Publications by authors named "Cheng-Chieh Yang"

53 Publications

Current Insights into Oral Cancer Diagnostics.

Diagnostics (Basel) 2021 Jul 16;11(7). Epub 2021 Jul 16.

Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.

Oral cancer is one of the most common head and neck malignancies and has an overall 5-year survival rate that remains below 50%. Oral cancer is generally preceded by oral potentially malignant disorders (OPMDs) but determining the risk of OPMD progressing to cancer remains a difficult task. Several diagnostic technologies have been developed to facilitate the detection of OPMD and oral cancer, and some of these have been translated into regulatory-approved in vitro diagnostic systems or medical devices. Furthermore, the rapid development of novel biomarkers, electronic systems, and artificial intelligence may help to develop a new era where OPMD and oral cancer are detected at an early stage. To date, a visual oral examination remains the routine first-line method of identifying oral lesions; however, this method has certain limitations and as a result, patients are either diagnosed when their cancer reaches a severe stage or a high-risk patient with OPMD is misdiagnosed and left untreated. The purpose of this article is to review the currently available diagnostic methods for oral cancer as well as possible future applications of novel promising technologies to oral cancer diagnosis. This will potentially increase diagnostic options and improve our ability to effectively diagnose and treat oral cancerous-related lesions.
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http://dx.doi.org/10.3390/diagnostics11071287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303371PMC
July 2021

Restrictive cardiomyopathy caused by diffuse calcification of the left ventricle after 20 years of haemodialysis.

Cardiovasc J Afr 2021 Jul 5;32:1-3. Epub 2021 Jul 5.

Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan. Email:

Valvular and vascular calcifications are common among patients with end-stage renal disease, but diffuse calcification of the left ventricle is rarely reported. We report on a rare case of restrictive cardiomyopathy resulting from severe myocardial calcification and review the literature. A 77-year-old man was diagnosed with end-stage renal disease after having received regular haemodialysis for 20 years. He was referred to our emergency room due to exertional dyspnoea and exacerbated shortness of breath. A chest X-ray revealed severe pulmonary oedema and bilateral massive pleural effusion. Transthoracic echocardiography revealed impaired diastolic function of the left ventricle but preserved systolic function with a 50% ejection fraction. Repeat chest computed tomography demonstrated exacerbation of the calcification from the mitral annulus to the whole circular left ventricle. A coronary angiogram revealed non-significant stenosis, and right heart catheterisation demonstrated elevated pulmonary capillary wedge pressure. He was discharged after two weeks of conservative medication.
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http://dx.doi.org/10.5830/CVJA-2021-031DOI Listing
July 2021

Activation of the miRNA Cluster Enhances Oncogenicity and Drug Resistance in Oral Carcinoma Cells.

Int J Mol Sci 2020 Dec 11;21(24). Epub 2020 Dec 11.

Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11221, Taiwan.

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated deaths worldwide. Family members in miRNA cluster, which is localized at human chromosome 19q13.4, are co-expressed in both human stem cells and malignancies. The individual miRNA in this cluster are also involved in modulating the pathogenesis of malignancies as either oncogenes or suppressors. The 19q13 region is frequently gained in head and neck cancers. High expression of and are survival predictors for OSCC. However, the role of the cluster in oral carcinogenesis remains to be fully investigated. We use the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system to establish OSCC cell subclones that had the cluster deleted. In addition, further subclones were established that had the promoter of this cluster deleted. Concordant silencing in SAS cells of decreased oncogenic potential, increased cisplatin sensitivity, activated p53, and upregulated the expression of Bad and DKK1. We also employed the CRISPR/dCas9 synergistic activation mediator system, which allowed robust transcriptional activation of the whole cistron. Upregulation of endogenous expression increased both oncogenicity and drug resistance. These were accompanied by a slight activation of AKT, β-catenin, and Src. This study identifies the oncogenic role of the cluster in OSCC. Using CRISPR based strategy can be a powerful paradigm that will provide mechanistic insights into miRNA cluster functionality, which will also likely help the development of targeting options for malignancies.
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http://dx.doi.org/10.3390/ijms21249442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764723PMC
December 2020

Overexpression of Platelet-Derived Growth Factor and Its Receptor Are Correlated with Oral Tumorigenesis and Poor Prognosis in Oral Squamous Cell Carcinoma.

Int J Mol Sci 2020 Mar 29;21(7). Epub 2020 Mar 29.

Department of Oral and Maxillofacial Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan.

Oral squamous cell carcinoma (OSCC) is a cancerous disease with poor prognosis. According to the statistics, the 5-year survival rate has not improved significantly over the past 20 years. The platelet-derived growth factor (PDGF) and its signaling pathway is a key regulator of angiogenesis and tumorigenesis. High level of PDGF and its receptor (PDGFR) have been reported in several types of malignancies. In this study, we investigated the relationship of the molecular expression levels of PDGF and PDGFR with clinicopathological parameters in OSCC. To this end, we measured the mRNA and protein levels of PDGF and PDGFR by real-time quantitative PCR (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA), respectively. We found positive correlations of the mRNA levels of PDGFA, PDGFB, and PDGFRB with lymph node metastasis and poor overall survival (OS). High expression of PDGF, PDGFRA, and PDGFRB were remarkably associated with lymph node metastasis and poor OS, as determined by immunohistochemistry. Preoperative serum levels of PDGF-AA and PDGF-BB had a positive correlation with preoperative platelet count. Elevated serum levels of PDGF-AA. PDGF-BB, and platelet count correlated with lymph node metastasis and an unfavorable outcome. In multivariate Cox regression analysis, PDGFA mRNA, PDGFB mRNA, PDGFRB mRNA, PDGF immunoexpression, PDGFRB immunoexpression, serum PDGF-AA, serum PDGF-BB, and platelet count emerged as significant independent prognostic factors for OS. In vitro, we found that elevated PDGF promotes colony formation, migration, and invasiveness of SAS and OECM-1 cancer cell lines. Our results suggest that the expression level of serum PDGF has the potential to become a useful diagnostic marker for the prognosis of OSCC. In addition, PDGFR should be considered as a potential therapeutic target for OSCC. Furthermore, research should be undertaken to elucidate the role of PDGF and PDGFR regarding the behavior of tumor cells in OSCC.
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http://dx.doi.org/10.3390/ijms21072360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177415PMC
March 2020

Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells.

Oncogenesis 2020 Mar 23;9(3):38. Epub 2020 Mar 23.

Department of Biomedical Sciences, and Cornell Stem Cell Program, Cornell University, Ithaca, NY, 14850, USA.

Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency and delay growth of human prostate cancer xenografts by reducing the number of cancer-propagating cells. In sum, our study provides a definitive proof of tumor-suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer-propagating cells in prostate cancers with MME downregulation.
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http://dx.doi.org/10.1038/s41389-020-0222-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090072PMC
March 2020

Evaluation of factors associated with the risk stratification of survivorship for stage IV squamous cell carcinoma of the oral cavity: A 10-year retrospective study.

J Chin Med Assoc 2020 May;83(5):491-499

Department of Stomatology, Oral and Maxillofacial Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: Oral squamous cell carcinoma (OSCC) leads to thousands of deaths every year in Taiwan. Nearly 40% of OSCC patients are diagnosed with stage IV disease, which has a poor prognosis. Multimodality treatments including surgery and adjuvant therapy have been utilized, but their treatment outcomes are generally poor. In this study, we sought to identify possible clinical impact factors that may contribute to the survival of stage IV OSCC.

Methods: Data for patients with malignant neoplasms of the oral cavity registered in the Cancer Registry Database of Taipei Veterans General Hospital between 2002 and 2011 were retrieved. The study patients consisted of OSCC patients with clinical stage IV disease who had undergone a surgery and adjuvant therapy. The primary endpoints were the 5-year disease-free survival (DFS) and overall survival (OS) rates. The clinicopathological characteristics of the patients were also stratified and compared.

Results: A total of 191 OSCC patients were included for retrospective analysis. The different subgroups of stage IV disease presented different treatment outcomes. The 5-year OS versus DFS rates of each subgroup were as follows: T4N0: 70.9% versus 52.6%; T1-3N23: 66.1% versus 49.8%; T4N1: 49.6% versus 31.6%; and T4N23: 40.9% versus 31.0% (p < 0.01). Patients with diabetes, moderate or poor cell differentiation, perineural invasion, and extracapsular spread presented lower 5-year OS rates (hazard ratio [HR] = 1.87, 1.65, 2.42, and 2.14, respectively), and patients with perineural invasion, positive cut margin, and extracapsular spread presented lower 5-year DFS rates (HR = 1.57, 1.62, and 1.71, respectively).

Conclusion: In this study, we elucidated the different survival rates of different subgroups of stage IV OSCC following the same treatment scheme. The results of the study provide clinical physicians with references by which to evaluate prognosis and determine post-operative disease monitoring timetables based upon different characteristics.
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http://dx.doi.org/10.1097/JCMA.0000000000000292DOI Listing
May 2020

The -ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma.

Front Oncol 2020 31;10:47. Epub 2020 Jan 31.

Department of Dentistry, School of Dentistry, Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.

has been shown a potent oncogenic miRNA in the pathogenesis of oral squamous cell carcinoma (OSCC). The zinc finger and BTB domain containing 7A protein (ZBTB7A) is a transcriptional regulator that is involved in a great diversity of physiological and oncogenic regulation. However, the modulation of ZBTB7A in OSCC remains unclear. Tissue analysis identifies a reverse correlation in expression between and ZBTB7A in OSCC tumors. When OSCC cells have stable knockdown of ZBTB7A, their oncogenic potential and drug resistance is increased. By way of contrast, such an increase is attenuated by expression of ZBTB7A. Screening and validation confirms that ZBTB7A is able to modulate expression of the death receptors TRAIL-R1, TRAIL-R2, Fas and p53 phosphorylated at serine-15. In addition, ZBTB7A transactivates TRAIL-R2, which sensitizes cells to cisplatin-induced apoptosis. The ZBTB7A-TRAIL-R2 cascade is involved in both the extrinsic and intrinsic cisplatin-induced pathways of apoptosis. Database analysis indicates that the expression level of and the copy status of ZBTB7A and TRAIL-R2 are important survival predictors for head and neck cancers. Collectively, this study indicates the importance of the -ZBTB7A-TRAIL-R2 axis in mediating OSCC pathogenesis and in controlling OSCC drug resistance. Therefore, silencing and/or upregulating ZBTB7A would seem to be promising strategies for enhancing the sensitivity of OSCC to cisplatin therapy.
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http://dx.doi.org/10.3389/fonc.2020.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005910PMC
January 2020

The significance of tumor budding in oral cancer survival and its relevance to the eighth edition of the American Joint Committee on Cancer staging system.

