Publications by authors named "Ya-Ling Hsu"

152 Publications

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma.

J Pers Med 2021 Feb 13;11(2). Epub 2021 Feb 13.

Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan.

Immune tumor microenvironment (TME) in neuroblastoma (NBL) contributes to tumor behavior and treatment response. T cells and natural killer (NK) cells have been shown to play important roles in the neuroblastoma TME. However, few reports address the clinical relevance of natural killer T cells (NKTs) and interleukin-15 (IL-15), one of the crucial cytokines controlling the activation and expansion of NK/NKT cells, in NBL. In this study, we examined NKT immunoscores and IL-15 expression in both MYCN-amplified and MYCN-non-amplified NBL to correlate with clinical outcomes such as event-free survival (EFS) and overall survival (OS). From Gene Expression Omnibus (GEO) datasets GSE45480 ( = 643) and GSE49711 ( = 493), we found that NKT immunoscore and IL-15 expression were both significantly lower in MYCN-amplified NBL, and similar results were observed using our clinical NBL samples ( = 53). Moreover, NBL patients (GEO dataset GSE49711 and our clinical samples) with both lower NKT immunoscore and IL-15 expression exhibited decreased EFS and OS regardless of MYCN gene amplification status. Multivariate analysis further showed that the combination of low NKT immunoscore and low IL-15 expression level was an independent prognostic factor for poor EFS and OS in our NBL patients. These findings provide the rationale for the development of strategy to incorporate IL-15 and NKT cell therapy into the treatment regimen for neuroblastoma.
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http://dx.doi.org/10.3390/jpm11020122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918138PMC
February 2021

The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients.

Sci Rep 2021 Feb 15;11(1):3786. Epub 2021 Feb 15.

Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Protein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C-C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.
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http://dx.doi.org/10.1038/s41598-021-83383-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884394PMC
February 2021

High B3GALT5 expression confers poor clinical outcome and contributes to tumor progression and metastasis in breast cancer.

Breast Cancer Res 2021 Jan 7;23(1). Epub 2021 Jan 7.

Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan.

Background: Existence of breast cancer stem cells (BCSCs) is implicated in disease relapse, metastasis, and resistance of treatment. β1,3-Galactosyltransferase 5 (B3GALT5) has been shown to be a pro-survival marker for BCSCs. However, little is known about the prognostic significance of B3GALT5 in breast cancer.

Methods: Paired tissues (tumor part and adjacent non-tumor part) from a cohort of 202 women with breast cancer were used to determine the expression levels of B3GALT5 mRNA by qRT-PCR. Kaplan-Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of relapse-free survival (RFS) and overall survival (OS). Both breast cancer cells and cancer stem cells (BCSCs) were used to see the in vitro effects of knockdown or overexpression of B3GALT5 on cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). A patient-derived xenograft (PDX) model was used to see the in vivo effects of knockdown of B3GALT5 in BCSCs on tumor growth and metastasis.

Results: Higher expression of B3GALT5 in 202 breast cancer tissues, especially in adjacent non-tumor tissue, correlated with poor clinical outcomes including shorter OS and RFS in all patients, especially those with early stage breast cancer. In vitro studies showed B3GALT5 could enhance cell migration, invasion, mammosphere formation, and EMT. Of note, B3GALT5 upregulated the expression of β-catenin and EMT activator zinc finger E-box binding homeobox 1 (ZEB1) pathway in BCSCs. In vivo studies showed B3GALT5 expression in BCSCs is critical for not only tumor growth but also lymph node and lung metastasis in PDX mice.

Conclusion: Our results demonstrated the value of B3GALT5 as a prognostic marker of breast cancer, especially among the early stage patients, and its crucial roles in regulating EMT, cell migration, and stemness thereby promoting breast cancer progression.
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http://dx.doi.org/10.1186/s13058-020-01381-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792347PMC
January 2021

The Potential Effects of Curcumin on Pulmonary Fibroblasts of Idiopathic Pulmonary Fibrosis (IPF)-Approaching with Next-Generation Sequencing and Bioinformatics.

Molecules 2020 Nov 21;25(22). Epub 2020 Nov 21.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. Currently, therapeutic options are limited for this fatal disease. Curcumin, with its pleiotropic effects, has been studied for its potential therapeutic utilities in various diseases, including pulmonary fibrosis. However, the detailed mechanisms have not been studied comprehensively. We conducted a next-generation sequencing and bioinformatics study to investigate changes in the profiles of mRNA and microRNA after curcumin treatment in IPF fibroblasts. We identified 23 downregulated and 8 upregulated protein-coding genes in curcumin-treated IPF fibroblasts. Using STRING and IPA, we identified that suppression of cell cycle progression was the main cellular function associated with these differentially expressed genes. We also identified 13 downregulated and 57 upregulated microRNAs in curcumin-treated IPF fibroblasts. Further analysis identified a potential microRNA-mediated gene expression alteration in curcumin-treated IPF fibroblasts, namely, downregulated hsa-miR-6724-5p and upregulated . Therefore, curcumin might decrease the level of hsa-miR-6724-5p, leading to increased expression, resulting in cell cycle arrest in curcumin-treated IPF fibroblasts. In conclusion, our findings might support the potential role of curcumin in the treatment of IPF, but further in-depth study is warranted to confirm our findings.
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http://dx.doi.org/10.3390/molecules25225458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700625PMC
November 2020

The Expression Profile of mRNA and tRNA Genes in Splenocytes and Neutrophils after In Vivo Delivery of Antitumor Short Hairpin RNA of Indoleamine 2,3- Dioxygenase.

