Muh-Hwa Yang

National Yang Ming University, T’ai-pei, Taipei, Taiwan

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Publications (88)398 Total impact

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    ABSTRACT: MicroRNA (miRNA) machinery regulates cancer cell behavior, and has been implicated in patients' clinical status and prognosis. We found that microRNA-29b (miR-29b) increased significantly in advanced migratory cells. However, miR-29b controls the migration ability, and its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unknown. We triggered miR-29b expression in OSCC patients and cell lines by conducting real-time quantitative PCR. We determined the functions of miR-29b in the migration of OSCC cells by using gain- and loss-of-function approaches. We elevated the target genes of miR29b through software predictions and a luciferase report assay. We used an orthotopic OSCC animal model to investigate the effects of miR29b on OSCC cell metastasis in vivo. The clinical data revealed that miR-29b expression was correlated with lymph node metastasis and an advanced tumor stage in 98 OSCC patients. Furthermore, multivariate analysis revealed that miR-29b expression was significantly correlated with recurrence, and indicated poor survival. MiR-29b promoted OSCC cell migration and downregulated CX3CL1, a cell-cell adhesion regulator, which plays an essential role in miR-29b-regulated OSCC cell migration machinery. Furthermore, we found that CX3CL1 expression was correlated with lymph node metastasis and an early tumor stage in OSCC patients, and negatively correlated with miR-29b expression. MiR-29b acts as an oncomir, promoting cell migration through CX3CL1 suppression, and could be a potential therapeutic target for preventing OSCC progression. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Oral Oncology. 11/2014;
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    ABSTRACT: Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-α, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment.
    Cancer cell. 10/2014; 26(4):534-548.
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    ABSTRACT: Management of cN0 neck, elective neck dissection (END) or observation, remains controversial for T1-2 oral squamous cell carcinoma (OSCC). To allow for the safe observation of cN0 neck, it is mandatory to define predictors with high negative predictive value (NPV) for cervical lymph node (LN) status.
    Oral Oncology 07/2014; · 2.70 Impact Factor
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    ABSTRACT: Gastric cancer is the second leading cause of cancer-related death worldwide. Herein, we investigated the role of transcription factor Yin Yang 1 (YY1), a multi-functional protein, in tumorigenesis of gastric cancer cells. Results showed that YY1 contributed to gastric carcinogenesis of SC-M1 cells including growth, viability, and abilities of colony formation, migration, invasion, and tumorsphere formation. Levels of pluripotency genes CD44, Oct4, SOX-2, and Nanog were also up-regulated by YY1 in SC-M1 cells. Additionally, the 3'-untranslated region (3'-UTR) of YY1 mRNA was the target of microRNA-34 (miR-34) family consisting of miR-34a, miR-34b, and miR-34c. Overexpression of miR-34 family suppressed carcinogenesis through down-regulation of YY1 in NUGC-3 gastric cancer cells scarcely expressing miR-34 family. Alternatively, knockdown of miR-34 family promoted tumorigenesis via up-regulation of YY1 in SC-M1 and AZ521 gastric cancer cells with higher levels of miR-34 family. The miR-34 family also affected tumorsphere ultra-structure and inhibited the xenografted tumor growth as well as lung metastasis of SC-M1 cells through YY1. Expressions of miR-34a and miR-34c in gastric cancer tissues of patients were lower than those in normal tissues. Taken together, these results suggest that miR-34 family-YY1 axis plays an important role in the control of gastric carcinogenesis.
    Oncotarget 06/2014; · 6.64 Impact Factor
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    ABSTRACT: Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. In cancer cells, the deregulation of ACD disrupts the homeostasis of the stem cell pool and promotes tumour growth. However, this mechanism is unclear. Here, we show a reduction of ACD in spheroid-derived colorectal cancer stem cells (CRCSCs) compared with differentiated cancer cells. The epithelial-mesenchymal transition (EMT) inducer Snail is responsible for the ACD-to-symmetrical cell division (SCD) switch in CRCSCs. Mechanistically, Snail induces the expression of microRNA-146a (miR-146a) through the β-catenin-TCF4 complex. miR-146a targets Numb to stabilize β-catenin, which forms a feedback circuit to maintain Wnt activity and directs SCD. Interference with the Snail-miR-146a-β-catenin loop by inhibiting the MEK or Wnt activity reduces the symmetrical division of CRCSCs and attenuates tumorigenicity. In colorectal cancer patients, the Snail(High)Numb(Low) profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.