Head Neck 2019 09 23;41(9):2991-3001. Epub 2019 Apr 23.

Department of Stomatology, Oral & Maxillofacial Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: To explore the clinicopathological significance of tumor budding (TB) on oral squamous cell carcinoma (OSCC) prognosis.

Methods: Data of 200 patients with OSCC were retrieved from the cancer registration database in Taipei Veterans General Hospital. Clinicopathological characteristics and survival relevant to TB were analyzed.

Results: The data showed that TB was predominant in the tongue and floor of the mouth in younger patients with OSCC and correlated with several pathological factors, such as perineural invasion and lymphovascular invasion. Patients with TB have significantly lower recurrence-free survival (P ≤ .0001). TB was significantly associated with lymph node metastasis in patients with early cancer stage (P = .042). Multivariate analysis demonstrated extranodal extension and TB as independent predictors of lymph node recurrence (adjusted hazard ratio = 9.90 and 3.89, respectively).

Conclusion: TB is a significant predictor of tumor aggression with locoregional failure even in the revised 8th American Joint Committee on Cancer staging system.
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http://dx.doi.org/10.1002/hed.25780DOI Listing
September 2019

Arecoline-regulated ataxia telangiectasia mutated expression level in oral cancer progression.

Head Neck 2019 08 28;41(8):2525-2537. Epub 2019 Feb 28.

Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan.

Background: Ataxia telangiectasia mutated (ATM) regulates DNA repair and cell cycle. The present study analyzed arecoline-induced ATM expression during oral cancer progression.

Methods: In vitro studies were performed using oral squamous cell carcinoma (OSCC) cell lines treated with arecoline to analyze cell response and ATM regulation. in vivo studies were performed using immunohistochemistry to detect ATM expression in normal, oral potentially malignant disorder (OPMD), and OSCC tissues.

Results: Low-dose arecoline induced cell proliferation, ATM promoter activity, and DNA repair. High-dose arecoline induced cell cycle arrest, apoptosis, and DNA damage. ATM was overexpressed in OPMD tissues but was downregulated in OSCC tissues. ATM expression level was associated with the risk of developing dysplasia, buccal-OSCC, and with OSCC survival rate.

Conclusion: High ATM expression helps DNA repair mechanisms to maintain the cells in the OPMD stage, but low ATM expression causes DNA damage accumulation to increase cell malignancy.
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http://dx.doi.org/10.1002/hed.25718DOI Listing
August 2019

miR-125b suppresses oral oncogenicity by targeting the anti-oxidative gene PRXL2A.

Redox Biol 2019 04 13;22:101140. Epub 2019 Feb 13.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; Department of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

Oral squamous cell carcinoma (OSCC) is a globally prevalent malignancy. The molecular mechanisms of this cancer are not well understood and acquire elucidation. Peroxiredoxin like 2A (PRXL2A) has been reported to be an antioxidant protein that protects cells from oxidative stress. Our previous study identified an association between PRXL2A upregulation in OSCC and a worse patient prognosis. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the modulation of biological/pathological properties. The miR-125 family of genes drive pluripotent regulation across a wide variety of cancers. In this study, we identify the oncogenic eligibility of PRXL2A and clarify miR-125b as its upstream regulator. Downregulation of miR-125b can be observed in OSCC tumors. Lower miR-125b expression in tumors results in a worse patient prognosis at the relatively early stage. Reporter assays are able to validate that PRXL2A is a direct target of miR-125b. Exogenous miR-125b expression in OSCC cells results in increased oxidative stress, increased drug sensitivity, and suppressor activity that is paralleled by the knockout of PRXL2A gene. The suppressor activity of miR-125b is able to be rescued by PRXL2A, which suggests the existence of a miR-125b-PRXL2A regulatory axis that is part of OSCC pathogenesis. Nuclear factor-erythroid 2-related factor 2 (NRF2) was found to be a downstream effector of the miR-125b-PRXL2A cascade. As a whole, this study has pinpointed novel clues demonstrating that downregulation of miR-125b suppressor underlies upregulation of PRXL2A in OSCC, and this then protects the affected tumor cells from oxidative stress.
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http://dx.doi.org/10.1016/j.redox.2019.101140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383183PMC
April 2019

HSP40 co-chaperone protein Tid1 suppresses metastasis of head and neck cancer by inhibiting Galectin-7-TCF3-MMP9 axis signaling.

Theranostics 2018 13;8(14):3841-3855. Epub 2018 Jun 13.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.

