73.
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http://dx.doi.org/10.1016/j.bbrc.2014.05.026DOI Listing
July 2014

Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier.

ACS Nano 2013 Oct 18;7(10):8583-92. Epub 2013 Sep 18.

Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Ligand-mediated drug delivery systems have enormous potential for improving the efficacy of cancer treatment. In particular, Arg-Gly-Asp peptides are promising ligand molecules for targeting αvβ3/αvβ5 integrins, which are overexpressed in angiogenic sites and tumors, such as intractable human glioblastoma (U87MG). We here achieved highly efficient drug delivery to U87MG tumors by using a platinum anticancer drug-incorporating polymeric micelle (PM) with cyclic Arg-Gly-Asp (cRGD) ligand molecules. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma compared with the PM having nontargeted ligand, "cyclic-Arg-Ala-Asp" (cRAD). As both cRGD/m- and cRAD-linked polymeric micelles have similar characteristics, including their size, surface charge, and the amount of incorporated drugs, it is likely that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant antitumor effects in an orthotopic mouse model of U87MG human glioblastoma.
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http://dx.doi.org/10.1021/nn402662dDOI Listing
October 2013

Determination of the role of DDX3 a factor involved in mammalian RNAi pathway using an shRNA-expression library.

PLoS One 2013 19;8(3):e59445. Epub 2013 Mar 19.

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

RNA interference (RNAi) is an endogenous RNA-destruction phenomenon induced by certain double-stranded RNAs (dsRNAs). In RNAi, dsRNAs are processed into small interfering RNAs (siRNAs) which in turn trigger the cleavage of the target mRNA. Here, using a short hairpin RNA-expression library, we identified a DEAD-box helicase 3, DDX3, as an essential factor involved in RNAi pathway and revealed that DDX3 is colocalized with Ago2, an essential factor in RNAi pathway that cleaves target mRNA. Results of experiments with a dominant negative mutant of DDX3 further confirmed that this factor affects the RNAi activity. Together, DDX3 functions to assure mammalian RNAi pathway. Together, our results indicate that DDX3 is a new key molecule to understand the molecular mechanism underlying RNAi pathway in mammals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059445PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602433PMC
September 2013

Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor HIF-1α in a p53-independent manner.

Cancer Res 2013 Mar 17;73(6):1787-99. Epub 2013 Jan 17.

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.

In response to hypoxic stress, hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1α target genes. Interestingly, our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0366DOI Listing
March 2013

Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting.

Sci Transl Med 2011 Jan;3(64):64ra2

Department of Bioengineering, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.
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http://dx.doi.org/10.1126/scitranslmed.3001385DOI Listing
January 2011

Introduction of stearoyl moieties into a biocompatible cationic polyaspartamide derivative, PAsp(DET), with endosomal escaping function for enhanced siRNA-mediated gene knockdown.

J Control Release 2010 Jul 30;145(2):141-8. Epub 2010 Mar 30.

Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Applications of siRNA for cancer therapy have been spotlighted in recent years, but the rational design of efficient siRNA delivery carriers is still controversial, especially because of possible toxicity of the carrier components. Previously, a cationic polyaspartamide derivative, poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PAsp(DET)), was reported to exert high transfection efficacy for plasmid DNA with negligible cytotoxicity. However, its direct application for siRNA delivery was fairly limited due to the unstable polymer/siRNA complex formation. In this study, to overcome such instability, stearic acid as a hydrophobic moiety was conjugated to the side chain of PAsp(DET) with various substitution degrees. The stearoyl introduction contributed not only to siRNA complex formation with higher association numbers but also to complex stabilization. The obtained stearoyl PAsp(DET)/siRNA complex significantly accomplished more efficient endogenous gene (BCL-2 and VEGF) knockdown in vitro against the human pancreatic adenocarcinoma (Panc-1) cells than did the unmodified PAsp(DET) complex and commercially available reagents, probably due to the facilitated cellular internalization. This finding suggests that the hydrophobic PAsp(DET)-mediated siRNA delivery is a promising platform for in vivo siRNA delivery.
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http://dx.doi.org/10.1016/j.jconrel.2010.03.019DOI Listing
July 2010

Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene.