    Nature Cell Biology 04/2014; 16(4):383. · 20.76 Impact Factor
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    ABSTRACT: Background and Purpose. This study aimed to analyze survival, clinical responses, compliance, and adverse effects in locally advanced head and neck cancer (LAHNC) patients treated with split-dose cisplatin-based concurrent chemoradiation therapy (SD-CCRT) or cetuximab with concurrent radiation therapy (BioRT). Materials and Methods. We retrospectively evaluated 170 LAHNC patients diagnosed between January 1, 2009, and July 31, 2012: 116 received CCRT and 54 received BioRT. Results. Complete response rates were similar in the SD-CCRT and BioRT groups (63.8% versus 59.3%; P = 0.807), and locoregional relapse rates were 18.1% and 13.0%, respectively (P = 0.400). The 3-year relapse-free survival rate was 65.8% in the SD-CCRT group and 65.5% in the BioRT group, respectively (P = 0.647). The 3-year overall survival rate was 78.5% in the SD-CCRT group and 70.9% in the BioRT group, respectively (P = 0.879). Hematologic side effects were significantly more frequent in the SD-CCRT than in the BioRT group. Mucositis frequency was similar. Conclusions. Primary SD-CCRT and BioRT both showed good clinical response and survival. Hematologic toxicities were more frequent, but tolerable, in the SD-CCRT group. Both groups showed good compliance.
    BioMed Research International 01/2014; 2014:904341. · 2.71 Impact Factor
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    ABSTRACT: We investigated whether a diagnosis of colonic diverticular disease is associated with an increased risk for subsequent development of colorectal cancer (CRC) in a nationwide population-based retrospective study. We identified 41,359 individuals diagnosed with colonic diverticular disease as inpatients from 2000 through 2009 from the Taiwan National Health Insurance Research Database (study cohort), and collected data for a randomly selected 165,436 additional subjects, matched by sex, age, and baseline year (comparison cohort). Data were collected until individuals developed CRC or withdrew from the national health insurance (NHI) system, or until December 31, 2010. Cumulative incidences and hazard ratios (HRs) of CRC development were determined. To assess for ascertainment bias, we conducted analysis excluding the first 12 months of follow up. The risk of CRC was significantly higher in the study cohort than the comparison cohort (HR adjusted for age, sex, and comorbidities=4.54; 95% confidence interval, 4.19- 4.91; P value < .0001). In a sensitivity analysis, we excluded the first 12 months of follow up after a diagnosis of colonic diverticular disease; subsequent incidence rates for CRC in the study and comparison cohorts were 15.13 and 15.74 per 10000 person-years, respectively (adjusted HR= 0.96; 95% confidence interval, 0.83-1.11). Colonic diverticular disease is not associated with an increased risk of subsequent CRC after the first year of diagnosis of colonic diverticular disease. An increased risk was observed in the first year, possibly due to misclassification and screening effects.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2013; · 5.64 Impact Factor
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    ABSTRACT: Patterns of global histone modifications have been suggested to be predictors of clinical outcome in many cancers. However, the role of global histone modification patterns in oral squamous cell carcinoma (OSCC) is unclear. A retrospective clinicopathologic analysis was undertaken of 186 patients with oral squamous cell carcinoma who received complete ablative surgical treatment. Tissue arrays were made from those paraffin-embedded OSCC samples and examined by immunohistochemistry for histone 3 lysine 4 acetylation (H3K4ac), histone 3 lysine 18 acetylation (H3K18ac), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3). A low level of H3K4ac and a high level of H3K27me3 were associated with advanced T status, N status, tumor stage, and perineural invasion. They were also correlated with cancer-specific survival (CSS) and disease-free survival (DFS). The 5-year CSS and DFS in H3K4ac(low) vs. H3K4ac(high) were 74.8% versus 92.5% (P = .010), and 51.4% versus 76.2% (P = .001), respectively. The 5-year CSS and DFS in H3K27me3(low) versus H3K27me3(high) were 94.7% versus 62.3% (P < .001) and 76.4% versus 32.3% (P < .001), respectively. We also found improved prediction for DFS after combining the H3K4ac(low) and H3K27me3(high) profiles and comparing the scores with the other modification patterns (P < .0001). This research demonstrates the potential prognostic utility of global histone modification analysis for OSCC. Cancer 2013;119:4259-4267. © 2013 American Cancer Society.
