Publications by authors named "Shao-Chun Wang"

80 Publications

Peimine inhibits variants of SARS-CoV-2 cell entry via blocking the interaction between viral spike protein and ACE2.

J Food Biochem 2022 Jul 27:e14354. Epub 2022 Jul 27.

Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.

Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several vaccines against SARS-CoV-2 have been approved; however, variants of concern (VOCs) can evade vaccine protection. Therefore, developing small compound drugs that directly block the interaction between the viral spike glycoprotein and ACE2 is urgently needed to provide a complementary or alternative treatment for COVID-19 patients. We developed a viral infection assay to screen a library of approximately 126 small molecules and showed that peimine inhibits VOCs viral infections. In addition, a fluorescence resonance energy transfer (FRET) assay showed that peimine suppresses the interaction of spike and ACE2. Molecular docking analysis revealed that peimine exhibits a higher binding affinity for variant spike proteins and is able to form hydrogen bonds with N501Y in the spike protein. These results suggest that peimine, a compound isolated from Fritillaria, may be a potent inhibitor of SARS-CoV-2 variant infection. PRACTICAL APPLICATIONS: In this study, we identified a naturally derived compound of peimine, a major bioactive alkaloid extracted from Fritillaria, that could inhibit SARS-CoV-2 variants of concern (VOCs) viral infection in 293T/ACE2 and Calu-3 lung cells. In addition, peimine blocks viral entry through interruption of spike and ACE2 interaction. Moreover, molecular docking analysis demonstrates that peimine has a higher binding affinity on N501Y in the spike protein. Furthermore, we found that Fritillaria significantly inhibits SARS-CoV-2 viral infection. These results suggested that peimine and Fritillaria could be a potential functional drug and food for COVID-19 patients.
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http://dx.doi.org/10.1111/jfbc.14354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353385PMC
July 2022

Natural tannins as anti-SARS-CoV-2 compounds.

Int J Biol Sci 2022 11;18(12):4669-4676. Epub 2022 Jul 11.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan, 40402.

Tannins are polyphenols enriched in wood, bark, roots, leaves, seeds and fruits of a variety of plants. Over the last two decades, there has been an increasing interest in understanding the biological functions of tannins and their applications as antioxidants, anticancer drugs, and food additives. Since the outbreak of the COVID-19 pandemic, much effort has been devoted to finding an expedient cure. Tannins have been put forward as having possible anti-COVID-19 properties; however, owing to the profuse nature of the structurally diverse derivatives of tannins, the tannin species in the family associated with an indication of anti-COVID-19 have been poorly defined, compounded by frequent terminology misnomers. This article reviews the tannin family in fruits and the current knowledge about the activities of the compounds with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It will aid molecular and cellular biologists in developing natural anti-viral chemicals as means of overcoming the current and future pandemics.
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http://dx.doi.org/10.7150/ijbs.74676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305278PMC
July 2022

Prospects of Coffee Leaf against SARS-CoV-2 Infection.

Int J Biol Sci 2022 11;18(12):4677-4689. Epub 2022 Jul 11.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan.

In the current climate, many countries are in dire need of effective preventive methods to curb the Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) pandemic. The purpose of this research is to screen and explore natural plant extracts that have the potential to against SARS-CoV-2 and provide alternative options for SARS-CoV-2 prevention and hand sanitizer or spray-like disinfectants. We first used Spike-ACE2 ELISA and TMPRSS2 fluorescence resonance energy transfer (FRET) assays to screen extracts from agricultural by-products from Taiwan with the potential to impede SARS-CoV-2 infection. Next, the SARS-CoV-2 pseudo-particles (Vpp) infection assay was tested to validate the effectiveness. We identified an extract from coffee leaf (), a natural plant that effectively inhibited wild-type SARS-CoV-2, and five Variants of Concern (Alpha, Beta, Gamma, Delta, and Omicron strain) from entering host cells. In an attempt to apply coffee leaf extract for hand sanitizer or spray-like disinfectants, we designed a skin-like gelatin membrane experiment. We showed that the high concentration of coffee leaf extract on the skin surface could block SARS-CoV-2 into cells more potently than 75% Ethanol, a standard disinfectant to inactivate SARS-CoV-2. Finally, LC-HRMS analysis was used to identify compounds such as caffeine, chlorogenic acid (CGA), quinic acid, and mangiferin that are associated with an anti-SARS-CoV-2 activity. Our results demonstrated that coffee leaf extract, an agricultural by-product effectively inhibits SARS-CoV-2 Vpp infection through an ACE2-dependent mechanism and may be utilized to develop products against SARS-CoV-2 infection.
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http://dx.doi.org/10.7150/ijbs.76058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305275PMC
July 2022

The Functions of PCNA in Tumor Stemness and Invasion.

