Publications by authors named "Leng Han"

156 Publications

ADEIP: an integrated platform of age-dependent expression and immune profiles across human tissues.

Brief Bioinform 2021 Jul 13. Epub 2021 Jul 13.

College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China.

Gene expression and immune status in human tissues are changed with aging. There is a need to develop a comprehensive platform to explore the dynamics of age-related gene expression and immune profiles across tissues in genome-wide studies. Here, we collected RNA-Seq datasets from GTEx project, containing 16 704 samples from 30 major tissues in six age groups ranging from 20 to 79 years old. Dynamic gene expression along with aging were depicted and gene set enrichment analysis was performed among those age groups. Genes from 34 known immune function categories and immune cell compositions were investigated and compared among different age groups. Finally, we integrated all the results and developed a platform named ADEIP (http://gb.whu.edu.cn/ADEIP or http://geneyun.net/ADEIP), integrating the age-dependent gene expression and immune profiles across tissues. To demonstrate the usage of ADEIP, we applied two datasets: severe acute respiratory syndrome coronavirus 2 and human mesenchymal stem cells-assoicated genes. We also included the expression and immune dynamics of these genes in the platform. Collectively, ADEIP is a powerful platform for studying age-related immune regulation in organogenesis and other infectious or genetic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bib/bbab274DOI Listing
July 2021

Effects of Cold-Pressing and Hydrodistillation on the Active Non-volatile Components in Lemon Essential Oil and the Effects of the Resulting Oils on Aging-Related Oxidative Stress in Mice.

Front Nutr 2021 14;8:689094. Epub 2021 Jun 14.

Chongqing Collaborative Innovation Center for Functional Food, Chongqing Engineering Research Center of Functional Food, Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, China.

The aim of this study was to analyze the non-volatile composition and antioxidant differences of lemon essential oils (LEOs) obtained by cold-pressing vs. hydrodistillation. Pathological observations showed that LEO effectively inhibited liver injury caused by oxidative stress, and CPLEO was more effective than HDLEO. CPLEO increased serum T-AOC, SOD, GSH, and GSH-Px levels while decreasing NO, COX-2, IL-6, IL-1β, IFN-γ, and TNF-α levels in mice with oxidative damage. The effects of CPLEO were stronger than those of HDLEO and similar to those of vitamin C. CPLEO upregulated mRNA and protein expressions of Cu/Zn-SOD, Mn-SOD, CAT, HO-1, Nrf2, and NQO1 while downregulating nNOS, iNOS, IL-1β, COX-2, TNF-α, and NF-κB mRNA expression and nNOS, eNOS, iNOS, and COX-2 protein expression in mice with oxidative damage. The results demonstrate that LEO has good antioxidant effects and that CPLEO has a better antioxidant effect than HDLEO as it retains more active non-volatile substances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnut.2021.689094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236505PMC
June 2021

SMG9 drives ferroptosis by directly inhibiting GPX4 degradation.

Biochem Biophys Res Commun 2021 Aug 16;567:92-98. Epub 2021 Jun 16.

Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130031, China. Electronic address:

Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that plays an integral role in eliminating abnormal mRNA and corresponding proteins. It is unclear whether the NMD pathway is involved in regulating ferroptosis, which is a type of iron-dependent cell death mainly caused by the inhibition of the antioxidant SLC7A11-GPX4 axis. In this study, we conducted a small-scale RNAi screen and proved that SMG9, a component of the NMD machinery, is a selective driver for ferroptosis in human cancer cells. SMG9 positively regulates ferroptosis independent of its activity in NMD. Instead, SMG9 is a direct binding protein of GPX4 to promote the degradation of GPX4 in response to RSL3 (a GPX4 inhibitor), but not erastin (a SLC7A11 inhibitor). The genetic inhibition of SMG9 increases the accumulation of GPX4 in the mitochondria, thereby preventing mitochondrial oxidative damage, and ultimately favoring ferroptosis resistance in vitro or in xenograft mouse models. Overall, these findings establish a new mitochondrial regulation mechanism that can affect ferroptosis-mediated tumor suppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.06.038DOI Listing
August 2021

Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition.

Cancer Res 2021 Jun 11. Epub 2021 Jun 11.

Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center

Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-3792DOI Listing
June 2021

RNA mA modification orchestrates a LINE-1-host interaction that facilitates retrotransposition and contributes to long gene vulnerability.

Cell Res 2021 Jun 9. Epub 2021 Jun 9.

Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.