Int J Mol Sci 2020 Sep 13;21(18). Epub 2020 Sep 13.

Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

RNA-based therapeutics are considered as novel treatments for human diseases. Our previous study demonstrated that treatment with short-hairpin RNA against (IDO shRNA) suppresses tumor growth, detects Th1-bias immune responses, and elevates expression of tryptophan transfer RNA (tRNA) in total splenocytes. In addition, depletion of Ly6g neutrophils attenuates the effect of IDO shRNA. The aim of this study was to investigate the regulatory network and the expression profile of tRNAs and other non-coding RNAs in IDO shRNA-treated spleens. The total splenocytes and magnetic bead-enriched splenic neutrophils were collected from the lung tumor bearing mice, which were treated with IDO shRNA or scramble IDO shRNA, and the collected cells were subsequently subjected to RNA sequencing. The gene ontology analysis revealed the different enrichment pathways in total splenocytes and splenic neutrophils. Furthermore, the expression of tRNA genes was identified and validated. Six isoacceptors of tRNA, with different expression patterns between total splenocytes and splenic neutrophils, were observed. In summary, our findings not only revealed novel biological processes in IDO shRNA-treated total splenocytes and splenic neutrophils, but the identified tRNAs and other non-coding RNAs may contribute to developing a novel biomarker gene set for evaluating the clinical efficiency of RNA-based cancer immunotherapies.
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http://dx.doi.org/10.3390/ijms21186703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555719PMC
September 2020

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis.

Int J Mol Sci 2020 Jul 18;21(14). Epub 2020 Jul 18.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF's over-activation affects lung cancer angiogenesis not only in a normoxic condition, but also a hypoxic niche. Our study shows that human lung cancer exhibits elevated levels of ceruloplasmin (CP), which has a negative impact on the prognosis of patients. CP affects the cellular Fe level, which inactivates prolyl hydroxylase (PHD) 1 and 2, resulting in HIF-2α enhancement. Increased HIF-2α leads to vascular endothelial growth factor-A (VEGF-A) secretion and angiogenesis. The expression of CP is under the epigenetic control of miR-145-5p. Restoration of miR-145-5p by miRNA mimics transfection decreases CP expression, increases Fe and PHD1/2 levels and HIF hydroxylation while reduced HIF-2α levels resulting in the inhibition of tumor angiogenesis. In contrast, inhibition of miR-145-5p by miRNA inhibitors increases the expression of CP and VEGF-A in lung cancer cells. Significantly, miR-145-5p expression is lost in the tumor samples of lung cancer patients, and low miR-145-5p expression is strongly correlated with a shorter overall survival time. In conclusion, the current study reveals the clinical importance and prognostic value of miR-145-5p and CP. It identifies a unique mechanism of HIF-2α over-activation, which is mediated by iron imbalance of the iron-PHD coupling that modulates tumor angiogenesis.
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http://dx.doi.org/10.3390/ijms21145081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404111PMC
July 2020

Associations of Bone Turnover Markers with Cognitive Function in Patients Undergoing Hemodialysis.

Dis Markers 2020 21;2020:8641749. Epub 2020 Apr 21.

Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Patients undergoing hemodialysis experience a greater risk of cognitive impairment than the general population, but limited data elucidates the biomarkers on this. We evaluated the association of bone turnover markers on cognitive function among 251 prevalent hemodialysis enrollees in a cross-sectional study.

Methods: 251 hemodialysis patients (median age = 57.8, 55% men) and 37 control subjects (mean age = 61.2, 56% men) without a prior stroke or dementia diagnosis were enrolled. Serum concentrations of 8 bone markers were analyzed as the association of cognitive function (Montreal Cognitive Assessment (MoCA) and Cognitive Abilities Screening Instrument (CASI)) using linear regression analysis.

Results: A lower cognitive function was noted in hemodialysis patients compared to control subjects. The receptor activator of nuclear factor kappa-B ligand (RANKL) was the only bone marker found to be associated with cognitive function (MoCA and CASI tests) in hemodialysis patients without a prior stroke or dementia diagnosis. In stepwise multiple linear regression analysis, the association remained significant in MoCA ( = 1.14, 95% CI 0.17 to 2.11) and CASI ( = 3.06, 95% CI 0.24 to 5.88). Short-term memory ( = 0.52, 95% CI 0.01 to 1.02), mental manipulation ( = 0.51, 95% CI 0.05 to 0.96), and abstract thinking ( = 0.57, 95% CI 0.06 to 1.09) were the significant subdomains in the CASI score related to RANKL.

Conclusions: Serum RANKL levels were potentially associated with better cognitive function in hemodialysis patients. Further large-scale and prospective studies are needed to confirm our findings.
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http://dx.doi.org/10.1155/2020/8641749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196142PMC
February 2021

Upregulation of / Increases the Cancer Progression by Neurotensin and Dihydropyrimidinase-Like 3 in Lung Cancer.