    Cancer 12/2013; 119(24):4259-67. · 5.20 Impact Factor
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    ABSTRACT: SIRT3-mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-3-plays an important role in regulating cell metabolism and carcinogenesis. The role of SIRT3 in gastric cancer has not yet been investigated. A total of 221 gastric cancer patients who underwent curative surgery were enrolled at the Department of Surgery, Taipei Veterans General Hospital. SIRT3 expression in gastric tissues and tumors were examined in these patients using immunohistochemical staining. Clinicopathologic characteristics and survival were analyzed and compared in gastric cancer patients with or without SIRT3 expression. The 5-year survival rates of patients with or without SIRT3 expression were 51.2 and 39.1 %, respectively (p = 0.005). The 5-year disease-free survival rates of patients with or without SIRT3 expression were 49.6 and 38.0 %, respectively (p = 0.010). Microscopic features showed that there are more poor cell differentiation (p = 0.001), more diffuse-type Lauren's histology (p = 0.018), and more scirrhous-type stromal reactions (p = 0.027) in gastric cancer without SIRT expression. Multivariate analysis with overall survival as an endpoint showed that age (p < 0.001), Lauren's histology (p = 0.007), stromal reaction (p = 0.035), TNM pathologic N category (p < 0.001), and SIRT3 expression (p < 0.001) were significantly correlated with gastric cancer. Gastric cancer patients with SIRT3 expression have a better prognosis than those without. SIRT3 expression is an independent prognostic marker for overall survival and may act as a tumor suppressor in gastric cancer.
    World Journal of Surgery 12/2013; · 2.23 Impact Factor
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide. In recent studies, a crucial link has been discovered between the acquisition of metastatic traits and tumour-initiating abilities in cancer cells during the epithelial-mesenchymal transition (EMT). Herein, we demonstrated that the ectopic expression of TWIST1, the EMT regulator, in HNSCC FaDu cells triggered EMT and resulted in the acquisition of a mesenchymal phenotype. Moreover, FaDu-pFLAG-TWIST1 cancer cell populations that were induced to EMT displayed an increased proportion of cells with the CD44 marker, which is associated with tumour initiation. Interestingly, we found that emodin treatment reduced the tumour-initiating abilities and inhibited cell migration and invasion in FaDu-pFLAG-TWIST1 cells. Emodin directly inhibited TWIST1 expression, upregulated E-cadherin mRNA and protein expression, and downregulated vimentin mRNA and protein expression. Moreover, we found that emodin inhibited TWIST1 binding to the E-cadherin promoter and repressed E-cadherin transcription activity. We also found that emodin inhibited TWIST1-induced EMT by inhibiting the β-catenin and Akt pathways. More interestingly, emodin significantly inhibited TWIST1-induced invasion in vivo. Therefore, emodin might be applicable to anticancer therapy and could be a potential new therapeutic drug for HNSCC.