The molecular basis underlying the interaction between retrotransposable elements (RTEs) and the human genome remains poorly understood. Here, we profiled N-methyladenosine (mA) deposition on nascent RNAs in human cells by developing a new method MINT-Seq, which revealed that many classes of RTE RNAs, particularly intronic LINE-1s (L1s), are strongly methylated. These mA-marked intronic L1s (MILs) are evolutionarily young, sense-oriented to hosting genes, and are bound by a dozen RNA binding proteins (RBPs) that are putative novel readers of mA-modified RNAs, including a nuclear matrix protein SAFB. Notably, mA positively controls the expression of both autonomous L1s and co-transcribed L1 relics, promoting L1 retrotransposition. We showed that MILs preferentially reside in long genes with critical roles in DNA damage repair and sometimes in L1 suppression per se, where they act as transcriptional "roadblocks" to impede the hosting gene expression, revealing a novel host-weakening strategy by the L1s. In counteraction, the host uses the SAFB reader complex to bind mA-L1s to reduce their levels, and to safeguard hosting gene transcription. Remarkably, our analysis identified thousands of MILs in multiple human fetal tissues, enlisting them as a novel category of cell-type-specific regulatory elements that often compromise transcription of long genes and confer their vulnerability in neurodevelopmental disorders. We propose that this mA-orchestrated L1-host interaction plays widespread roles in gene regulation, genome integrity, human development and diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41422-021-00515-8DOI Listing
June 2021

The HMGB1-AGER-STING1 pathway mediates the sterile inflammatory response to alkaliptosis.

Biochem Biophys Res Commun 2021 Jun 13;560:165-171. Epub 2021 May 13.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address:

Alkaliptosis is a recently discovered form of regulated cell death driven by intracellular alkalization. However, the immune characteristics and mechanisms of alkaliptosis are still poorly understood. Here, we show that HMGB1, a multifunctional alarm protein that drives innate immunity, is necessary for inflammation caused by alkaliptotic damage. During alkaliptosis, HMGB1 translocation and release from the nucleus to the cytoplasm to the extracellular space requires nuclear DNA damage signals, whereas the FANCD2-dependent (but not ATM-mediated) DNA repair pathway inhibits this process. Once released by alkaliptotic cancer cells, extracellular HMGB1 binds to the AGER receptor in macrophages and then activates the STING1 pathway to produce pro-inflammatory cytokines (e.g., TNF and IL6). Consequently, the pharmacological or genetic inhibition of the HMGB1-AGER-STING1 pathway limits cytokine production during alkaliptosis. These findings provide new insight into the sterile inflammatory response to cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2021.05.003DOI Listing
June 2021

Circular RNAs sequenced at last.

Authors:
Zhao Zhang Leng Han

Nat Biotechnol 2021 Jul;39(7):811-812

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-021-00916-5DOI Listing
July 2021

Inter- and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic.

Adv Sci (Weinh) 2021 04 18;8(7):2002715. Epub 2021 Feb 18.

Division of Endocrinology Department of Medicine Baylor College of Medicine Houston TX 77030 USA.

The rise of metabolic disorders in modern times is mainly attributed to the environment. However, heritable effects of environmental chemicals on mammalian offsprings' metabolic health are unclear. Inorganic arsenic (iAs) is the top chemical on the Agency for Toxic Substances and Disease Registry priority list of hazardous substances. Here, we assess cross-generational effects of iAs in an exclusive male-lineage transmission paradigm. The exposure of male mice to 250 ppb iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males, without affecting body weight. Hepatic expression of glucose metabolic genes, glucose output, and insulin signaling are disrupted in F1 females. Inhibition of the glucose 6-phosphatase complex masks the intergenerational effect of iAs, demonstrating a causative role of hepatic glucose production. F2 offspring from grandpaternal iAs exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and increased brown adipose thermogenesis. In contrast, F3 offspring of the male-lineage iAs exposure show increased adiposity, especially on a high-calorie diet. These findings have unveiled sex- and generation-specific heritable effects of iAs on metabolic physiology, which has broad implications in understanding gene-environment interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202002715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025034PMC
April 2021

Career pathways, part 4.

Nat Metab 2021 04;3(4):446-448

Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-021-00379-7DOI Listing
April 2021

Association Between Sex and Immune-Related Adverse Events During Immune Checkpoint Inhibitor Therapy.

J Natl Cancer Inst 2021 Mar 10. Epub 2021 Mar 10.

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.

Background: Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy.

Methods: We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas (TCGA) omics data. We further validated our observations in two independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors.