Int J Mol Sci 2020 Feb 28;21(5). Epub 2020 Feb 28.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Lung cancer is one of the leading causes of cancer-related death globally, thus elucidation of its molecular pathology is highly highlighted. Aberrant alterations of the spindle assembly checkpoint (SAC) are implicated in the development of cancer due to abnormal cell division. TTK (, a dual serine/threonine kinase, is considered to act as a cancer promoter by controlling SAC. However, the mechanistic details of how TTK-mediated signaling network supports cancer development is still a mystery. Here, we found that TTK was upregulated in the tumor tissue of patients with lung cancer, and enhanced tumor growth and metastasis in vitro and in vivo. Mechanistically, TTK exerted a significant enhancement in cancer growth by neurotensin (NTS) upregulation, and subsequently increased the expression of cyclin A and cdk2, which was resulting in the increase of DNA synthesis. In contrast, TTK increased cell migration and epithelial-to-mesenchymal transition (EMT) by enhancing the expression of dihydropyrimidinase-like 3 (DPYSL3) followed by the increase of snail-regulated EMT, thus reinforce metastatic potential and ultimately tumor metastasis. TTK and DPYSL3 upregulation was positively correlated with a poor clinical outcome in patients with lung cancer. Together, our findings revealed a novel mechanism underlying the oncogenic potential effect of TTK and clarified its downstream factors NTS and DPYSL3 might represent a novel, promising candidate oncogenes with potential therapeutic vulnerabilities in lung cancer.
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http://dx.doi.org/10.3390/ijms21051640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084211PMC
February 2020

High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery.

Mol Ther 2020 03 15;28(3):963-974. Epub 2020 Jan 15.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Diabetic nephropathy (DN) is an increasing threat to human health and is regarded as an important public issue. The pathophysiologic mechanisms of DN are complicated. The initiating molecular events triggering the loss function in mesangial cells (MCs) in DN are not well known. In this cross-disciplinary study, transcriptome analysis of high glucose (HG)-treated mouse MCs (MMCs) using next-generation sequencing and systematic bioinformatics analyses indicated that miR-15b-5p and its downstream target B cell lymphoma 2 (BCL-2) contribute to HG-induced apoptosis in MMCs. HG elevated miR-15b-5p expression, which in turn decreased the translation of BCL-2, leading to MMC apoptosis under HG. Apoptosis of MCs was enhanced in the presence of extracellular vesicles isolated from the urine of type 2 diabetic patients with high levels of miR-15b-5p. Furthermore, increased levels of urinary miR-15b-5p were found in db/db mice and type 2 diabetic patients, and such levels correlated with low baseline kidney function and rapid decline in kidney function during a mean of follow-up period of 2.4 ± 0.1 years. Therefore, miR-15b-5p induced mesangial cells apoptosis by targeting BCL-2 under HG. miR-15b-5p has the potential to predict kidney injury in DN. Blocking the miR-15b-5p epigenetic regulatory network could be a potential therapeutic strategy to prevent mesangial apoptosis in DN.
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http://dx.doi.org/10.1016/j.ymthe.2020.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054723PMC
March 2020

Protein-bound uremic toxins are associated with cognitive function among patients undergoing maintenance hemodialysis.

Sci Rep 2019 12 31;9(1):20388. Epub 2019 Dec 31.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Patients with chronic kidney disease have a greater risk of cognitive impairment. Cerebral uremic solute accumulation causes uremic encephalopathy; however, the association of protein-bound uremic toxins on cognitive function remains unclear. The present study aimed to investigate the association of two protein-bound uremic toxins, namely indoxyl sulfate (IS) and p-cresyl sulfate (PCS), on cognitive function in patients receiving hemodialysis (HD) for at least 90 days. Circulating free form IS and PCS were quantified by liquid chromatography/mass spectrometry. Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI) were used to evaluate cognitive function. In total, 260 HD patients were recruited with a mean age of 58.1 ± 11.3 years, of which, 53.8% were men, 40% had diabetes, and 75.4% had hypertension. The analysis revealed that both free IS and free PCS were negatively associated with the CASI score and MMSE. After controlling for confounders, circulating free IS levels persisted to be negatively associated with MMSE scores [β = -0.62, 95% confidence interval (CI): -1.16 to -0.08] and CASI scores (β = -1.97, 95% CI: -3.78 to -0.16), mainly in the CASI domains of long-term memory, mental manipulation, language ability, and spatial construction. However, there was no correlation between free PCS and total MMSE or total CASI scores after controlling for confounders. In conclusion, circulating free form IS, but not PCS is associated with lower cognitive function test scores in HD patients. Thus, a further study is needed to evaluate whether a decrease in free IS levels can slow down cognitive decline in HD patients.
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http://dx.doi.org/10.1038/s41598-019-57004-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938492PMC
December 2019

Ratio of Early Mitral Inflow Velocity to the Global Diastolic Strain Rate and Global Left Ventricular Longitudinal Systolic Strain Predict Overall Mortality and Major Adverse Cardiovascular Events in Hemodialysis Patients.

Dis Markers 2019 5;2019:7512805. Epub 2019 Sep 5.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: The ratio of early mitral inflow velocity to the global diastolic strain rate (E/E'sr) and global longitudinal systolic strain (GLS) of the left ventricle (LV) are emerging indices of diastolic and systolic functions, respectively, for the LV. Their prognostic significance in the prediction of mortality and cardiovascular (CV) outcomes remains underexplored in hemodialysis (HD) patients.