Human tumorous imaginal disc (Tid1), a DnaJ co-chaperone protein, is classified as a tumor suppressor. Previously, we demonstrated that Tid1 reduces head and neck squamous cell carcinoma (HNSCC) malignancy. However, the molecular details of Tid1-mediated anti-metastasis remain elusive. We used affinity chromatography and systemic mass spectrometry to identify Tid1-interacting client proteins. Immunohistochemical staining of Tid1 in HNSCC patient tissues was examined to evaluate the association between the expression profile of Tid1-interacting client proteins with pathologic features and prognosis. The roles of Tid1-interacting client proteins in metastasis were validated both in and in . The interacting partner and downstream target of Tid1-interacting client protein were determined. Herein, we first revealed that Galectin-7 was one of the Tid1-interacting client proteins. An inverse association of protein expression profile between Tid1 and Galectin-7 was determined in HNSCC patients. Low Tid1 and high Galectin-7 expression predicted poor overall survival in HNSCC. Furthermore, Tid1 abolished the nuclear translocation of Galectin-7 and suppressed Galectin-7-induced tumorigenesis and metastasis. Keratinocyte-specific Tid1-deficient mice with 4-nitroquinoline-1-oxide (4NQO) treatment exhibited increased protein levels of Galectin-7 and had a poor survival rate. Tid1 interacted with Galectin-7 through its N-linked glycosylation to promote Tid1-mediated ubiquitination and proteasomal degradation of Galectin-7. Additionally, Galectin-7 played a critical role in promoting tumorigenesis and metastatic progression by enhancing the transcriptional activity of TCF3 transcription factor through elevating MMP-9 expression. Overall, future treatments through activating Tid1 expression or inversely repressing the oncogenic function of Galectin-7 may exhibit great potential in targeting HNSCC progression.
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http://dx.doi.org/10.7150/thno.25784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071538PMC
August 2019

miR-134 targets PDCD7 to reduce E-cadherin expression and enhance oral cancer progression.

Int J Cancer 2018 12 4;143(11):2892-2904. Epub 2018 Oct 4.

Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.

Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide. This study clarified the oncogenic role of miR-134 in OSCC. Reporter assays, using both wild-type and mutant constructs, confirmed that Programmed Cell Death 7 (PDCD7) gene was a potential target of miR-134. The OSCC cells exogenously expressed miR-134 exhibited reduced PDCD7 expression. As expected, exogenous miRZip-134 expression increased PDCD7 expression in the OSCC cells; additionally, PDCD7 expression suppressed the oncogenicity of the OSCC cells. By contrast, PDCD7 knockout through gene editing increased in vitro oncogenicity and neck nodal metastasis in mice, and reduced E-cadherin (E-cad) expression. PDCD7 transactivated E-cad expression via the GC-box in the promoter. Moreover, miR-134-associated cellular transformation and E-cad downregulation was attenuated by PDCD7. Downregulation of both PDCD7 and E-cad and high levels miR-134 expression was observed in OSCC tumor tissues. Activation of the miR-134-PDCD7-E-cad pathogenesis cascade occurred early during the human and murine oral carcinogenesis process. In conclusion, the oncogenic effect of miR-134 in oral carcinoma is mediated by reducing PDCD7 and E-cad expression.
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http://dx.doi.org/10.1002/ijc.31638DOI Listing
December 2018

Eicosanoids and HB-EGF/EGFR in cancer.

Cancer Metastasis Rev 2018 09;37(2-3):385-395

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.

Eicosanoids are bioactive lipids that play crucial roles in various pathophysiological conditions, including inflammation and cancer. They include both the COX-derived prostaglandins and the LOX-derived leukotrienes. Furthermore, the epidermal growth factor receptor (EGFR) pathways family of receptor tyrosine kinases also are known to play a central role in the tumorigenesis. Various antitumor modalities have been approved cancer treatments that target therapeutically the COX-2 and EGFR pathways; these include selective COX-2 inhibitors and EGFR monoclonal antibodies. Research has shown that the COX-2 and epidermal growth factor receptor pathways actively interact with each other in order to orchestrate carcinogenesis. This has been used to justify a targeted combinatorial approach aimed at these two pathways. Although combined therapies have been found to have a greater antitumor effect than the administration of single agent, this does not exempt them from the possible fatal cardiac effects that are associated with COX-2 inhibition. In this review, we delineate the contribution of HB-EGF, an important EGFR ligand, to the cardiac dysfunction related to decreased shedding of HB-EGF after COX-2/PGE2 inhibition. A better understanding of the molecular mechanisms underlying these cardiac side effects will make possible more effective regimens that use the dual-targeting approach.
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http://dx.doi.org/10.1007/s10555-018-9746-9DOI Listing
September 2018

ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells.

Cell Death Dis 2018 02 7;9(2):194. Epub 2018 Feb 7.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.

Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROS cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROS cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co-expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs.
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http://dx.doi.org/10.1038/s41419-017-0250-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833380PMC
February 2018

WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death.

Sci Adv 2017 06 21;3(6):e1700090. Epub 2017 Jun 21.

OncoMed Pharmaceuticals Inc., Redwood City, CA 94063, USA.

The WNT pathway mediates intercellular signaling that regulates cell fate in both normal development and cancer. It is widely appreciated that the WNT pathway is frequently dysregulated in human cancers through a variety of genetic and epigenetic mechanisms. Targets in the WNT pathway are being extensively pursued for the development of new anticancer therapies, and we have advanced two WNT antagonists for clinical development: vantictumab (anti-FZD) and ipafricept (FZD8-Fc). We examined the antitumor efficacy of these WNT antagonists in combination with various chemotherapies in a large set of patient-derived xenograft models. In responsive models, WNT blockade led to profound synergy with taxanes such as paclitaxel, and the combination activity with taxanes was consistently more effective than with other classes of chemotherapy. Taxane monotherapy increased the frequency of cells with active WNT signaling. This selection of WNT-active chemotherapy-resistant tumorigenic cells was prevented by WNT-antagonizing biologics and required sequential dosing of the WNT antagonist followed by the taxane. The WNT antagonists potentiated paclitaxel-mediated mitotic blockade and promoted widespread mitotic cell death. By blocking WNT/β-catenin signaling before mitotic blockade by paclitaxel, we found that this treatment effectively sensitizes cancer stem cells to taxanes. This combination strategy and treatment regimen has been incorporated into ongoing clinical testing for vantictumab and ipafricept.
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http://dx.doi.org/10.1126/sciadv.1700090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479655PMC
June 2017

The prognosis outcome of oral squamous cell carcinoma using HIF-2α.