Int J Mol Sci 2022 May 19;23(10). Epub 2022 May 19.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.

Invasion is the most prominent lethal feature of malignant cancer. However, how cell proliferation, another important feature of tumor development, is integrated with tumor invasion and the subsequent cell dissemination from primary tumors is not well understood. Proliferating cell nuclear antigen (PCNA) is essential for DNA replication in cancer cells. Loss of phosphorylation at tyrosine 211 (Y211) in PCNA (pY211-PCNA) mitigates PCNA function in proliferation, triggers replication fork arrest/collapse, which in turn sets off an anti-tumor inflammatory response, and suppresses distant metastasis. Here, we show that pY211-PCNA is important in stromal activation in tumor tissues. Loss of the phosphorylation resulted in reduced expression of mesenchymal proteins as well as tumor progenitor markers, and of the ability of invasion. Spontaneous mammary tumors that developed in mice lacking Y211 phosphorylation contained fewer tumor-initiating cells compared to tumors in wild-type mice. Our study demonstrates a novel function of PCNA as an essential factor for maintaining cancer stemness through Y211 phosphorylation.
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http://dx.doi.org/10.3390/ijms23105679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143764PMC
May 2022

Prospects of the potential strategies to improve the efficacy of anti-PD-1/PD-L1 therapy.

Clin Transl Med 2022 05;12(5):e803

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.

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http://dx.doi.org/10.1002/ctm2.803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119611PMC
May 2022

Erratum to 'Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma' [J Hepatol 2021 (907-918)].

J Hepatol 2022 Aug 27;77(2):580. Epub 2022 Apr 27.

Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2022.04.004DOI Listing
August 2022

Evaluation of Shear Capacity of Steel Fiber Reinforced Concrete Beams without Stirrups Using Artificial Intelligence Models.

Materials (Basel) 2022 Mar 24;15(7). Epub 2022 Mar 24.

School of Engineering, RMIT University, Melbourne, VIC 3000, Australia.

The shear transfer mechanism of steel fiber reinforced concrete (SFRC) beams without stirrups is still not well understood. This is demonstrated herein by examining the accuracy of typical empirical formulas for 488 SFRC beam test records compiled from the literature. To steer clear of these cognitive limitations, this study turned to artificial intelligence (AI) models. A gray relational analysis (GRA) was first conducted to evaluate the importance of different parameters for the problem at hand. The outcomes indicate that the shear capacity depends heavily on the material properties of concrete, the amount of longitudinal reinforcement, the attributes of steel fibers, and the geometrical and loading characteristics of SFRC beams. After this, AI models, including back-propagation artificial neural network, random forest and multi-gene genetic programming, were developed to capture the shear strength of SFRC beams without stirrups. The findings unequivocally show that the AI models predict the shear strength more accurately than do the empirical formulas. A parametric analysis was performed using the established AI model to investigate the effects of the main influential factors (determined by GRA) on the shear capacity. Overall, this paper provides an accurate, instantaneous and meaningful approach for evaluating the shear capacity of SFRC beams containing no stirrups.
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http://dx.doi.org/10.3390/ma15072407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254746PMC
March 2022

De-glycosylated membrane PD-L1 in tumor tissues as a biomarker for responsiveness to atezolizumab (Tecentriq) in advanced breast cancer patients.

Am J Cancer Res 2022 15;12(1):123-137. Epub 2022 Jan 15.

Research Center for Cancer Biology, China Medical University Taichung 40402, Taiwan.

The atezolizumab (Tecentriq), a humanized antibody against human programmed death ligand 1 (PD-L1), combined with nab-paclitaxel was granted with accelerated approval to treat unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) due to the encouraging positive results of the phase 3 IMpassion130 trial using PD-L1 biomarker from immune cells to stratify patients. However, the post-market study IMpassion131 did not support the original observation, resulting in the voluntary withdrawal of atezolizumab from the indication in breast cancer by Genentech in 2021. Emerging evidence has revealed a high frequency of false negative result using the standard immunohistochemical (IHC) staining due to heavy glycosylation of PD-L1. The removal of glycosylation prevents from the false negative staining, enabling more accurate assessment of PD-L1 levels and improving prediction for response to immune checkpoint therapy. In the present study, the natural and de-glycosylated PD-L1 expression in tumor and immune cells from nine TNBC patients were analyzed by using clone 28-8 monoclonal antibody to correlate with treatment outcome. Our results demonstrate that: (1) Removal of the glycosylation indeed enhances the detection of PD-L1 by IHC staining, (2) The PD-L1 levels on tumor cell surface after removal of the glycosylation correlates well with clinical responses for atezolizumab treatment; (3) The criteria used in the IMpassion130 and IMpassion131 trials which scored the natural PD-L1 in the immune cells failed to correlate with the clinical response. Taken together, tumor cell surface staining of PD-L1 with de-glycosylation has a significant correlation with the clinical response for atezolizumab treatment, suggesting that treatment of atezolizumab may be worthy of further consideration with de-glycosylation procedure as a patient stratification strategy. A larger cohort to validate this important issue is warranted to ensure right patient population who could benefit from the existing FDA-approved drugs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822291PMC
January 2022