Methods: This prospective study included 190 maintenance HD patients. The E/E'sr ratio and GLS were assessed using two-dimensional speckle tracking echocardiography. The clinical outcomes included overall mortality, CV mortality, and major adverse cardiovascular events (MACE). The associations between the E/E'sr ratio, GLS, and clinical outcomes were evaluated using multivariate Cox regression analysis. The incremental values of the E/E'sr ratio and GLS in outcome prediction were assessed by changes in Cox models.

Results: Over a median follow-up period of 3.7 years, there were 35 overall deaths, 16 CV deaths, and 45 MACE. Impaired diastolic function with a higher E/E'sr ratio was associated with overall mortality (HR, 1.484; 95% CI, 1.201-1.834; < 0.001), CV mortality (HR, 1.584; 95% CI, 1.058-2.371; = 0.025), and MACE (HR, 1.205; 95% CI, 1.040-1.397; = 0.013) in multivariate adjusted Cox analysis. Worsening GLS was associated with overall mortality (HR, 1.276; 95% CI, 1.101-1.480; = 0.001), CV mortality (HR, 1.513; 95% CI, 1.088-2.104; = 0.014), and MACE (HR, 1.214; 95% CI, 1.103-1.337; < 0.001). The E/E'sr ratio and GLS had better outcome prediction than the E to early diastolic mitral annular velocity (E/E') ratio and left ventricular ejection fraction (LVEF). Moreover, adding the E/E'sr ratio and GLS to Cox models containing relevant clinical and conventional echocardiographic parameters improved the prediction of overall mortality ( < 0.001), CV mortality ( < 0.001), and MACE ( < 0.001).

Conclusion: The E/E'sr ratio and GLS, as emerging indices of LV diastolic and systolic functions, significantly predict mortality and CV outcomes and outperform conventional echocardiographic parameters in outcome prediction in HD patients.
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http://dx.doi.org/10.1155/2019/7512805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748193PMC
February 2020

Bone-marrow-derived cell-released extracellular vesicle miR-92a regulates hepatic pre-metastatic niche in lung cancer.

Oncogene 2020 01 26;39(4):739-753. Epub 2019 Sep 26.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, 807, Kaohsiung, Taiwan.

Metastatic tumors have been shown to establish a supportive pre-metastatic niche (PMN) in distant organs, which in turn determines disseminated tumor cells' targeting of such organs. PMN is formed through the recruitment of bone-marrow-derived cells (BMDCs); however, the role of BMDCs in PMN formation is not fully understood. On the basis of RNA-seq data and bioinformatic analysis, secretion of extracellular vesicle (EV) miR-92a by BMDCs of lung cancer-bearing mice contributes to the establishment of liver PMN. Both BMDC-derived EVs and miR-92a mimics potentiate the activation of hepatic stellate cells (HSCs), subsequently increasing extracellular matrix (ECM) deposition in mice. Consequently, remodeling of the liver microenvironment enhanced immunosuppressive cell accumulation and cancer cell attachment. EVs miR-92a directly suppressed its target SMAD7, leading to the enhancement of transforming growth factor-β signaling in HSC. Elevated levels of circulating miR-92a are found in the sera of lung cancer patients, and EVs isolated from these patients have a similar ability to increase HSCs activation and ECM protein expression. Our study reveals the sequential steps of liver PMN formation in lung cancer, providing critical mediators that prepare PMN in the liver, and identifies new targets that offer valuable options for diagnosis and therapeutic intervention.
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http://dx.doi.org/10.1038/s41388-019-1024-yDOI Listing
January 2020

The prognostic value of CSN6 expression in upper tract urothelial carcinomas.

Kaohsiung J Med Sci 2019 Sep 24;35(9):559-565. Epub 2019 Jul 24.

Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

CSN6 is a subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN). CSN is involved in cellular and developmental processes such as signal transduction, transcriptional activation, cell cycle control, and tumorigenesis. CSN6 is highly expressed in several human cancers, including colorectal cancer, and breast cancer. However, no previous research has elaborated on the relationship between CSN6 expression and survival in patients with upper tract urothelial carcinoma (UTUC). Therefore, the purpose of this study is to evaluate the clinical significance of CSN6 in UTUC. CSN6 expression in 89 patients with UTUC enrolled in this study was examined using immunohistochemistry. The associations between CSN6 expression and clinicopathological variables were analyzed. CSN6 expression was significantly correlated with patients with high pathological stage (P = .006), male gender (P = .025), and high serum creatinine levels (P = .014). In univariate and multivariable analysis, high CSN6 expression was associated with a higher bladder recurrence (P = .005) and poor cancer-specific survival (P = .001) for UTUC. In conclusion, CSN6 expression is a potential biomarker for predicting cancer recurrence and clinical survival in UTUC. Further research is necessary to investigate its role in the progression of UTUC.
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http://dx.doi.org/10.1002/kjm2.12104DOI Listing
September 2019

Differential expression profiles of the transcriptome in bone marrow-derived cells in lung cancer revealed by next generation sequencing and bioinformatics.