    European journal of cancer (Oxford, England: 1990) 10/2013; · 4.12 Impact Factor
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    ABSTRACT: Massive hemorrhages occur in 6%-10% of patients with advanced cancer. Acute carotid blowout syndrome is the most severe massive hemorrhagic complication in head and neck cancer patients. This was a single institute, retrospective, case control study. A total of 45 patients were enrolled in this study. The predisposing factors, management, and prognosis of acute carotid blowout syndrome were evaluated. Among the baseline characteristics, the site of the primary tumor (P = .003), origin of bleeding (P = .048), method of intervention (P = .005), and time to intervention (P = .006) were significantly different factors between survivor and nonsurvivor patients. After 24 hours of onset, a Glasgow Coma Scale score (P = .000), the use of inotropic agents (P = .007), and neutrophil-to-lymphocyte ratio (P = .019) were significantly predicting factors for outcome. Multivariate logistic regression analyses revealed bleeding from common carotid artery was an independent factor for long-term survival (odds ratio, 25.951; 95% confidence interval [CI], 1.373-490.441; P < .030). The median overall survival of survivors and nonsurvivors were 12.1 (range, 3.7-118.7; 95% CI, 4.33-54.87) and 11.9 (range, 0.7-53.5; 95% CI, 5.78-25.69) months, respectively (P = .092). Early and aggressive intervention is important for the successful management of acute carotid blowout syndrome. The Glasgow Coma Scale score, the use of inotropic agents, and neutrophil-to-lymphocyte ratio 24 hours after the onset were predictive factors for patients' outcomes. Bleeding from common carotid artery is an independent prognostic factor in multivariate analysis. Long-term survival can be achieved after successful management.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 08/2013; · 3.52 Impact Factor
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    ABSTRACT: Neck management for cN0 neck remains controversial for T1-2 oral tongue and buccal squamous cell carcinoma (SCC). Increased tumor thickness and perineural invasion (PNI) are two pathologic features that correlated with cervical lymph node (LN) metastasis and poor survival. However, the relationships between these two features remain unclear. Detailed histologic reevaluation under hematoxylin and eosin staining was performed in tumors of 212 consecutive patients with T1-2, cN0 oral tongue and buccal SCC. The interrelationships between the impacts of tumor thickness and PNI on cervical LN metastasis and disease-specific survival (DSS) were analyzed. Increased tumor thickness (>6 mm) correlated with higher LN metastasis and poor 5-year DSS rates in univariate analysis. However, only PNI independently predicted both in multivariate analysis (P = 0.004 and P = 0.039, respectively). When stratified by PNI status, increased tumor thickness did not correlate with higher LN metastasis rate in either PNI-negative or PNI-positive groups (P = 0.337 and P = 0.730). Compared to patients with thin tumors (≤6 mm), patient with thick tumors revealed significantly higher LN metastasis rate (41.9 vs. 16.4 %, P = 0.001) and lower 5-year DSS rate (77.5 vs. 93.7 %, P = 0.006) only at the presence of PNI. PNI can be a major determinant for higher LN metastasis and poor 5-year DSS rates associated with increased tumor thickness in T1-2 oral tongue and buccal SCC. Careful evaluation of PNI should be mandatory in routine pathologic examination, aside from the measurement of tumor thickness.
    Annals of Surgical Oncology 07/2013; · 4.12 Impact Factor
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    ABSTRACT: PURPOSEThe role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation before rituximab-based chemotherapy in patients with lymphoma and resolved hepatitis B is unclear. PATIENTS AND METHODS Eighty patients with CD20(+) lymphoma and resolved hepatitis B were randomly assigned to receive either prophylactic entecavir (ETV) before chemotherapy to 3 months after completing chemotherapy (ETV prophylactic group, n = 41) or to receive therapeutic ETV at the time of HBV reactivation and hepatitis B surface antigen (HBsAg) reverse seroconversion since chemotherapy (control group, n = 39).ResultsFifty-eight patients (72.5%) were positive for hepatitis B surface antibody, and HBV DNA was undetectable in 50 patients (62.5%). During a mean 18-month follow-up period, one patient (2.4%) in the ETV prophylactic group and seven patients (17.9%) in the control group developed HBV reactivation (P = .027). The cumulative HBV reactivation rates at months 6, 12, and 18 after chemotherapy were 8%, 11.2%, and 25.9%, respectively, in the control group, and 0%, 0%, and 4.3% in the ETV prophylactic group (P = .019). Four patients (50%) in the control group had HBsAg reverse seroconversion after HBV reactivation. The cumulative HBsAg reverse seroconversion rates at months 6, 12, and 18 since chemotherapy were 0%, 6.4%, and 16.3% in the control group, respectively, which were significantly higher than those in the ETV prophylactic group (P = .032). Patients with detectable or undetectable viral load could develop HBV reactivation and HBsAg reverse seroconversion. CONCLUSION Undetectable HBV viral load before chemotherapy did not confer reactivation-free status. Antiviral prophylaxis can potentially prevent rituximab-associated HBV reactivation in patients with lymphoma and resolved hepatitis B.