miR-4759 suppresses breast cancer through immune checkpoint blockade.

Comput Struct Biotechnol J 2022 16;20:241-251. Epub 2021 Dec 16.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.

Programmed cell death protein 1 (PD-1)/ programmed cell death protein ligand 1 (PD-L1) is the key immune checkpoint governing evasion of advanced cancer from immune surveillance. Immuno-oncology (IO) therapy targeting PD-1/PD-L1 with traditional antibodies is a promising approach to multiple cancer types but to which the response rate remains moderate in breast cancer, calling for the need of exploring alternative IO targeting approaches. A miRNA-gene network was integrated by a bioinformatics approach and corroborated with The Cancer Genome Atlas (TCGA) to screen miRNAs regulating immune checkpoint genes and associated with patient survival. Here we show the identification of a novel microRNA miR-4759 which repressed RNA expression of the PD-L1 gene. miR-4759 targeted the PD-L1 gene through two binding motifs in the 3' untranslated region (3'-UTR) of PD-L1. Reconstitution of miR-4759 inhibited PD-L1 expression and sensitized breast cancer cells to killing by immune cells. Treatment with miR-4759 suppressed tumor growth of orthotopic xenografts and promoted tumor infiltration of CD8 T lymphocytes in immunocompetent mice. In contrast, miR-4759 had no effect to tumor growth in immunodeficient mice. In patients with breast cancer, expression of miR-4759 was preferentially downregulated in tumors compared to normal tissues and was associated with poor overall survival. Together, our results demonstrated miR-4759 as a novel non-coding RNA which promotes anti-tumor immunity of breast cancer.
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http://dx.doi.org/10.1016/j.csbj.2021.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718579PMC
December 2021

Suppression of breast cancer cells resistant to a pure anti-estrogen with CAR-transduced natural killer cells.

Am J Cancer Res 2021 15;11(9):4455-4469. Epub 2021 Sep 15.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University Taichung 40402, Taiwan.

Anti-estrogens as hormone therapy are the mainstay treatment for estrogen receptor (ER)-positive breast cancer. ER inhibitors through modulating the transcriptional function of ER have been the frontline anti-estrogens to which refractory phenotype often developed in advanced cancer. The anti-estrogen fulvestrant is currently the only clinically approved pure anti-estrogen which causes ER degradation. However, resistance to fulvestrant still occurs and unfortunately it leaves few choices other than chemotherapy as the later-line treatments to fulvestrant-resistant tumors. Here we show that fulvestrant resistance was accompanied by increased expression of a number of innate immune response genes including the natural killer (NK) cell ligand B7-H6 on the cell surface. In an attempt to overcome the drug resistance phenotype, a NK-based molecular approach taking advantage of a chimeric antigen receptor (CAR) system targeting B7-H6 was established and tested in cells with acquired resistance to fulvestrant. The results demonstrate that the cell therapy approach as a single agent can effectively induce cell death of the resistant cancer cells which is enhanced by the increased expression of cell surface B7-H6. This approach departs from the traditional strategies of conquering anti-estrogen resistant breast cancer and offers a new avenue to eradicate hormone-refractory malignant solid tumors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493389PMC
September 2021

Interdisciplinary treatment with implant-supported two-unit cantilever prosthesis for a patient with hypodontia: A clinical report.

J Prosthet Dent 2021 Sep 3. Epub 2021 Sep 3.

Attending Physician, Division of Periodontics, Department of Stomatology, National Cheng Kung University Hospital, Tainan, Taiwan, ROC.