Oncol Lett 2019 May 28;17(5):4341-4350. Epub 2019 Feb 28.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.

A pre-metastatic niche (PMN) facilitates cancer metastasis through mobilization and recruitment of bone marrow-derived cells (BMDCs) and associated factors. In bone marrow, hematogenous cells, including osteoclasts, macrophages and lymphocytes, and mesenchymal cells, including mesenchymal stem cells, osteoblasts and adipocytes, are involved in PMN formation. Patients with lung cancer and metastasis have a poor prognosis and shortened median survival time. Bone marrow has been considered fertile ground for dormant and proliferating tumor cells, and mobilizing and recruiting BMDCs and immune cells can establish a PMN. However, the role of BMDCs in PMN formation is not yet fully understood. The present study aimed to investigate the association between BMDCs and PMN in bone marrow tissue samples. The results demonstrated that bone marrow served an important role in lung cancer progression and that eight pathways were potentially involved, including 'T-cell receptor signaling pathway', 'osteoclast differentiation', 'MAPK signaling pathway', 'VEGF signaling pathway', 'leukocyte transendothelial migration', 'signaling pathways regulating the pluripotency of stem cells', 'oxytocin signaling pathway' and 'cell adhesion molecules (CAMs)'. In addition, the present study investigated the role of BMDCs in facilitating lung cancer metastasis. In conclusion, the results from the present study suggested that molecular alterations in gene expression may provide a novel signature in lung cancer, which may aid in the development of novel diagnostic and therapeutic strategies for patients with lung cancer and bone metastasis.
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http://dx.doi.org/10.3892/ol.2019.10085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444499PMC
May 2019

New Insight on Solute Carrier Family 27 Member 6 (SLC27A6) in Tumoral and Non-Tumoral Breast Cells.

Int J Med Sci 2019 24;16(3):366-375. Epub 2019 Jan 24.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Long-chain fatty acids are the most abundant fatty acids and are essential for various physiological processes. Translocation of long-chain fatty acids across cell membrane is dependent on transport proteins. Solute carrier family 27 member 6 (SLC27A6) is a transport protein which mediates long-chain fatty acid uptake. The bioinformatic analysis revealed that the expression of SLC27A6 in non-tumoral breast tissue was higher than that in tumoral breast cancer in clinic samples. When SLC27A6 expression in non-tumorigenic cell H184B5F5/M10 was repressed, the fatty acids uptake capacity and cell proliferation was inhibited, and cell cycle was delayed. The protein expression of cell cycle regulators including cell division protein kinase 4 (CDK4), CDK6, and cyclin D1 was significantly decreased in SLC27A6-silenced H184B5F5/M10. By contrast, relatively low SLC27A6 expression in tumorigenic breast cancer cell Hs578T when compared to H184B5F5/M10. Repressing SLC27A6 expression did not affect these phenotypes in Hs578T. The interaction network of SLC27A6 was further investigated via STRING database. The function of these SLC27A6-associated proteins mainly involved in lipid biosynthesis, fatty acid metabolic process, and fatty acid transport. In conclusion, this study reveals inverse correlation between SLC27A6 expression and tumoral tissues and provides a new insight into SLC27A6-mediated cell growth and cell cycle regulation in non-tumorigenic breast cells.
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http://dx.doi.org/10.7150/ijms.29946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428986PMC
July 2019

Indoxyl Sulfate Induces Apoptosis Through Oxidative Stress and Mitogen-Activated Protein Kinase Signaling Pathway Inhibition in Human Astrocytes.

J Clin Med 2019 Feb 5;8(2). Epub 2019 Feb 5.

Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Uremic toxins accumulated in chronic kidney disease (CKD) increases the risk of cognitive impairment. Indoxyl sulfate (IS) is a well-known protein-bound uremic toxin that is correlated with several systemic diseases, but no studies on human brain cells are available. We investigated the effect of IS on primary human astrocytes through next-generation sequencing and cell experiment confirmation to explore the mechanism of IS-associated brain damage. Total RNAs extracted from IS-treated and control astrocytes were evaluated by performing functional and pathway enrichment analysis. The toxicities of IS in the astrocytes were investigated in terms of cell viability through flow cytometry; the signal pathway was then investigated through immunoblotting. IS stimulated the release of reactive oxygen species, increased nuclear factor (erythroid-derived 2)-like 2 levels, and reduced mitochondrial membrane potential. IS triggered astrocyte apoptosis by inhibiting the mitogen-activated protein kinase (MAPK) pathway, including extracellular-signal-regulated kinase (ERK), MAPK/ERK kinase, c-Jun N-terminal kinase, and p38. The decreased ERK phosphorylation was mediated by the upregulated dual-specificity phosphatase 1, 5, 8, and 16. In conclusion, IS can induce neurotoxicity in patients with CKD and the pathogenesis involves cell apoptosis through oxidative stress induction and MAPK pathway inhibition in human astrocytes.
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http://dx.doi.org/10.3390/jcm8020191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406290PMC
February 2019

CXCL17-derived CD11bGr-1 myeloid-derived suppressor cells contribute to lung metastasis of breast cancer through platelet-derived growth factor-BB.

Breast Cancer Res 2019 02 12;21(1):23. Epub 2019 Feb 12.

Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.