    Journal of Clinical Oncology 06/2013; · 18.04 Impact Factor
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    ABSTRACT: The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multi-functional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through αvβ3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Co-expression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC.
    Cancer Research 05/2013; · 9.28 Impact Factor
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    ABSTRACT: Observation or elective neck dissection (END) for cN0 neck remains controversial for the treatment of T1-2 oral squamous cell carcinoma (OSCC). Perineural invasion (PNI) has been recognized as a poor prognostic factor for OSCC. However, its significance in T1 OSCC remains unclear. A detailed histologic reevaluation of PNI was carried out in 307 patients with T1-2 OSCC who received surgical treatment between June 2001 and January 2009. We found that the presence of PNI correlated with cervical lymph node metastasis in both T1 and T2 OSCC, with a lower PNI-positive rate in T1 (17.1% vs. 36.6%; P<0.001). Importantly, observation for cN0 neck was used twice as often in T1 than in T2 patients (47.4% vs. 22.8%; P<0.001). Although patients with T1 OSCC achieved significantly better outcomes, PNI correlated with neck recurrence and poor disease-specific survival (DSS) only in T1 (P<0.001 and P<0.0001) but not in T2 patients (P=0.399 and 0.1478). Of the 146 patients with T1 OSCC, PNI independently predicted cervical lymph node metastasis, neck recurrence, and poor DSS. END significantly reduced neck recurrence of T1 OSCC in PNI-positive (P=0.001) but not in PNI-negative (P=0.114) patients. In addition, END improved the 5-year DSS of T1 OSCC more in PNI-positive than in PNI-negative patients (16.2% vs. 5.4%). Our results indicate that PNI independently predicts a poor prognosis in T1 OSCC patients who are potentially curable but tend to be treated conservatively. For its efficacy in improving treatment outcomes, aggressive END is indicated for T1 OSCC patients at the presence of PNI.
    The American journal of surgical pathology 05/2013; · 4.06 Impact Factor
  • Article: OP192
    Oral Oncology 05/2013; 49:S76. · 2.70 Impact Factor
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    ABSTRACT: The optimal treatment for tonsillar squamous cell carcinoma (SCC) remains controversial. The purpose of this study was to evaluate long-term treatment outcomes of patients with tonsillar SCC, in order to aid in appropriate treatment selection. We conducted a retrospective chart review of 105 patients with curatively treated tonsillar SCC between January 1996 and December 2005. Forty-three patients (41.0%) underwent primary surgery with or without adjuvant therapy (primary surgery group), and 62 patients (59.0%) were treated with radiotherapy/chemoradiotherapy (RT/CRT, organ preservation group). Twenty patients (19%) received tumor tonsillectomy before definitive RT/CRT and were grouped into the organ preservation group. No significant differences were observed between the primary surgery and organ preservation groups in terms of local control (p = 0.212), regional control (p = 0.684), distant metastasis (p = 0.627), 5-year disease-specific survival (DSS, p = 0.774), and overall survival rates (OS, p = 0.667). The rates of major complication (p = 0.216), long-term dependency on feeding tubes (p = 0.876), and tracheostomy (p = 0.401) were also similar. Advanced T classification (T3-4) was the only factor associated with significantly worse DSS (p = 0.007) and OS (p = 0.012). However, there was also no difference in final treatment outcomes in T3-4 patients regardless of whether they were treated with primary surgery or RT/CRT. In the organ preservation group, tumor tonsillectomy before RT/CRT did not improve local control (p = 0.520) or other treatment outcomes, including 5-year DSS (p = 0.707) and OS (p = 0.745). Both primary surgery and RT/CRT organ preservation are effective treatments for tonsillar SCC. Single modality treatment, either surgery or RT/CRT, can typically be provided for stage I-II diseases. Although RT/CRT organ preservation is used more frequently for stage III-IV tonsillar SCC in recent years, primary surgery combined with adjuvant therapy still achieves equivalent outcomes. Multidisciplinary pretreatment counseling and the facilities and personnel available are therefore important for decision-making. In addition, if RT/CRT organ preservation is selected as the primary treatment, tumor tonsillectomy is not indicated.