A 21-year-old woman with multiple congenitally missing maxillary anterior teeth received interdisciplinary treatment to restore function and esthetics. The treatment was initiated with orthodontic treatment, followed by implant placement, bone and soft-tissue augmentation, and prosthetic treatment including a screw-retained implant-supported 2-unit cantilever fixed dental prosthesis.
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http://dx.doi.org/10.1016/j.prosdent.2021.07.023DOI Listing
September 2021

Evading immune surveillance via tyrosine phosphorylation of nuclear PCNA.

Cell Rep 2021 08;36(8):109537

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan; Research Center for Tumor Medical Science, China Medical University, Taichung 40402, Taiwan; Drug Development Center, China Medical University, Taichung 40402, Taiwan; Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address:

Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer.
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http://dx.doi.org/10.1016/j.celrep.2021.109537DOI Listing
August 2021

Reducing Antisolvent Use in the STRAP Process by Enabling a Temperature-Controlled Polymer Dissolution and Precipitation for the Recycling of Multilayer Plastic Films.

ChemSusChem 2021 Oct 6;14(19):4317-4329. Epub 2021 Sep 6.

Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI, 53706, USA.

The recently reported processing strategy called solvent-targeted recovery and precipitation (STRAP) enables deconstruction of multilayer plastic packaging films into their constituent resins by selective dissolution. It uses a series of solvent washes that are guided by thermodynamic calculations of polymer solubility. In this work, the use of antisolvents in the STRAP process was reduced and solvent mixtures were considered to enable the temperature-controlled dissolution and precipitation of the target polymers in multilayer films. This was considered as a means to further improve the STRAP process and its estimated costs. Two STRAP approaches were compared based on different polymer precipitation techniques: precipitation by the addition of an antisolvent (STRAP-A) and precipitation by decreasing the solvent temperature (STRAP-B). Both approaches were able to separate the constituent polymers in a post-industrial film composed primarily of polyethylene (PE), ethylene vinyl alcohol (EVOH), and polyethylene terephthalate (PET) with near 100 % material efficiency. Technoeconomic analysis indicates that the minimum selling price (MSP) of the recycled resins with STRAP-B is 21.0 % lower than that achieved with STRAP-A. This provides evidence that thermally driven polymer precipitation is an option to reduce the use of antisolvents, making the STRAP process more economically and environmentally attractive. A third process, STRAP-C, was demonstrated with another post-industrial multilayer film of a different composition. The results demonstrate that this process can also recover polymers at similar costs to those of virgin resins, indicating that the STRAP technology is flexible and can remain economically competitive as the plastic feed complexity is increased.
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http://dx.doi.org/10.1002/cssc.202101128DOI Listing
October 2021

Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles.

Int J Mol Sci 2021 Jun 28;22(13). Epub 2021 Jun 28.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.
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http://dx.doi.org/10.3390/ijms22136938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268654PMC
June 2021

D. Don Inhibits the Main Proteases (M and TMPRSS2) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Viruses 2021 05 2;13(5). Epub 2021 May 2.

Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan.

In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, M and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of M and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or M. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting M and TMPRSS2 protease activities.
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http://dx.doi.org/10.3390/v13050826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147405PMC
May 2021

Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation.

Nat Commun 2021 05 13;12(1):2788. Epub 2021 May 13.

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

Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.
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http://dx.doi.org/10.1038/s41467-021-23075-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119676PMC
May 2021

Aptamer-guided targeting of the intracellular long-noncoding RNA .

Am J Cancer Res 2021 1;11(3):945-954. Epub 2021 Mar 1.

Center for Molecular Medicine, China Medical University Hospital Taichung 40402, Taiwan.

Long non-coding RNAs (lncRNAs) are increasingly recognized as promising targets in cancer treatment. However, compared to targeting the ordinary protein-coding genes, suppressing non-coding RNAs expressed in cancer cells has been a more challenging task. The major hurdles lay on the requirement of a tumor-specific delivery system for the designated inhibitor to suppress the target transcripts within the cellular compartment. EGFR is a cancer driver gene which is frequently associated with the triple-negative phenotype of breast cancer. Prior studies have shown that expression of the tumor-promoting lncRNA () is positively regulated by the epithelial growth factor receptor (EGFR) in triple-negative breast cancer (TNBC), and consistently the expression of both genes is closely correlated in breast cancer. Here we show that a chimeric aptamer recognizing the epithelial growth factor receptor (EGFR) coupled with a siRNA against (EGFR aptamer-coupled ) preferentially and effectively down-regulated in EGFR-expressing cancer cells. Functionally, the EGFR aptamer-coupled more potently inhibited the growth, migration, and invasion of EGFR-expressing TNBC cells as well as cells with reconstituted EGFR compared to cancer cells with low EGFR expression. Our results demonstrate a novel strategy of targeting cancer progression by aptamer-directed delivery of anti-lncRNA RNA interference that can be applicable to other cellular contexts and cancer types.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994153PMC
March 2021

Aryl hydrocarbon receptor promotes lipid droplet biogenesis and metabolic shift in respiratory Club cells.