Background: Metastasis is the major cause of death from breast cancer. Colonization and adaption of metastatic cells in distant organs is a rate-limiting step of the cancer spreading. The underlying mechanisms responsible for the colonization of breast cancer to lung metastatic niches are not fully understood.

Methods: Specific gene contributions to lung metastasis were identified by comparing gene profiles of 4T1 tumors metastasizing to various organs via microarray. The oncogenic properties CXCL17 were examined by in vivo spontaneous metastasis mouse model. The chemotactic activity of CXCL17 on CD11bGr-1 myeloid-derived suppressor cells (MDSCs) was examined by both in vitro and in vivo models. The therapeutic effects of MDSC depletion and platelet-derived growth factor-BB (PDGF-BB) inhibition were examined by orthotic models.

Results: Here, we demonstrate that breast cancer cells secrete CXCL17, which increases the accumulation of CD11bGr-1 MDSCs in the lungs. Metastatic lung-infiltrating CD11bGr-1 MDSCs induce angiogenesis in the lungs and facilitate cancer extravasation and survival that ultimately promote lung metastases. CXCL17 increases CD11bGr-1 MDSCs to express PDGF-BB, which not only contributes to CD11bGr-1 MDSC-mediated angiogenesis in the lung metastatic niche, but is also involved in the colonization of breast cancer. Consequently, both CD11bGr-1 MDSC depletion and PDGF receptor inhibitor effectively prevents CXCL17-driven lung metastasis in breast cancer. More importantly, patients with high levels of CXCL17 have shorter distant metastasis-free and overall survival rates, indicators of poor prognosis.

Conclusion: Our study reveals that MDSCs derived by CXCL17 contribute to the establishment of a lung metastatic niche by PDGF-BB secretion and provide a rationale for development of CXCL17 or PDGF-BB antagonists to inhibit or prevent lung metastasis in cases of breast cancer.
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http://dx.doi.org/10.1186/s13058-019-1114-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373011PMC
February 2019

Correction: Identification of novel gene expression signature in lung adenocarcinoma by using next-generation sequencing data and bioinformatics analysis.

Oncotarget 2019 01 15;10(5):616. Epub 2019 Jan 15.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

[This corrects the article DOI: 10.18632/oncotarget.21022.].
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http://dx.doi.org/10.18632/oncotarget.26609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355176PMC
January 2019

Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease-A Next-Generation Sequencing-Guided Bioinformatic Approach.

Int J Mol Sci 2019 Jan 28;20(3). Epub 2019 Jan 28.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in bronchial epithelial cells of asthma and COPD. The microRNA profiles in primary bronchial epithelial cells from asthma (AHBE) and COPD (CHBE) patients and healthy subjects (NHBE) were analyzed with next-generation sequencing (NGS) and the significant microRNA changes common in AHBE and CHBE were extracted. The upregulation of hsa-miR-10a-5p and hsa-miR-146a-5p in both AHBE and CHBE was confirmed with quantitative polymerase chain reaction (qPCR). Using bioinformatic methods, we further identified putative targets of these microRNAs, which were downregulated in both AHBE and CHBE: miR-10a-5p might suppress , , , , and ; miR-146a-5p might suppress , , , , , and . We further validated significantly decreased expression levels of and in AHBE and CHBE than in NHBE with qPCR. Increased serum miR-146a-5p level was also noted in patients with asthma and COPD as compared with normal control subjects. In summary, our study revealed possible mechanisms mediated by miR-10a-5p and miR-146a-5p in the pathogenesis of both asthma and COPD. The findings might provide a scientific basis for developing novel diagnostic and therapeutic strategies.
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http://dx.doi.org/10.3390/ijms20030553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386886PMC
January 2019

Deduction of Novel Genes Potentially Involved in Upper Tract Urothelial Carcinoma Using Next-Generation Sequencing and Bioinformatics Approaches.

Int J Med Sci 2019 1;16(1):93-105. Epub 2019 Jan 1.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Upper tract urothelial carcinoma (UTUC) is a relatively uncommon cancer worldwide, however it accounts for approximately 30% of urothelial cancer in the Taiwanese population. The aim of the current study is to identify differential molecular signatures and novel miRNA regulations in UTUC, using next-generation sequencing and bioinformatics approaches. Two pairs of UTUC tumor and non-tumor tissues were collected during surgical resection, and RNAs extracted for deep sequencing. There were 317 differentially expressed genes identified in UTUC tissues, and the systematic bioinformatics analyses indicated dysregulated genes were enriched in biological processes related to aberration in cell cycle and matrisome-related genes. Additionally, 15 candidate genes with potential miRNA-mRNA interactions were identified. Using the clinical outcome prediction database, low expression of was found to be a prognostic predictor of poor survival in urothelial cancer, and a novel miRNA, miR-34a-5p, was a potential regulator of , which may infer the potential role of miR-34a-5p- regulation in the altered tumor microenvironment in UTUC. Our findings suggested novel miRNA target with regulation exerts potential prognostic value in UTUC, and future investigation is necessary to explore the role of in the tumor development and progression of UTUC.
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http://dx.doi.org/10.7150/ijms.29560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332486PMC
April 2019

Systematic Analysis of Transcriptomic Profile of Chondrocytes in Osteoarthritic Knee Using Next-Generation Sequencing and Bioinformatics.