J Chin Med Assoc 2017 Oct 6;80(10):651-656. Epub 2017 Jul 6.

Department of Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. Electronic address:

Background: Hypoxia-induced factors (HIF) has a role in angiogenesis and regulate tumorigenesis of cancer cell. The HIF is the best-identified mechanism that shows imbalance between consumption and oxygen supply in progressing tumor. This study of HIF-2α expression in oral squamous cell carcinoma (OSCC) aimed to investigate the relationship of HIF-2α and pathology characteristics related to its clinical correlation.

Methods: Fifty-eight samples of OSCC and adjacent tissues were fixed in paraffin for microarray preparation. The tissue array then was stained using primary antibody HIF-2α (NB100-122) and autoprobe II ABC universal staining kit. Each tissue sample was captured using camera microscope, and images were analyzed with Photoshop 6.0 using the CMYK method. A statistical analysis was performed with the two-tailed t-test, Kaplan-Meier and log-rank test using Prism for Windows version 5.0.

Results: The samples of the non-cancerous matched tissues (NCMTs) paired with their OSCC samples showed HIF-2α overexpression with significance difference p < 0.0001. Although no significant difference was found between HIF-2α expression and overall survival rate, cancer-specific survival rate, and disease-free survival rate, the HIF-2α expression showed statistical significance for overall cancer stages with p = 0.013. In addition, patients with high HIF-2α expression tended to develop recurrence within 2 years compared to the low expression group.

Conclusion: HIF-2 expression has complicated roles in different cancer types, including OSCC. Our study indicated that HIF-2α overexpression can serve as a good biomarker for cancer status for all tumor stages and may predict an early recurrence within two years.
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http://dx.doi.org/10.1016/j.jcma.2017.06.005DOI Listing
October 2017

The expression of transglutaminase 2 (TG-2) in oral squamous cell carcinoma and its clinical significance.

J Chin Med Assoc 2017 Aug 1;80(8):515-520. Epub 2017 Jul 1.

Department of Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Stomatology, Taipei Veteran General Hospital, Taipei, Taiwan, ROC. Electronic address:

Background: Glutamine has a very important role in the human body, including pH balance in an acidic environment, as well as supporting the TCA cycle in cancer cell growth. However, the expression of transglutaminase-2 (TG-2) in oral cancer growth related to renal function is unknown. Here we examined TG-2 and its expression as a prognostic tool.

Methods: Fifty-six oral squamous cell carcinoma (OSCC) tissues were collected with the inclusion of tumor in any region of oral area, and patients with creatinine (Cr) and blood urea nitrogen (BUN) results. The tissues were stained using immunohistochemistry (IHC) with a TG-2 antibody [N3C3], then observed under the microscope. The staining were calculated using Adobe Photoshop CS software and statistical analyses using SPSS ver. 21.

Results: We found that TG-2 expression showed a significant difference in the expression levels between tumor and the adjacent groups without disease-free survival, disease-specific survival, and recurrence between, with p < 0.05. The average staining intensity with 25 percentile of TG-2 becomes a vital score for the diagnosis. Furthermore, our study demonstrates a good prognosis outcome if the intensity score showed a difference in TG-2 expression between the adjacent and tumor tissue.

Conclusion: To our knowledge, this is the first clinical study on TG-2 expression in OSCC, and it demonstrates that TG-2 can serve as a predictor of tumorigenesis and prognosis outcome.
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http://dx.doi.org/10.1016/j.jcma.2017.05.004DOI Listing
August 2017

Analysis of Disparity Error for Stereo Autofocus.

IEEE Trans Image Process 2018 Apr 27;27(4):1575-1585. Epub 2017 Apr 27.

As more and more stereo cameras are installed on electronic devices, we are motivated to investigate how to leverage disparity information for autofocus. The main challenge is that stereo images captured for disparity estimation are subject to defocus blur unless the lenses of the stereo cameras are at the in-focus position. Therefore, it is important to investigate how the presence of defocus blur would affect stereo matching and, in turn, the performance of disparity estimation. In this paper, we give an analytical treatment of this fundamental issue of disparity-based autofocus by examining the relation between image sharpness and disparity error. A statistical approach that treats the disparity estimate as a random variable is developed. Our analysis provides a theoretical backbone for the empirical observation that, regardless of the initial lens position, disparity-based autofocus can bring the lens to the hill zone of the focus profile in one movement. The insight gained from the analysis is useful for the implementation of an autofocus system.
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http://dx.doi.org/10.1109/TIP.2017.2698924DOI Listing
April 2018

MicroRNA-21 promotes perineural invasion and impacts survival in patients with oral carcinoma.

J Chin Med Assoc 2017 Jun 27;80(6):383-388. Epub 2017 Feb 27.

Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. Electronic address:

Background: Perineural invasion is a pathological feature that may affect cancer cell progression and thus can result in prognostic impacts, especially in oral squamous cell carcinoma (OSCC). However, factors regulating perineural invasion during OSCC remain obscure.