Hum Cell 2021 May 8;34(3):785-799. Epub 2021 Mar 8.

National Institute of Environmental Health Sciences, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli County, 35053, Taiwan.

Club cells are critical in maintaining airway integrity via, in part, secretion of immunomodulatory Club cell 10 kd protein (CC10) and xenobiotic detoxification. Aryl hydrocarbon receptor (AhR) is important in xenobiotic metabolism, but its role in Club cell function is unclear. To this end, an AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ, 10 nM) was found to induce, in a ligand and AhR-dependent manner, endoplasmic reticulum stress, phospholipid remodeling, free fatty acid and triglyceride synthesis, leading to perilipin 2-dependent lipid droplet (LD) biogenesis in a Club cell-like cell line, NL20. The increase in LDs was due, in part, to the blockade of adipose triglyceride lipase to LDs, while perilipin 5 facilitated LDs-mitochondria connection, leading to the breakdown of LDs via mitochondrial β-oxidation and acetyl-coA generation. In FICZ-treated cells, increased CC10 secretion and its intracellular association with LDs were noted. Administration of low (0.28 ng), medium (1.42 ng), and high (7.10 ng) doses of FICZ in C57BL/6 mice significantly enhanced lipopolysaccharide (LPS, 0.1 μg)-induced airway inflammation, mucin secretion, pro-inflammatory cytokines and CC10 in the bronchoalveolar lavage fluids, as compared to those seen in mice receiving LPS alone, suggesting the importance of AhR signaling in controlling the metabolic homeostasis and functions of Club cells.
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http://dx.doi.org/10.1007/s13577-021-00491-6DOI Listing
May 2021

Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease.

Am J Cancer Res 2020 1;10(12):4538-4546. Epub 2020 Dec 1.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University Taichung 40402, Taiwan.

The cell surface protein TMPRSS2 (transmembrane protease serine 2) is an androgen-responsive serine protease important for prostate cancer progression and therefore an attractive therapeutic target. Besides its role in tumor biology, TMPRSS2 is also a key player in cellular entry by the SARS-CoV viruses. The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has resulted in huge losses in socio-economy, culture, and human lives for which safe and effective cures are highly demanded. The main protease (M/3CL) of SARS-CoV-2 is a critical enzyme for viral propagation in host cells and, like TMPRSS2, has been exploited for treatment of the infectious disease. Numerous natural compounds abundant in common fruits have been suggested with anti-coronavirus infection in the previous outbreaks of SARS-CoV. Here we show that screening of these compounds identified tannic acid a potent inhibitor of both SARS-CoV-2 M and TMPRSS2. Molecular analysis demonstrated that tannic acid formed a thermodynamically stable complex with the two proteins at a K of 1.1 mM for M and 1.77 mM for TMPRSS2. Tannic acid inhibited the activities of the two proteases with an IC of 13.4 mM for M and 2.31 mM for TMPRSS2. M protein. Consistently, functional assays using the virus particles pseudotyped (Vpp) of SARS-CoV2-S demonstrated that tannic acid suppressed viral entry into cells. Thus, our results demonstrate that tannic acid has high potential of developing anti-COVID-19 therapeutics as a potent dual inhibitor of two independent enzymes essential for SARS-CoV-2 infection.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783773PMC
December 2020

Single-cell analysis reveals immune modulation and metabolic switch in tumor-draining lymph nodes.

Oncoimmunology 2020 10 19;9(1):1830513. Epub 2020 Oct 19.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Lymph-node metastasis is a prognosis factor for poor clinical outcome of breast cancer patients. Currently, how breast cancer cells establish pre-metastatic niche in the tumor-draining lymph nodes (TDLNs) is still unclear. To address this question, we isolated heterogeneous cells including immune and stromal cells from naive lymph nodes (LNs) of the FVB/NJ mice and TDLNs of the MMTV-PyMT mice. Single-cell RNA sequencing was performed to investigate the transcriptome of the cells and various bioinformatics analyses were used to identify the altered pathways. Our results revealed several significant changes between naïve LNs and TDLNs. First, according to immunologic signature and pathway analysis, CD4+ and CD8 + T cells showed upregulated angiogenesis pathway genes and higher regulatory T (Treg)-associated genes while they demonstrated downregulation of interferon response and inflammatory response gene signatures, concurrently suggesting an immunosuppressive microenvironment in the TDLNs. Second, profiling of B cells showed down-regulation of marginal zone B lymphocytes in the TDLNs, which was validated by flow cytometric analysis. Third, we found the enhancement of oxidative phosphorylation pathway in the fibroblastic reticular cells (FRCs) of the MMTV-PyMT mice and the elevation of related genes including and , suggesting massive ATP consumption and TCA cycle metabolism in the FRCs. Collectively, our results reveal the reprogramming of TDLNs during breast cancer progression at single-cell level in a spontaneous breast cancer model and suggest the changes in immune modulation and metabolic switch are key alterations in the preparation of pre-metastatic niche by breast cancer cells.
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http://dx.doi.org/10.1080/2162402X.2020.1830513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575008PMC
October 2020

Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma.

J Hepatol 2021 04 5;74(4):907-918. Epub 2020 Oct 5.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan. Electronic address:

Background & Aims: There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC.

Methods: Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and invasion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent patient cohorts were analyzed to evaluate the pathological relevance of RNase7/ROS1.

Results: RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice.

Conclusions: RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment.

Lay Summary: Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeutically for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important pathophysiological and therapeutic implications. Anti-ROS1 inhibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels.
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http://dx.doi.org/10.1016/j.jhep.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979498PMC
April 2021

EFHD2 contributes to non-small cell lung cancer cisplatin resistance by the activation of NOX4-ROS-ABCC1 axis.

Redox Biol 2020 07 16;34:101571. Epub 2020 May 16.

Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address:

Recurrence and metastasis remain the major cause of cancer mortality. Even for early-stage lung cancer, adjuvant chemotherapy yields merely slight increase to patient survival. EF-hand domain-containing protein D2 (EFHD2) has recently been implicated in recurrence of patients with stage I lung adenocarcinoma. In this study, we investigated the correlation between EFHD2 and chemoresistance in non-small cell lung cancer (NSCLC). High expression of EFHD2 was significantly associated with poor overall survival of NSCLC patients with chemotherapy in in silica analysis. Ectopic EFHD2 overexpression increased cisplatin resistance, whereas EFHD2 knockdown improved chemoresponse. Mechanistically, EFHD2 induced the production of NADPH oxidase 4 (NOX4) and in turn the increase of intracellular reactive oxygen species (ROS), consequently activating membrane expression of the ATP-binding cassette subfamily C member 1 (ABCC1) for drug efflux. Non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppressed EFHD2 expression by leading to the proteasomal and lysosomal degradation of EFHD2 through a cyclooxygenase (COX)-independent mechanism. Combining ibuprofen with cisplatin enhanced antitumor responsiveness in a murine xenograft model in comparison with the individual treatment. In conclusion, we demonstrate that EFHD2 promotes chemoresistance through the NOX4-ROS-ABCC1 axis and therefore developing EFHD2-targeting strategies may offer a new avenue to improve adjuvant chemotherapy of lung cancer.
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http://dx.doi.org/10.1016/j.redox.2020.101571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243194PMC
July 2020

Association of Interleukin-4 Polymorphisms With Breast Cancer in Taiwan.

In Vivo 2020 May-Jun;34(3):1111-1116

Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, R.O.C.

Background/aim: The present study aimed at evaluating the contribution of IL-4 promoter T-1099G (rs2243248), C-589T (rs2243250), C-33T (rs2070874) genotypes to the risk of breast cancer in Taiwanese.

Materials And Methods: A total of 1232 breast cancer patients and 1232 age-matched controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.

Results: Genotypic frequencies of IL-4 rs2243248, rs2243250 and rs2070874 were not differentially distributed between case and control groups. Consistently, there was no difference in the distribution of allelic frequencies among patients and controls.

Conclusion: IL-4 rs2243248, rs2243250 and rs2070874 do not confer breast cancer susceptibility in Taiwanese.
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http://dx.doi.org/10.21873/invivo.11882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279797PMC
February 2021

Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy.

Cancer Cell 2019 08 18;36(2):168-178.e4. Epub 2019 Jul 18.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address:

Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.
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http://dx.doi.org/10.1016/j.ccell.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6793936PMC
August 2019

IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion.

J Clin Invest 2019 07 15;129(8):3324-3338. Epub 2019 Jul 15.

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

Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy.
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http://dx.doi.org/10.1172/JCI126022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668668PMC
July 2019

Long non-coding RNA HOTAIR in circulatory exosomes is correlated with ErbB2/HER2 positivity in breast cancer.