J Clin Med 2018 Dec 10;7(12). Epub 2018 Dec 10.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

The phenotypic change of chondrocytes and the interplay between cartilage and subchondral bone in osteoarthritis (OA) has received much attention. Structural changes with nerve ingrowth and vascular penetration within OA cartilage may contribute to arthritic joint pain. The aim of this study was to identify differentially expressed genes and potential miRNA regulations in OA knee chondrocytes through next-generation sequencing and bioinformatics analysis. Results suggested the involvement of SMAD family member 3 () and Wnt family member 5A () in the growth of blood vessels and cell aggregation, representing features of cartilage damage in OA. Additionally, 26 dysregulated genes with potential miRNA⁻mRNA interactions were identified in OA knee chondrocytes. Myristoylated alanine rich protein kinase C substrate (), epiregulin (), leucine rich repeat containing 15 (), and phosphodiesterase 3A () expression patterns were similar among related OA cartilage, subchondral bone and synovial tissue arrays in Gene Expression Omnibus database. The Ingenuity Pathway Analysis identified to be associated with the outgrowth of neurite, and novel miRNA regulations were proposed to play critical roles in the pathogenesis of the altered OA knee joint microenvironment. The current findings suggest new perspectives in studying novel genes potentially contributing to arthritic joint pain in knee OA, which may assist in finding new targets for OA treatment.
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http://dx.doi.org/10.3390/jcm7120535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306862PMC
December 2018

Circulating Extracellular Vesicles in Human Disease.

N Engl J Med 2018 11;379(22):2179-80

Kaohsiung Medical University, Kaohsiung, Taiwan

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http://dx.doi.org/10.1056/NEJMc1813170DOI Listing
November 2018

The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy.

J Clin Med 2018 Nov 22;7(12). Epub 2018 Nov 22.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG-induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence-associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN.
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http://dx.doi.org/10.3390/jcm7120468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306775PMC
November 2018

Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy.

Mol Ther Nucleic Acids 2018 Dec 10;13:543-555. Epub 2018 Oct 10.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesangial cell (MC) loss is correlated with worsening renal function in DN. Disturbance of angiopoietin (Angpt)/Tie ligand-receptor system causes inflammation and abnormal angiogenesis. This association between elevated circulating Angpt2 and poor renal outcome has been in DN patients. However, the pathogenic role of Angpt2 in the MCs remains unknown. We found serum Angpt2 levels were elevated in type 2 diabetes mellitus (DM) patients and db/db mice, which correlated with albuminuria. Angpt2 synergistically induced MC apoptosis under high glucose (HG), and miR-33-5p regulated Angpt2-inducing MC apoptosis treated with HG. Loss of miR-33-5p increased suppressor of cytokine signaling 5 (SOCS5), leading to the inhibition of Janus kinase 1 and signal transducer and activator of transcription 3 signaling transduction. Elevated expression of SOCS5 was found in the MCs in kidney sections of both db/db mice and type 2 DM patients. Decreased miR-33-5p levels were found in the urine of db/db mice and type 2 DM patients, and miR-33-55p levels negatively correlated with albuminuria. Angpt2 leads to MC apoptosis via the miR-33-5p-SOCS5 loop in DN. miR-33-5p is predictive of kidney injury in DN. These findings may provide future applications in predicting renal dysfunction and the therapeutic potential of DN.
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http://dx.doi.org/10.1016/j.omtn.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226567PMC
December 2018

Solute Carrier Family 27 Member 4 (SLC27A4) Enhances Cell Growth, Migration, and Invasion in Breast Cancer Cells.

Int J Mol Sci 2018 Nov 1;19(11). Epub 2018 Nov 1.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Fatty acid metabolism is important in the regulation of breast cancer progression. Some of the proteins involved in fatty acid transport have been demonstrated to promote the proliferation, migration, and invasion in breast cancer cells. Solute carrier family 27 member 4 (SLC27A4) is a fatty acid transporter protein and is related to very long chain acyl-CoA synthetase activity. In the present study, bioinformatic analysis revealed that relatively high SLC27A4 expression was observed in all subtypes of breast tumor tissues when compared to normal breast tissues. Silencing SLC27A4 expression significantly reduced uptake of free fatty acids in two breast cancer cell lines, Hs578T and MDA-MB-231. Cell growth inhibition was observed in SLC27A4-silenced Hs578T and cell cycle was arrested at G2/M. In addition, the capacity of migration and invasion decreased in both cell lines after knockdown of SLC27A4. The epithelial⁻mesenchymal transition signaling pathway was inhibited because protein expression of Slug, vimentin, α-smooth muscle actin, and other regulators was lower than that in control cells. Taken together, our results confirm that high SLC27A4 is associated with tumor progression in breast cancer cells. It is worth investigating whether SLC27A4 serves a diagnostic marker and therapeutic target in further studies.
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http://dx.doi.org/10.3390/ijms19113434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274775PMC
November 2018

Systematic Analysis of Differential Expression Profile in Rheumatoid Arthritis Chondrocytes Using Next-Generation Sequencing and Bioinformatics Approaches.