Methods: Expression of miR-21 and phosphatase and tensin homolog was checked in surgical specimens from cases of OSCC. The results were analyzed for histopathologic factors, including perineural invasion and clinical prognosis.

Results: One-hundred cases of OSCC patients were enrolled in this study. High expression of miR-21 was related to perineural invasion and worse prognosis in OSCC patients.

Conclusion: miR-21 was an independent factor of disease survival of OSCC. miR-21/phosphatase and tensin homolog disregulation was related to perineural invasion.
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http://dx.doi.org/10.1016/j.jcma.2017.01.003DOI Listing
June 2017

Pretreatment pain predicts perineural invasion in oral squamous cell carcinoma: A prospective study.

Oral Oncol 2016 10 9;61:115-9. Epub 2016 Sep 9.

Department of Otorhinolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Taipei 11217, Taiwan; Department of Otolaryngology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Taipei 11221, Taiwan; Infection and Immunity Research Center, National Yang-Ming University, No. 155, Sec. 2, Linong St., Taipei 11221, Taiwan. Electronic address:

Objectives: Perineural invasion (PNI) is an established poor prognostic pathological feature for oral squamous cell carcinoma (OSCC). The purpose of this study was to analyze the role of pretreatment parameters in predicting PNI for OSCC.

Materials And Methods: We prospectively enrolled into our study 102 newly diagnosed OSCC patients, who were surgically treated from 2011 to 2012. Before treatment, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire H&N35 and the visual analogue scale (VAS) for cancer pain. Pathological examination was performed to ascertain PNI status in all patients. Patients were divided into two groups, those with PNI and without PNI. Pretreatment parameters were compared between the two groups.

Results: In univariate analysis, clinical T classification (P<0.001), painkiller use (P=0.001), problem with social eating (P<0.001) and social contact (P=0.002), VAS scores of primary pain (P<0.001) and referred pain (P=0.004) were found to be associated with PNI. Multivariate logistic regression analysis further revealed VAS score of primary pain (P=0.001, OR 2.014) and T3-4 classification (P=0.014, OR 6.422) were independent predictors of PNI. A regression equation incorporating pretreatment pain was developed to predict the probability of having PNI.

Conclusion: PNI can be predicted by higher pretreatment VAS score of primary pain, as well as more advanced clinical T classification. Careful evaluation of pretreatment pain of primary tumor can thus be helpful in improving treatment decision making for OSCC.
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http://dx.doi.org/10.1016/j.oraloncology.2016.07.016DOI Listing
October 2016

miR-31 targets ARID1A and enhances the oncogenicity and stemness of head and neck squamous cell carcinoma.

Oncotarget 2016 Aug;7(35):57254-57267

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.

miR-31 is oncogenic for head and neck squamous cell carcinoma (HNSCC). Proteins containing the AT-rich interacting domain (ARID) modulate the accessibility of chromatin to the transcription machinery needed for gene expression. In this study, we showed that miR-31 was able to target ARID1A in HNSCC. HNSCC tumors had an inverse miR-31 and ARID1A expression. miR-31 associated oncogenicities were rescued by ARID1A expression in HNSCC cells. Furthermore, ARID1A repressed the stemness properties and transcriptional activity of Nanog/OCT4/Sox2/EpCAM via the protein's affinity for AT-rich sites within promoters. HNSCC patients with tumors having high level of miR-31 expression and high levels of Nanog/OCT4/Sox2/EpCAM expression, together with low level of ARID1A expression, were found to have the worst survival. This study provides novel mechanistic clues demonstrating that miR-31 inhibits ARID1A and that this enriches the oncogenicity and stemness of HNSCC.
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http://dx.doi.org/10.18632/oncotarget.11138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302987PMC
August 2016

GSK3β inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers.

Oncotarget 2016 Aug;7(35):57131-57144

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. EZH2, a histone methyltransferase, promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. In this study, we show that glycogen synthase kinase 3 beta (GSK3β) negatively regulates H3K27 trimethylation. We also validate that GSKβ physically interacts with EZH2, and their interaction occurs in the cytosol. GSK3β phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3β upregulates Thr367 phosphorylationin vivo. Cells expressing GSK3β-non-phosphorylatable mutant EZH2 have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3β as measured by its phosphorylation at Ser9 is positively correlated with higher level of H3K27 trimethylation in tumor tissues from breast cancer patients. Our study indicated that GSK3β phosphorylates EZH2 at Ser363 and Thr367, resulting in reduced H3K27 trimethylation and biological activity of EZH2 in breast cancer.
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http://dx.doi.org/10.18632/oncotarget.11008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302978PMC
August 2016

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity.

Cancer Res 2016 08 24;76(16):4872-86. Epub 2016 May 24.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.

miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFP-miR-211 transgenic mice tagged with GFP. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that family with sequence similarity 213, member A (FAM213A), a peroxiredoxin-like antioxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population, and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo Overall, our findings develop a mouse model that recapitulates the molecular and histopathologic alterations of human OSCC pathogenesis and highlight a new miRNA-mediated oncogenic mechanism. Cancer Res; 76(16); 4872-86. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1664DOI Listing
August 2016

Up-regulation of HB-EGF by the COX-2/PGE2 signaling associates with the cisplatin resistance and tumor recurrence of advanced HNSCC.