Mol Ther 2008 Jul 20;16(7):1227-34. Epub 2008 May 20.

Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Hypoxia-inducible factor-1 (HIF-1) plays a central role in cellular response to hypoxia by activating vascular endothelial growth factor (VEGF) and other angiogenic factors. Prolyl hydroxylase domain-2 (PHD2) protein induces the degradation of HIF-1 by hydroxylating specific prolyl residues. Therefore gene silencing of PHD2 by RNA interference (RNAi) might increase the expression of angiogenic growth factors and, consequently, neoangiogenesis through the stabilization of HIF-1alpha. In this study we have shown that the specific silencing of PHD2 is sufficient for stabilizing HIF-1alpha and increasing its transcriptional activity, resulting in the increased expression of angiogenic factors including VEGF and fibroblast growth factor-2 (FGF2). Moreover, when PHD2-siRNA vector was used, the increase in VEGF secretion was observed for as long as 18 days after transfection. In vitro treatment of human umbilical vein endothelical cells with conditioned medium from PHD2-siRNA vector-transfected NIH3T3 cells was shown to increase cell proliferation. Also, in vivo angiogenesis was observed in mice implanted with Matrigel plugs mixed with NIH3T3 cells transfected with PHD2-siRNA vector. These results indicate that PHD2 silencing induces expressions of multiple angiogenic growth factors by stabilizing HIF-1alpha, and that the implantation of cells transfected with PHD2-siRNA vector is sufficient to enhance angiogenesis in vivo. In the light of these findings, PHD2 silencing by RNAi might offer a potential tool for angiogenic therapy.
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http://dx.doi.org/10.1038/mt.2008.90DOI Listing
July 2008

Cooperative regulation of p73 promoter by Yin Yang 1 and E2F1.

Nucleic Acids Symp Ser (Oxf) 2007 (51):347-8

Department of Chemistry and Biotechnology, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

The transcriptional factor Yin Yang 1 (YY1) plays multifunctional role in various biological processes. Here we report that the silencing of YY1 using siRNA expression vectors in U2OS cells led to a significant decrease in transcriptional activity of p73, which is a member of p53 family. Consistently, overexpression of YY1 could enhance the transcriptional activity of p73 in a dose-dependent manner. Moreover, synergistic cooperation between YY1 and E2F1, through a mechanism involving a physical interaction, was observed in the regulation of p73 promoter. In conclusion, our results provide new insights into the function of YY1, and might clarify the complex regulation mechanism by YY1 network in diverse biological processed, such as development, differentiation and cancer biology.
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http://dx.doi.org/10.1093/nass/nrm174DOI Listing
April 2008

Yin Yang 1 induces transcriptional activity of p73 through cooperation with E2F1.

Biochem Biophys Res Commun 2008 Jan 1;365(1):75-81. Epub 2007 Nov 1.

Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

The transcription factor p73 is a structural homologue of p53 and plays an important role in tumorigenesis, differentiation and development. However, the regulation of p73 pathway has not been wholly understood. Here we reported that YY1-silencing resulted in significant reductions in the activities of the p73 promoters and the endogenous p73 expression level, conversely, overexpression of YY1 could induce the activities of them. Furthermore, we showed that YY1 and E2F1 have synergistic effect on p73 promoter activity. The results of YY1-silencing and E2F1-silencing alone revealed that both factors are involved in the doxorubicin-induced activation of p73 promoter. Immunofluorescence staining and co-immunoprecipitation assays demonstrated that cooperation of YY1 and E2F1 is concomitant with physical interaction in nuclei. The results presented here suggested the cooperative transcriptional regulation of p73 by YY1 and E2F1, and might provide a new regulation mechanism by the YY1 network on tumorigenesis, differentiation and development.
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http://dx.doi.org/10.1016/j.bbrc.2007.10.145DOI Listing
January 2008
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