Results: A meta-analysis using 13 clinical studies that reported on 1,096 female patients (36.8%, 95% confidence interval [CI] = 35.0%-38.5%) and 1,886 male patients (63.2%, 95% CI = 61.5%-65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19; 95% CI = 0.91-1.54; 2-sided P = 0.21). Multivariable logistic regression analysis of 12,225 patients from FAERS and 10,979 patients from VigiBase showed no statistically significant difference in irAEs by sex. A propensity score algorithm used on multi-omics data for 6,019 patients from TCGA found no statistically significant difference by sex for irAE-related factors/pathways. The retrospective analysis of two in-house patient cohorts validated these results (OR = 1.55, 95% CI = 0.98-2.47; FDR = 0.13, for cohort 1; OR = 1.16, 95%CI = 0.86-1.57; FDR = 0.39, for cohort 2).

Conclusion: We observed minimal sex-associated differences in irAEs among cancer patients who received immune checkpoint inhibitor therapy. It may be unnecessary to consider gender effects for irAE management in clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djab035DOI Listing
March 2021

Characterization of Oxygenated Heterocyclic Compounds and in vitro Antioxidant Activity of Pomelo Essential Oil.

Drug Des Devel Ther 2021 2;15:937-947. Epub 2021 Mar 2.

College of Horticulture and Landscape Architecture, Southwest University, Chongqing, People's Republic of China.

Purpose: Citrus essential oils are widely used for aromatherapy and the alternative treatment of chronic diseases. Beyond the aroma substances, they are known to contain bioactive nonvolatile components; however, little knowledge has been gained about nonvolatiles in the essential oil of pomelo ( Osbeck), the largest citrus fruit. The purpose of this study was to analyze the nonvolatile oxygenated heterocyclic compounds (OHCs) of pomelo essential oils and evaluate their in vitro antioxidant activities for further development.

Methods: Cold-pressed essential oil (CPEO) and distilled essential oil (DEO) were obtained from the peel of the Liangping pomelo cultivar. High-performance liquid chromatography (HPLC) coupled with a photodiode array and fluorescence detection method was developed to identify and quantify the OHCs of the two essential oils. Ferric reducing antioxidant power and 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl 3-oxide (PTIO) radical scavenging assays were used to determine the antioxidative capabilities.

Results: Thirteen OHCs were identified in CPEO. Coumarins such as meranzin (2.0 mmol L) and furanocoumarins such as isoimperatorin (1.3 mmol L) composed the majority of nonvolatiles in CPEO. These OHCs were characterized by high proportion (58%) of side chain epoxides. Five OHCs, namely, auraptenol, 6',7'-dihydroxybergamottin (6',7'-DHB), imperatorin, isoimperatorin and 8-geranyloxypsoralen were first identified in pomelo CPEO. Eight OHCs were detected at trace amounts in pomelo DEO. Antioxidant assays showed that CPEO was multiple times more potent than DEO regarding the total reducing power and radical scavenging capacity. Clearance of PTIO, a stable reactive oxygen species, followed slow kinetics.

Conclusion: Coumarins and furanocoumarins, two families of OHCs, constituted most of the nonvolatile components in CPEO. The nonvolatiles contributed significantly to the in vitro antioxidant activity of CPEO. Pomelo CPEO showed good prospects as a potential long-lasting natural antioxidant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DDDT.S299678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936692PMC
March 2021

Optimized protocol for an inducible rat model of liver tumor with chronic hepatocellular injury, inflammation, fibrosis, and cirrhosis.

STAR Protoc 2021 Mar 19;2(1):100353. Epub 2021 Feb 19.

Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Animal models of liver cancer are instrumental in the study of hepatocarcinogenesis and development of novel therapeutic approaches. Here, we describe steps to establish liver cancer in a rat model, via chronic administration of diethylnitrosamine. This causes liver tumors with a sequential progression of hepatitis, cirrhosis, and tumor formation, which closely mimics the development of human liver cancer. This protocol was optimized to significantly increase the incidence of liver tumor formation and reduce the duration of the procedure. For complete details on the use and execution of this protocol, please refer to Chen et al. (2020).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xpro.2021.100353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905469PMC
March 2021

MEK Inhibition Remodels the Immune Landscape of Mutant Tumors to Overcome Resistance to PARP and Immune Checkpoint Inhibitors.

Cancer Res 2021 May 15;81(10):2714-2729. Epub 2021 Feb 15.

Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.