Oral Oncol 2016 May 25;56:54-61. Epub 2016 Mar 25.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

Objectives: When treating advanced HNSCC, a cisplatin-based systemic regimen benefit patient survival. However, chemoresistance will greatly reduce the effectiveness of this approach. The identification of molecules that contribute to cisplatin resistance may potentially improve the survival. Both HB-EGF and COX-2 have been reported to increase cisplatin-resistance. Here, we have focused on the regulation of HB-EGF/COX-2 and their roles in cisplatin resistance.

Materials And Methods: IHC staining was used to measure the expression levels of HB-EGF and COX-2 on the tissue microarray from 43 tissue samples of patients with advanced HNSCC. siRNA, western blot and qRT-PCR were used to dissect the regulation between EGF, Akt, COX-2, PGE2, and cisplatin sensitivity. The correlation between HB-EGF, COX2 and HNSCC progression was analyzed by the receiver operating characteristic (ROC) curve and Kaplan-Meier disease free survival.

Results: Patients of advanced HNSCC patients with increased HB-EGF and COX-2 expression have higher tumor recurrent rates that was related to cisplatin resistance. The resistance was mediated via an increased expression of HB-EGF and COX-2. The activation of Akt by either EGF or areca nut extract were able to upregulate COX-2, which would increase the expression of HB-EGF in a PGE2 dependent manner. Inhibition and knockdown of COX-2 resulted in a decrease in HB-EGF. In the tissue samples from HNSCC patients, there was a significant positive correlation between the expression of COX-2 and HB-EGF.

Conclusion: Our results suggested that COX-2 and HB-EGF are important in development of HNSCC cisplatin resistance. These findings may help the development of new strategies for overcoming cisplatin resistance.
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http://dx.doi.org/10.1016/j.oraloncology.2016.03.010DOI Listing
May 2016

One-Year Mortality after Traumatic Brain Injury in Liver Cirrhosis Patients--A Ten-Year Population-Based Study.

Medicine (Baltimore) 2015 Oct;94(40):e1468

From the Departments of Neurosurgery (C-YC, C-CW, C-CC, C-HC, J-RK); Medical Research, Chi-Mei Medical Center, Tainan, Taiwan (C-HH, J-JW, J-RK); Departments of Biotechnology (J-RK); ChildCare, Southern Taiwan University of Science and Technology, Tainan, Taiwan (C-CW); Departments of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan (F-WL); and Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan, Taiwan (C-HH).

This study investigated the 1-year mortality of patients who underwent brain surgery following traumatic brain injury (TBI) who also had alcoholic and/or nonalcoholic liver cirrhosis (LC) using a nationwide database in Taiwan. A longitudinal cohort study matched by propensity score with age, gender, length of ICU stay, HTN, DM, MI, stroke, HF, renal diseases, and year of TBI diagnosis in TBI patients with alcoholic and/or nonalcoholic LC and TBI patients without LC was conducted using the National Health Insurance Research Database in Taiwan between January 1997 and December 2007. The main outcome studied was 1-year mortality. In total, 7296 subjects (2432 TBI patients with LC and 4864 TBI patients without LC) were enrolled in this study. The main findings were (1) TBI patients with LC had a higher 1-year mortality (52.18% vs 30.61%) and a 1.75-fold increased risk of mortality (95% CI 1.61-1.90) compared with non-LC TBI patients, (2) renal diseases and HF are risk factors, but hypertension could be a protective factor in cirrhotic TBI patients, and (3) TBI patients with non-alcoholic LC and the coexistence of alcoholic and nonalcoholic LC had higher 1-year mortality compared with TBI patients with alcoholic cirrhosis. This study showed that patients with LC who have undergone brain surgery might have higher risk of 1-year mortality than those without LC. In addition, nonalcoholic and the coexistence of alcoholic and nonalcoholic LC show higher 1-year mortality risk than alcoholic in TBI patients with LC, especially in those with comorbidities of hypertension, diabetes mellitus, and stroke.
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http://dx.doi.org/10.1097/MD.0000000000001468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616736PMC
October 2015

Phosphorylation of EZH2 at T416 by CDK2 contributes to the malignancy of triple negative breast cancers.

Am J Transl Res 2015 15;7(6):1009-20. Epub 2015 Jun 15.

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

Triple-negative breast cancer (TNBC), which is closely related to basal-like breast cancer, is a highly aggressive subtype of breast cancer that initially responds to chemotherapy but eventually develops resistance. This presents a major clinical challenge as there are currently no effective targeted therapies available due to its lack of HER2 and estrogen receptor expression. Here, we show that cyclin E and the enhancer of zeste 2 (EZH2) are closely co-expressed in TNBC patients, and cyclin E/CDK2 phosphorylates EZH2 at T416 (pT416-EZH2) in vivo. Phosphorylation of EZH2 at T416 enhances the ability of EZH2 to promote TNBC cell migration/invasion, tumorsphere formation, and in vivo tumor growth. In addition, high pT416-EZH2 correlates with poorer survival in TNBC patients. These findings suggest that pT416 has the potential to serve as a therapeutic biomarker for the aggressive forms of breast cancer and provide a rationale for the use of CDK2 inhibitors to treat TNBC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532735PMC
August 2015

EGF up-regulates miR-31 through the C/EBPβ signal cascade in oral carcinoma.

PLoS One 2014 17;9(9):e108049. Epub 2014 Sep 17.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan; Department of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPβ expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPβ expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPβ, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPβ and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPβ and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPβ expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108049PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168139PMC
December 2015

Distinct subpopulations of head and neck cancer cells with different levels of intracellular reactive oxygen species exhibit diverse stemness, proliferation, and chemosensitivity.