Breast 2019 Aug 3;46:64-69. Epub 2019 May 3.

Center for Molecular Medicine, China Medical University Hospital, Taichung, 40447, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, 40402, Taiwan; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45267, USA; Department of Biotechnology, Asia University, Taichung, 413, Taiwan; China Medical University-Academia Sinica PhD Program of Cancer Biology and Drug Development, Taiwan; China Medical University-Academia Sinica PhD Program of Translational Medicine, Taiwan. Electronic address:

Cancer cells are known to produce and secret extracellular vesicles for intercellular communication through the carried cargos. HOTAIR (HOX transcript antisense intergenic RNA), a well-studied long non-coding RNA (lncRNA), plays a critical role in cancer progression. In several cancer types it has been shown that HOTAIR-containing exosomes are produced by cancer cells. Here we show that circulatory exosomal HOTAIR is present in breast cancer patients and explores the pathological correlation with the disease. Exosomes were isolated by matrix-based precipitation from conditioned media of cultured breast cancer cell lines as well as blood samples of recently recruited breast cancer patients. HOTAIR RNA in exosomes was detected by quantitative reverse transcriptase-mediated polymerase chain reaction (qRT-PCR). Expression of exosomal HOTAIR was positively correlated with status of the receptor tyrosine kinase (RTK) ErbB2 (also known as HER2/neu) in tumor tissues. The causal correlation of ErbB2 and HOTAIR was validated in isogenic breast cancer cell lines with and without ectopic ErbB2 expression. Our finding provides a molecular basis to develop novel liquid biopsy biomarkers and targeted therapies with improved precision for malignant breast cancer.
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http://dx.doi.org/10.1016/j.breast.2019.05.003DOI Listing
August 2019

Long noncoding RNA HOTAIR promotes invasion of breast cancer cells through chondroitin sulfotransferase CHST15.

Int J Cancer 2019 11 26;145(9):2478-2487. Epub 2019 Apr 26.

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.

The long noncoding RNA HOTAIR plays significant roles in promoting cancer metastasis. However, how it conveys an invasive advantage in cancer cells is not clear. Here we identify the chondroitin sulfotransferase CHST15 (GalNAc4S-6ST) as a novel HOX transcript antisense intergenic RNA (HOTAIR) target gene using RNA profiling and show that CHST15 is required for HOTAIR-mediated invasiveness in breast cancer cells. CHST15 catalyzes sulfation of the C6 hydroxyl group of the N-acetyl galactosamine 4-sulfate moiety in chondroitin sulfate to form the 4,6-disulfated chondroitin sulfate variant known as the CS-E isoform. We show that HOTAIR is necessary and sufficient for CHST15 transcript expression. Inhibition of CHST15 by RNA interference abolished cell invasion promoted by HOTAIR but not on HOTAIR-mediated migratory activity. Conversely, reconstitution of CHST15 expression rescued the invasive activity of HOTAIR-depleted cells. In corroboration with this mechanism, blocking cell surface chondroitin sulfate using a pan-CS antibody or an antibody specifically recognizes the CS-E isoform significantly suppressed HOTAIR-induced invasion. Inhibition of CHST15 compromised tumorigenesis and metastasis in orthotopic breast cancer xenograft models. Furthermore, the expression of HOTAIR closely correlated with the level of CHST15 protein in primary as well as metastatic tumor lesions. Our results demonstrate a novel mechanism underlying the function of HOTAIR in tumor progression through programming the context of cell surface glycosaminoglycans. Our results further establish that the invasive and migratory activities downstream of HOTAIR are distinctly regulated, whereby CHST15 preferentially controls the arm of invasiveness. Thus, the HOTAIR-CHST15 axis may provide a new avenue toward novel therapeutic strategies and prognosis biomarkers for advanced breast cancer.
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http://dx.doi.org/10.1002/ijc.32319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263025PMC
November 2019

Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells.

Am J Cancer Res 2019 1;9(3):608-618. Epub 2019 Mar 1.