Mutant tumors are associated with poor outcomes, at least in part, due to decreased therapeutic sensitivity. Here, we show that mutations are associated with resistance to monotherapy and combination therapy with PARP inhibitors (PARPi) and immune checkpoint blockade with anti-PD-L1 antibodies. In mutant tumors, inhibition of KRAS signaling with MEK inhibitors (MEKi) triggered and amplified PARPi-induced DNA damage, cytosolic double-stranded DNA accumulation, STING pathway activation, and CD8 T-cell recruitment. Moreover, MEKi decreased myeloid-derived suppressor cell infiltration, in part, by inhibiting IL6 and GMCSF production. Importantly, addition of MEKi to PARPi and anti-PD-L1 resulted in marked tumor inhibition in immunocompetent mutant tumor models. This study provides the underlying mechanistic data to support evaluation of PARPi, MEKi, and anti-PD-L1 combination in clinical trials of mutant tumors. SIGNIFICANCE: This study provides key insights into the potential for using MEKi combined with PARPi and anti-PD-L1 for the treatment of all mutant tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2714/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-2370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265237PMC
May 2021

3-Year Outcomes of the ULTIMATE Trial Comparing Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation.

JACC Cardiovasc Interv 2021 02 29;14(3):247-257. Epub 2020 Oct 29.

Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address:

Objectives: The aim of this study was to explore the difference in target vessel failure (TVF) 3 years after intravascular ultrasound (IVUS) guidance versus angiographic guidance among all comers undergoing second-generation drug-eluting stent (DES) implantation.

Background: The multicenter randomized ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions) trial showed a lower incidence of 1-year TVF after IVUS-guided DES implantation among all comers compared with angiographic guidance. However, the 3-year clinical outcomes of the ULTIMATE trial remain unknown.

Methods: A total of 1,448 all comers undergoing DES implantation who were randomly assigned to either IVUS guidance or angiographic guidance in the ULTIMATE trial were followed for 3 years. The primary endpoint was the risk for TVF at 3 years. The safety endpoint was definite or probable stent thrombosis (ST).

Results: At 3 years, TVF occurred in 47 patients (6.6%) in the IVUS-guided group and in 76 patients (10.7%) in the angiography-guided group (p = 0.01), driven mainly by the decrease in clinically driven target vessel revascularization (4.5% vs. 6.9%; p = 0.05). The rate of definite or probable ST was 0.1% in the IVUS-guided group and 1.1% in the angiography-guided group (p = 0.02). Notably, the IVUS-defined optimal procedure was associated with a significant reduction in 3-year TVF relative to that with the suboptimal procedure.

Conclusions: IVUS-guided DES implantation was associated with significantly lower rates of TVF and ST during 3-year follow-up among all comers, particularly those who underwent the IVUS-defined optimal procedure compared with those with angiographic guidance. (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions; NCT02215915).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcin.2020.10.001DOI Listing
February 2021

Engineering of axially vascularized bone tissue using natural coral scaffold and osteogenic bone marrow mesenchymal stem cell sheets.

J Stomatol Oral Maxillofac Surg 2021 Jan 30. Epub 2021 Jan 30.

State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Introduction: Blood supply remains one of the obstacles to large bone tissue engineering. This study aimed to generate vascularized bone tissue by inducing axial vascularization into a construct combining natural coral scaffold and a bone marrow mesenchymal stem cells (BMSCs) sheet.

Material And Methods: Isolated BMSCs were cultured to form an osteogenic cell sheet using a continuous culture method. Natural coral scaffolds were prepared into customized shape with a cylinder of 20 mm length, 8 mm in outer diameter and 5 mm in inner diameter. Then, the freed superficial inferior epigastric vessel of rabbits was first wrapped with a cell sheet, and then inserted into the central passage of the scaffold, after being wrapped with another cell sheet, the complexes were implanted subcutaneously into a rabbit groin area. In contrast, the sheet-scaffold construct that implanted into groin subcutaneous area of the other side of the same rabbit with the distal end of the blood vessel was ligated, which was considered as control. New bone and vascularization formation were evaluated at 12 weeks postoperatively.

Results: The volume of new bone formation and amount of capillary infiltration in the vascular circulation group were significantly greater than that in the vascular ligation group, which suggested that insertion of axial vessels could significantly promote angiogenesis and osteogenesis of the tissue-engineered bone.

Conclusions: These findings indicate that inserting an arteriovenous bundle into the constructs of mesenchymal stem cell sheet and coral has great potential for clinical applications to repair large bone defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jormas.2021.01.013DOI Listing
January 2021

The Beneficial Role of Sunitinib in Tumor Immune Surveillance by Regulating Tumor PD-L1.

Adv Sci (Weinh) 2021 Jan 27;8(2):2001596. Epub 2020 Nov 27.

Department of Dermatology Xiangya Hospital Central South University Changsha Hunan 410008 China.