Int J Med Sci 2018 13;15(11):1129-1142. Epub 2018 Jul 13.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Cartilage destruction in rheumatoid arthritis (RA) occurs primarily in the pannus-cartilage interface. The close contact of the synovium-cartilage interface implicates crosstalk between synovial fibroblasts and chondrocytes. The aim of this study is to explore the differentially expressed genes and novel microRNA regulations potentially implicated in the dysregulated cartilage homeostasis in joint destruction of RA. Total RNAs were extracted from human primary cultured normal and RA chondrocytes for RNA and small RNA expression profiling using next-generation sequencing. Using systematic bioinformatics analyses, we identified 463 differentially expressed genes in RA chondrocytes were enriched in biological functions related to altered cell cycle process, inflammatory response and hypoxic stimulation. Moreover, fibroblast growth factor 9 (), kynureninase (), and regulator of cell cycle () were among the top dysregulated genes identified to be potentially affected in the RA joint microenvironment, having similar expression patterns observed in arrays of clinical RA synovial tissues from the Gene Expression Omnibus database. Additionally, among the 31 differentially expressed microRNAs and 10 candidate genes with potential microRNA-mRNA interactions in RA chondrocytes, the novel miR-140-3p- interaction was validated in different microRNA prediction databases, and proposed to participate in the pathogenesis of joint destruction through dysregulated cell growth in RA. The findings provide new perspectives for target genes in the management of cartilage destruction in RA.
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http://dx.doi.org/10.7150/ijms.27056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097257PMC
December 2018

Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1.

Int J Mol Sci 2018 Aug 16;19(8). Epub 2018 Aug 16.

Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including , , , and . Concurrently, CXCL1 displays a specific microRNA (miR) upregulated by the prototypical colon cancer onco-miR miR-105. Analysis of publicly available data reveals CXCL1-driven oncogenes and miR-105 have a negative prognostic impact on the outcome of colon cancer. This study indicates a new mechanism by which the colon cancer milieu exploits DC plasticity to support cancer progression.
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http://dx.doi.org/10.3390/ijms19082427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121631PMC
August 2018

Independent Association of Overhydration with All-Cause and Cardiovascular Mortality Adjusted for Global Left Ventricular Longitudinal Systolic Strain and E/E' Ratio in Maintenance Hemodialysis Patients.

Kidney Blood Press Res 2018 10;43(4):1322-1332. Epub 2018 Aug 10.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background/aims: Fluid overload is common and associated with morbidity and mortality in patients with end-stage renal disease. The relationship between fluid overload and cardiac function is complex, and whether fluid overload is associated with adverse outcomes in patients undergoing hemodialysis (HD) independently of systolic and diastolic function of the left ventricle (LV) remains unclear.

Methods: The present study aimed to investigate the relationship between overhydration and all-cause and cardiovascular (CV) mortality after adjusting for LV function in 178 maintenance HD patients. The relative hydration status (overhydration/ extracellular water, ∆HS) was measured using a body composition monitor, and then used to assess the fluid status. A ∆HS ≥7% was defined as fluid overload. Global left ventricular longitudinal systolic strain (GLS), and the early filling and early diastolic mitral annular velocity (E/E') ratio were assessed using speckle-tracking and tissue Doppler echocardiography.

Results: During a mean follow-up period of 2.7 years, 24 patients died, including 11 CV deaths. An increased ∆HS was significantly associated with all-cause and CV mortality in the univariate analysis. This prognostic significance remains after multivariate adjusting for GLS and E/E' ratio for all-cause (HR, 1.123; 95% CI, 1.063-1.186; p-value < 0.001) and CV (HR, 1.088; 95% CI, 1.005-1.178; p-value =0.037) mortality. Moreover, ∆HS significantly improved the prognostic value beyond conventional clinical and echocardiographic parameters.

Conclusion: A higher ∆HS was independently associated with increased all-cause and CV mortality after adjusting for systolic and diastolic function of the LV. This suggests that ∆HS may be a relevant target for improving outcomes in maintenance HD patients.
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http://dx.doi.org/10.1159/000492591DOI Listing
November 2018

Knockdown of GA-binding protein subunit β1 inhibits cell proliferation via p21 induction in renal cell carcinoma.

Int J Oncol 2018 Aug 17;53(2):886-894. Epub 2018 May 17.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. In the present study, bioinformatics tools were systematically used to investigate the potential upstream effector involved in the progression of ccRCC. Using the Gene Expression Omnibus database and Library of Integrated Network-based Cellular Signatures L1000 platform, it was identified that GA-binding protein subunit β1 (GABPB1) was a potential effector gene. GABPB1 is a transcription factor subunit and its function in ccRCC is unclear. Elevated expression of GABPB1 mRNA in ccRCC was also observed in other clinical datasets from the Oncomine database. Following reverse transcription-quantitative polymerase chain reaction and western blot analysis, the ccRCC 786-O and A498 cell lines showed higher expression levels of GABPB1 than HK-2, a normal kidney cell line. Knockdown of GABPB1 in the 786-O and A498 cells significantly decreased the ability to form colonies by inducing the expression of p21Waf/Cip1. SurvExpress database analysis indicated that a higher expression of GABPB1 was associated with poor survival outcome in patients with renal cancer. These findings imply that GABPB1 serves an important role in the progression of ccRCC.
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http://dx.doi.org/10.3892/ijo.2018.4411DOI Listing
August 2018