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

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are promising targeted therapeutics for breast and ovarian cancers bearing a germline mutation ( ), and several have already received regulatory approval in the United States. In patients with a cancer, PARPi can increase the burden of unrepaired DNA double-strand breaks by blocking PARP activity and trapping PARP1 onto damaged DNA. Resistance to PARP inhibitors can block the formation of DNA double-strand breaks through BRCA-related DNA repair pathway. MET is a hyper-activated receptor tyrosine kinase expressed in multiple cancer types and the activation contributes to resistance to DNA damage-inducing therapeutic drugs. Our previous study showed that MET inhibition by pan-kinase inhibitors has synergism with PARPi in suppressing growth of breast cancer and in xenograft tumor models. In this study, we validated the inhibitory effect of novel inhibitors, HS10241 (selective MET inhibitor) and HS10160 (PARPi), to their target respectively in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) cells. We further demonstrated that these two inhibitors function synergistically in eliminating TNBC and HGSOC cells; combining with HS10241 increased DNA double-strand breaks induced by HS10160 in cancer cells; and PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) can be an effective biomarker as an indicator of MET-mediated PARPi in HGSOC. Our results suggest that the combination of HS10241 and HS10160 may benefit patients bearing tumors overexpressing MET as well as those resistant to single-agent PARPi treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448061PMC
March 2019

The exosomal compartment protects epidermal growth factor receptor from small molecule inhibitors.

Biochem Biophys Res Commun 2019 02 23;510(1):42-47. Epub 2019 Jan 23.

Center for Molecular Medicine, China Medical University Hospital, Taichung, 40447, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, 40402, Taiwan; Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, 45267, USA; Department of Biotechnology, Asia University, Taichung, 413, Taiwan. Electronic address:

Epidermal growth factor receptor (EGFR) plays a significant role in promoting breast cancer progression. However, targeting EGFR as a single treatment only resulted in moderate efficacy to the disease. The underlying mechanism of low responsiveness to EGFR inhibition remains largely unclear. Tumor-secreted extracellular vesicles (EVs) play a crucial role in mediating intercellular communication between tumor and stromal cells in local microenvironment and distant metastatic niche. Extracellular vesicles mediate cell-to-cell transfer of lipids, nucleic acids, and proteins. Although numerous recent studies have demonstrated exchanges of extracellular vesicles between cancer cells and the recipient cells contribute to tumor proliferation, invasion, and metastasis, yet little is known how the exosomal compartment responds to targeted therapies and their role in promoting drug resistance. In the current study we used a triple-negative breast cancer model to show that EV-encapsulated EGFR is protected from targeted inhibitors of EGFR and can trigger signaling pathway in recipient cancer cells, promoting proliferation and migration ability in vitro. Taken together, our study suggested a novel mechanism of drug resistance entailing the EV compartment, such as exosomes, as a target shelter which when released can signal for tumor promotion in the recipient cancer cells.
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http://dx.doi.org/10.1016/j.bbrc.2018.12.187DOI Listing
February 2019

Echocardiographic strain in hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy.

Echocardiography 2019 02 18;36(2):257-265. Epub 2018 Dec 18.

State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Center for Vascular Evaluations, The Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: The myocardial structure differs between secondary left ventricular hypertrophy (LVH) and hypertrophic cardiomyopathy (HCM). We investigated left ventricular function of these two types of hypertrophy using multilayer strain analysis with two-dimensional echocardiography.

Methods: Transthoracic echocardiography (Vivid-E9) was performed in 240 patients with preserved left ventricular ejection fraction (LVEF ≥50%) and with either HCM (n = 80, 63 men, age 49.8 ± 14.1 years), hypertensive LVH (n = 80, 63 men, age 51.4 ± 13.3 years) or normal blood pressure and left ventricular structure (n = 80, 63 men, 50.8 ± 12.4 years). Quantitative multilayer longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were analyzed. The ratio of endo-/epi-myocardial strain was calculated.

Results: Longitudinal strain was significantly (P < 0.001) lower in HCM patients than normal controls (15.2 ± 4.2% vs 23.1 ± 2.7%), especially in hypertrophic segments (14.5 ± 4.4% vs 17.2 ± 3.2% in nonhypertrophic segments, P < 0.01). LS was lower in patients with hypertensive LVH, similarly in all left ventricular segments (20.7 ± 3.7%, P < 0.001 vs controls). CS was lower in the mid- and epicardium (P < 0.01), but not endocardium in HCM (P = 0.4), and preserved in all myocardial layers in hypertensive LVH. The endo-/epi-myocardial ratios of both LS and CS were higher in HCM than hypertensive LVH (P < 0.01). RS was higher (P < 0.01) in HCM than hypertensive LVH and controls. Endocardial CS and global RS were correlated with LVEF (r ≥ 0.32, P < 0.01).

Conclusions: Hypertrophic cardiomyopathy patients had marked reductions in LS and CS, whereas patients with hypertensive LVH had less reduction in LS and preserved CS. The increased endo-/epi-myocardial ratios of LS and CS may be useful in differentiating HCM from hypertensive LVH.
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http://dx.doi.org/10.1111/echo.14222DOI Listing
February 2019
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