Immune checkpoints blockades have shown promising clinical effects in various malignancies, but the overall response rate is low. Here, the immune features are comprehensively characterized in >10 000 cancer patients from The Cancer Genome Atlas and significantly positive correlations are observed between targets of Sunitinib and inhibitory immune checkpoints and suppressive immune cells. It is further confirmed that Sunitinib treatment increases the antitumor immunity in a phase III trial. Mechanistically, it is discovered that Sunitinib regulates the stability of tumor PD-L1 via p62, that p62 can bind to PD-L1 and specifically promote its translocation into autophagic lysosome for degradation. Preclinically, Sunitinib shows a synergistic antitumor effect with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb) in melanoma and nonsmall cell lung cancer (NSCLC) immune competent mice by promoting the tumor-infiltrating lymphocytes activity. Clinically, a higher PD-L1 level but a lower p62 level in the tumor region of responders as compared to those of nonresponders among anti-PD-1-treated NSCLC patients is observed. Taken together, by utilizing rigorous computational analysis, functional characterization in vitro and in vivo, and neoadjuvent clinical trial, a novel molecular mechanism is revealed regarding the regulation of PD-L1 via p62, thus providing a novel therapeutic strategy by the combination treatment of CTLA-4 with Sunitinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202001596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816704PMC
January 2021

Small non-coding RNAs in human cancer: function, clinical utility, and characterization.

Oncogene 2021 03 15;40(9):1570-1577. Epub 2021 Jan 15.

Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Small non-coding RNAs (sncRNAs) play critical roles in multiple regulatory processes, including transcription, post-transcription, and translation. Emerging evidence reveals the critical roles of sncRNAs in cancer development and their potential role as biomarkers and/or therapeutic targets. In this paper, we review recent research on four sncRNA species with functional significance in cancer: small nucleolar RNAs, transfer RNA, small nuclear RNAs, and piwi-interacting RNAs. We introduce their functional roles in tumorigenesis and discuss the potential utility of sncRNAs as prognostic and diagnostic biomarkers and therapeutic targets. We further summarize approaches to characterize sncRNAs in a high-throughput manner, including the specific library construction and computational framework. Our review provides a perspective of the functions, clinical utility, and characterization of sncRNAs in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-01630-3DOI Listing
March 2021

Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis.

Biochem Biophys Res Commun 2021 01 26;536:100-106. Epub 2020 Dec 26.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address:

In regulated cell death, genetically encoded molecular machinery destroys cells. This process is not only essential for organ development and homeostasis, but also leads to pathological diseases. One form of regulated cell death is ferroptosis, which is an iron-dependent oxidative cell death caused by lipid peroxidation. Although inducing ferroptosis is an emerging anticancer strategy, the molecular mechanism underlying tumor resistance to ferroptotic cell death is still unclear. Here, we show that pirin (PIR), an iron-binding nuclear protein, plays a previously unrecognized role in mediating ferroptosis resistance in human pancreatic cancer cells. The transcription factor NFE2L2 mediates the upregulation of PIR during ferroptosis caused by small-molecule compounds (e.g., erastin or RSL3). PIR is a nuclear redox sensor and regulator, and increasing it limits the oxidative damage of DNA and the subsequent cytoplasmic transport and extracellular release of HMGB1. In contrast, the depletion of PIR initiates HMGB1-dependent autophagy by binding to BECN1, and subsequently promotes ferroptosis by activating ACSL4. Consequently, in cell cultures and xenograft mouse models, blocking PIR signaling enhances ferroptosis-mediated tumor growth suppression. Together, these findings provide new insights into the molecular mechanisms of autophagy-dependent ferroptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.12.066DOI Listing
January 2021

Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway.

Nat Commun 2020 12 11;11(1):6339. Epub 2020 Dec 11.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Ferroptosis is a more recently recognized form of cell death that relies on iron-mediated oxidative damage. Here, we evaluate the impact of high-iron diets or depletion of Gpx4, an antioxidant enzyme reported as an important ferroptosis suppressor, in the pancreas of mice with cerulean- or L-arginine-induced pancreatitis, and in an oncogenic Kras murine model of spontaneous pancreatic ductal adenocarcinoma (PDAC). We find that either high-iron diets or Gpx4 depletion promotes 8-OHG release and thus activates the TMEM173/STING-dependent DNA sensor pathway, which results in macrophage infiltration and activation during Kras-driven PDAC in mice. Consequently, the administration of liproxstatin-1 (a ferroptosis inhibitor), clophosome-mediated macrophage depletion, or pharmacological and genetic inhibition of the 8-OHG-TMEM173 pathway suppresses Kras-driven pancreatic tumorigenesis in mice. GPX4 is also a prognostic marker in patients with PDAC. These findings provide pathological and mechanistic insights into ferroptotic damage in PDAC tumorigenesis in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20154-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732843PMC
December 2020

Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors.

Genome Med 2020 11 23;12(1):101. Epub 2020 Nov 23.

Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Background: Heat shock proteins (HSPs), a representative family of chaperone genes, play crucial roles in malignant progression and are pursued as attractive anti-cancer therapeutic targets. Despite tremendous efforts to develop anti-cancer drugs based on HSPs, no HSP inhibitors have thus far reached the milestone of FDA approval. There remains an unmet need to further understand the functional roles of HSPs in cancer.

Methods: We constructed the network for HSPs across ~ 10,000 tumor samples from The Cancer Genome Atlas (TCGA) and ~ 10,000 normal samples from Genotype-Tissue Expression (GTEx), and compared the network disruption between tumor and normal samples. We then examined the associations between HSPs and cancer hallmarks and validated these associations from multiple independent high-throughput functional screens, including Project Achilles and DRIVE. Finally, we experimentally characterized the dual function effects of HSPs in tumor proliferation and metastasis.

Results: We comprehensively analyzed the HSP expression landscape across multiple human cancers and revealed a global disruption of the co-expression network for HSPs. Through analyzing HSP expression alteration and its association with tumor proliferation and metastasis, we revealed dual functional effects of HSPs, in that they can simultaneously influence proliferation and metastasis in opposite directions. We experimentally characterized the dual function of two genes, DNAJC9 and HSPA14, in lung cancer cells. We further demonstrated the generalization of this dual direction of associations between HSPs and cancer hallmarks, suggesting the necessity to more carefully evaluate HSPs as therapeutic targets and develop highly specific HSP inhibitors for cancer intervention.

Conclusions: Our study furnishes a holistic view of functional associations of HSPs with cancer hallmarks to aid the development of HSP inhibitors as well as other drugs in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00795-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682077PMC
November 2020

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model.

iScience 2020 Nov 15;23(11):101690. Epub 2020 Oct 15.

Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Hepatocellular carcinoma (HCC) initiation is characterized by stepwise accumulation of molecular alterations, during which the early events are largely unknown. Here, we presented a comprehensive genomic and transcriptomic landscape at stages of hepatitis, cirrhosis, and HCC by using a diethylnitrosamine-induced rat HCC model. We observed the early occurrence of gene instability and aberrant cancer associated signaling pathways in liver hepatitis. We further characterized the progressive molecular changes during hepatocarcinogenesis, wherein the intense rivalry between tumor-suppressive and oncogenic strengths occurred in cirrhosis stage. Despite the significant pathological difference, mutation signatures and expression landscape are highly similar between hepatitis and cirrhosis stages. Furthermore, we identified PI3K-Akt signaling pathway as a key pathway in the process of hepatocarcinogenesis through integrative analysis, and PIK3CD is a potential biomarker indicating HCC recurrence. The dynamic immune response during hepatocarcinogenesis, such as continuous decline of monocytes, suggests an immunological intervention strategy beyond chemoprevention for liver cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600387PMC
November 2020

YTHDF3 Induces the Translation of mA-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis.

Cancer Cell 2020 12 29;38(6):857-871.e7. Epub 2020 Oct 29.

Department of Human and Molecular Genetics, Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Brain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of mA reader YTHDF3 in human diseases. Here, we show that YTHDF3 overexpression clinically correlates with brain metastases in breast cancer patients. YTHDF3 promotes cancer cell interactions with brain endothelial cells and astrocytes, blood-brain barrier extravasation, angiogenesis, and outgrow. Mechanistically, YTHDF3 enhances the translation of mA-enriched transcripts for ST6GALNAC5, GJA1, and EGFR, all associated with brain metastasis. Furthermore, overexpression of YTHDF3 in brain metastases is attributed to increased gene copy number and the autoregulation of YTHDF3 cap-independent translation by binding to mA residues within its own 5' UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby inducing brain metastatic competence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738369PMC
December 2020

HeRA: an atlas of enhancer RNAs across human tissues.

Nucleic Acids Res 2021 01;49(D1):D932-D938

Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Enhancer RNA (eRNA) is a type of long non-coding RNA transcribed from DNA enhancer regions. Despite critical roles of eRNA in gene regulation, the expression landscape of eRNAs in normal human tissue remains unexplored. Using numerous samples from the Genotype-Tissue Expression project, we characterized 45 411 detectable eRNAs and identified tens of thousands of associations between eRNAs and traits, including gender, race, and age. We constructed a co-expression network to identify millions of putative eRNA regulators and target genes across different tissues. We further constructed a user-friendly data portal, Human enhancer RNA Atlas (HeRA, https://hanlab.uth.edu/HeRA/). In HeRA, users can search, browse, and download the eRNA expression profile, trait-related eRNAs, and eRNA co-expression network by searching the eRNA ID, gene symbol, and genomic region in one or multiple tissues. HeRA is the first data portal to characterize eRNAs from 9577 samples across 54 human tissues and facilitates functional and mechanistic investigations of eRNAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkaa940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779069PMC
January 2021

The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin.