Cancer Res 2014 Nov 12;74(21):6291-305. Epub 2014 Sep 12.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan. Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan. Genome Research Center, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan. National Yang-Ming University VGH Genome Research Center, Taipei, Taiwan.

Head and neck squamous cell carcinoma (HNSCC) is driven by cancer-initiating cells (CIC), but their maintenance mechanisms are obscure. For hematopoietic stem cells, low levels of intracellular reactive oxygen species (ROS(Low)) is known to help sustain stemness properties. In this report, we evaluated the hypothesis that ROS(Low) character conferred CIC properties in HNSCC. Sphere cultures define CIC in HNSCC cell populations (HN-CIC). We found that ROS(Low) cells in HN-CIC defined in this manner were more numerous than in parental HNSCC cells. Further, ROS(Low) cells frequently coexpressed CIC surface markers such as memGrp78 and Glut3. Exploiting flow cytometry to sort cells on the basis of their ROS level, we found that isolated ROS(Low) cells displayed relatively more CIC properties, including quiescence, chemoresistance, in vitro malignant properties, and tumorigenicity. Pharmacological depletion of ROS modulators in cisplatin-treated HN-CIC reduced CIC properties, enhancing cell differentiation and enhancing cisplatin-induced cell death. Overall, our work defined cell subpopulations in HNSCC on the basis of differential intracellular ROS levels, which associated with stemness and chemoresistance properties. On the basis of our findings, we suggest that strategies to promote intracellular ROS levels may heighten the efficacy of conventional chemotherapy used for HNSCC treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0626DOI Listing
November 2014

K14-EGFP-miR-31 transgenic mice have high susceptibility to chemical-induced squamous cell tumorigenesis that is associating with Ku80 repression.

Int J Cancer 2015 Mar 6;136(6):1263-75. Epub 2014 Aug 6.

Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.

Squamous cell carcinoma (SCC) occurring in the head and neck region and the esophagus causes tremendous cancer mortality around the world. miR-31 is among the most eminently upregulated MicroRNAs in SCC, when it occurs in the head and neck region and the esophagus. We established miR-31 transgenic mouse lines, in which miR-31 is under the control of the K14 promoter. 4-nitroquinoline 1-oxide (4NQO) is a mutagen that causes double strand breaks. The transgenic mice exhibited a higher potential for tumor induction than wild-type (Wt) mice of the tongue and esophagus after 4NQO treatment. After 4NQO treatment or irradiation, p-γH2AX expression in squamous epithelium of transgenic mice was increased more than in Wt mice. Exogenous expression of miR-31 was also found to be associated with the higher p-γH2AX expression induced by 4NQO in human oral SCC (OSCC) cell lines. The repair genes PARP1 and Ku80 were validated as new targets of miR-31 in human OSCC cell lines, and were found to be downregulated in the squamous epithelium of the tongue in transgenic mice. However, only the downregulation of Ku80 was essential for maintaining the high level of p-γH2AX induced by 4NQO in OSCC cells. Inverse expression profiles for miR-31 and Ku80 were noted in human OSCC tissue. Our study identifies the high sensitivity of K14-EGFP-miR-31 transgenic mice to chemical carcinogen-induced squamous cell tumorigenesis and shows that this seems to be associated with the downregulation of Ku80 and an impairment of repair activity in squamous cells, which are mediated by miR-31.
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http://dx.doi.org/10.1002/ijc.29106DOI Listing
March 2015

Selective cerebral hypothermia induced via hypothermic retrograde jugular vein saline flush in a porcine model.

Neurol Res 2014 Oct 13;36(10):897-902. Epub 2014 Apr 13.

Objectives: Multiple methods of selective brain cooling have been used to prevent cerebral ischemia secondary to trauma and pathological or iatrogenic cerebral blood flow restriction. In this study, we tested the efficacy of hypothermic retrograde jugular vein flush (HRJVF) in eliciting selective brain hypothermia in a porcine model.

Methods: Twelve swine were divided into two groups: retrograde jugular vein infusion (RJVI) with cold saline (4°C RJVI, n  =  6) and with room temperature saline (24°C RJVI, n  =  6). For 90 minutes, the following parameters were measured: brain parenchymal temperature, rectal temperature, intracranial pressure (ICP), mean arterial pressure, and heart rate (HR).

Results: Swine receiving 4°C RJVI experienced a drop in mean brain parenchymal temperature of 1·1 ± 0·1°C, compared to 0·1 ± 0·1°C in swine receiving 24°C RJVI. At 90 minutes, mean brain parenchymal temperature in the 4°C RJVI treatment group was 35·5 ± 0·2°C, as compared to 37·1 ± 0·2°C in the 24°C RJVI treatment group (P < 0·001). In the 4°C RJVI group, the brain-systemic temperature gradient peaked 10 minutes after initiation of cooling and remained significantly different when comparing the two experimental groups (P < 0·001) throughout the duration of the 90 minutes experiment. Of note, ICP, mean arterial pressure, and HR remained constant without any significant changes or differences between treatment groups.

Discussion: These results suggest that HRJVF is an effective method for selective brain hypothermia in a large animal model. Clinical application may prove effective in delaying neural ischemia.
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http://dx.doi.org/10.1179/1743132814Y.0000000374DOI Listing
October 2014
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