Nat Cell Biol 2020 11 26;22(11):1332-1345. Epub 2020 Oct 26.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR-H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR-H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41556-020-00595-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951180PMC
November 2020

Overlapping Drug-Eluting Stent Is Associated with Increased Definite Stent Thrombosis and Revascularization: Results from 15,561 Patients in the AUTHENTIC Study.

Cardiovasc Drugs Ther 2021 04 21;35(2):331-341. Epub 2020 Oct 21.

Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Changle Road 68#, Nanjing, 210006, China.

Purpose: This study was to analyze the incidence of definite stent thrombosis (ST) after the implantation of drug-eluting stents (DESs) and cutoff value of overlapping length for predicting definite ST. An overlapping stent is associated with a high rate of clinical events after DES implantation compared with a non-overlapping stent. However, the rates of definite ST and clinical outcomes from a large patient population remain underreported.

Methods: A total of 15,561 patients with 24,183 lesions who underwent DES implantation from January 2005 to February 2017 were retrospectively included in 5 tertiary hospitals in China. The main endpoint was the incidence of definite ST after procedures.

Results: With a median of 1932 (IQR = 1194-2929) days, clinical follow-up was available in 7484 patients in the overlap group and in 8077 patients in the non-overlap group. The rates of definite ST were 3.1% in the overlap group and 1.2% in the non-overlap group (HR: 2.67 (95% CI: 2.11-3.38), p < 0.001). Of the 24,183 treated lesions, the incidences of definite ST were 2.4% in the overlap group and 0.9% in the non-overlap group (HR: 2.96 (95% CI: 2.38-3.69), p < 0.001). Stent overlap was associated with a higher rate of target lesion revascularization (TLR) (9.4%) compared with stent non-overlap (6.4%, p < 0.001). The length of overlapping stent ≥ 2.93 mm strongly correlated with definite ST.

Conclusion: The present study shows that overlapping DES increases definite ST and revascularization in patients during long-term follow-up. In addition, the longer overlapping zone was associated with worse clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10557-020-07094-7DOI Listing
April 2021

Extracellular matrix derived from allogenic decellularized bone marrow mesenchymal stem cell sheets for the reconstruction of osteochondral defects in rabbits.

Acta Biomater 2020 12 15;118:54-68. Epub 2020 Oct 15.

School of Stomatology, Southern Medical University, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China. Electronic address:

Bioactive scaffolds from synthetical polymers or decellularized cartilage matrices have been widely used in osteochondral regeneration. However, the risks of potential immunological reactions and the inevitable donor morbidity of these scaffolds have limited their practical applications. To address these issues, a biological extracellular matrix (ECM) scaffold derived from allogenic decellularized bone marrow mesenchymal stem cell (BMSC) sheets was established for osteochondral reconstruction. BMSCs were induced to form cell sheets. Three different concentrations of sodium dodecyl sulfate (SDS), namely, 0.5%, 1%, and 3%, were used to decellularize these BMSC sheets to prepare the ECM. Histological and microstructural observations were performed in vitro and then the ECM scaffolds were implanted into osteochondral defects in rabbits to evaluate the repair effect in vivo. Treatment with 0.5% SDS not only efficiently removed BMSCs but also successfully preserved the original structure and bioactive components of the ECM When compared with the 1% and 3% SDS groups, histological observations substantiated the superior repair effect of osteochondral defects, including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular cartilage integrated with native tissues in the 0.5% SDS group. Moreover, RT-PCR indicated that ECM scaffolds could promote the osteogenic differentiation potential of BMSCs under osteogenic conditions while increasing the chondrogenic differentiation potential of BMSCs under chondrogenic conditions. Allogenic BMSC sheets decellularized with 0.5% SDS treatment increased the recruitment of BMSCs and significantly improved the regeneration of osteochondral defects in rabbits, thus providing a prospective approach for both articular cartilage and subchondral bone reconstruction with cell-free transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2020.10.022DOI Listing
December 2020

Correlation of neutrophil-to-lymphocyte ratio with the prognosis of non-ST-segment elevation in patients with acute coronary syndrome undergoing selective percutaneous coronary intervention.

J Int Med Res 2020 Oct;48(10):300060520959510

Department of Cardiology, Changshu Hospital affiliated to Soochow University, Changshu No. 1 People's Hospital, Changshu, Jiangsu Province, China.

Objective: We aimed to explore the relationship between neutrophil-to-lymphocyte ratio (NLR) at three timepoints and prognosis of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing elective percutaneous coronary intervention (PCI) within 1 year of PCI.

Methods: This retrospective study enrolled 231 patients with NSTE-ACS who received PCI and were followed for 1 year after PCI. The study population was divided into major adverse cardiovascular and cerebrovascular events (MACE) and non-MACE groups.

Results: In total, 214 patients completed the 1-year follow-up; 32 patients (15.0%) had MACE and 182 (85.0%) had no MACE. The MACE and non-MACE groups differed significantly in age, preoperative neutrophil count, preoperative and postoperative NLR, proportion of three-vessel lesion disease, preoperative lymphocyte count, postoperative lymphocyte count within 24 hours, postoperative lymphocyte count over 24 hours, and left ventricular ejection fraction (LVEF). Multivariate logistic regression analysis showed that preoperative NLR, postoperative NLR within 24 hours, age, and LVEF values were independent risk factors for MACE in patients with NSTE-ACS after elective PCI.

Conclusion: Compared with preoperative NLR, postoperative NLR (within 24 hours) may have a stronger ability to predict the occurrence of MACE in NSTE-ACS patients within 1 year after elective PCI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0300060520959510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570302PMC
October 2020

Multi-omics prediction of immune-related adverse events during checkpoint immunotherapy.

Nat Commun 2020 10 2;11(1):4946. Epub 2020 Oct 2.

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA.

Immune-related adverse events (irAEs), caused by anti-PD-1/PD-L1 antibodies, can lead to fulminant and even fatal consequences and thus require early detection and aggressive management. However, a comprehensive approach to identify biomarkers of irAE is lacking. Here, we utilize a strategy that combines pharmacovigilance data and omics data, and evaluate associations between multi-omics factors and irAE reporting odds ratio across different cancer types. We identify a bivariate regression model of LCP1 and ADPGK that can accurately predict irAE. We further validate LCP1 and ADPGK as biomarkers in an independent patient-level cohort. Our approach provides a method for identifying potential biomarkers of irAE in cancer immunotherapy using both pharmacovigilance data and multi-omics data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18742-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532211PMC
October 2020

Adverse events associated with potential drugs for COVID-19: a case study from real-world data.

Brief Bioinform 2021 03;22(2):1232-1238

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, USA.

The coronavirus disease 2019 (COVID-19) has resulted as a global pandemic. The World Health Organization announced the most promising drugs in SOLIDARITY for the global trial, and several other drugs are under investigation through ongoing clinical trials to prove the effectiveness and safety of potential therapeutics. Here, we depicted the safety profile of these drugs and investigated their associated adverse events (AEs). We observed the associated AEs in different organs/systems, especially in skin and subcutaneous tissue, immune system and musculoskeletal and connective tissue. Furthermore, we observed strong bias of AEs in different groups of sex and age. Our study provides knowledge of the toxicity of potential COVID-19 drugs. While these drugs hold promise to fight the global pandemic, healthcare providers should pay attention to AEs to maximize the treatment benefit while minimizing toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bib/bbaa234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543289PMC
March 2021

Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1.

Genome Med 2020 09 28;12(1):83. Epub 2020 Sep 28.

Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Background: Immune checkpoint blockade (ICB) therapy has demonstrated considerable clinical benefit in several malignancies, but has shown favorable response in only a small proportion of cancer patients. Recent studies have shown that matrix metalloproteinases (MMPs) are highly associated with the microenvironment of tumors and immune cells. However, it is unknown whether MMPs are involved in immunotherapy.

Methods: Here, we used integrative analysis to explore the expression landscape of the MMP family and its association with immune features across multiple cancer types. We used T cell cytotoxicity-mediated tumor killing assay to determine the co-cultured T cell activity of SB-3CT, an MMP2/9 inhibitor. We then used in vitro assays to examine the regulating roles of SB-3CT on PD-L1. We further characterized the efficacy of SB-3CT, in combination with anti-PD-1 and/or anti-CTLA4 treatment in mouse models with melanoma and lung cancer.

Results: Our computational analysis demonstrated a strong association between MMP2/9 and immune features. We demonstrated that inhibition of MMP2/9 by SB-3CT significantly reduced the tumor burden and improved survival time by promoting anti-tumor immunity. Mechanistically, we showed that SB-3CT treatment significantly diminished both mRNA and protein levels of PD-L1 in cancer cells. Pre-clinically, SB-3CT treatment enhanced the therapeutic efficacy of PD-1 or CTLA-4 blockade in the treatment of both primary and metastatic tumors.

Conclusions: Our study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-020-00780-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523356PMC
September 2020
-->