    Journal of the Chinese Medical Association 04/2013; 76(4):211-7. · 0.75 Impact Factor
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    ABSTRACT: OBJECTIVE: Carotid blowout syndrome is a severe complication of head and neck cancer. High mortality and major neurologic morbidity are associated with carotid blowout syndrome with massive bleeding. Prediction of outcomes for carotid blowout syndrome patients is important for clinicians, especially for patients with the risk of massive bleeding. METHODS: Between 1 January 2001 and 31 December 2011, 103 patients with carotid blowout syndrome were enrolled in this study. The patients were divided into groups with and without massive bleeding. Prognostic factors were analysed with proportional hazard (Cox) regressions for carotid blowout syndrome-related prognoses. Survival analyses were based on the time from diagnosis of carotid blowout syndrome to massive bleeding and death. RESULTS: Patients with massive bleeding were more likely to have hypoalbuminemia (albumin <3.5 g/dl; P = 0.023). Univariate analysis of carotid blowout syndrome-related massive bleeding showed that treatment for carotid blowout syndrome (best supportive care, P = 0.000; embolization, P = 0.000), monocytosis (monocytes >1000 cells/μl, P = 0.041) and hypoalbuminemia (P = 0.010) were important to prognosis. Concurrent chemoradiotherapy (P = 0.007), elevated lactate dehydrogenase (>250 U/l; P = 0.050), local recurrence (P = 0.022) and hypoalbuminemia (P = 0.038) were related to poor prognosis in carotid blowout syndrome-related death. In multivariate analysis, best supportive care and hypoalbuminemia were independent factors for both carotid blowout syndrome-related massive bleeding (P = 0.000) and carotid blowout syndrome-related death (P = 0.013), respectively. CONCLUSION: Best supportive care and serum albumin are important prognostic factors in carotid blowout syndrome. It helps clinicians to evaluate and provide better supportive care for these patients.
    Japanese Journal of Clinical Oncology 03/2013; · 1.90 Impact Factor
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    ABSTRACT: The movement modes of epithelial cancer cells in three-dimensional (3D) environments include the mesenchymal mode, which is associated with local invasion, and the amoeboid mode, which facilitates distant metastasis. The migratory behavior of individual cancer cells is critical for tumor dissemination; however, the mechanism underlying regulation of the switch between movement modes is not clearly understood. For head and neck squamous cell carcinoma (HNSCC), local invasion is the major route of dissemination. We previously demonstrated that, in HNSCC cells, Twist1 represses let-7i expression to elicit mesenchymal-mode movement through activation of Ras-related C3 botulinum toxin substrate 1 (RAC1). In this study, we discover another important target gene of let-7i for regulating HNSCC migration. Using bioinformatic tools, we identified bone morphogenetic protein 4 (BMP4) as a candidate target of let-7i. Further experiments, including 3'-untranslated region (UTR) reporter assays, quantitative RT-PCR and western blotting, confirmed that BMP4 is a bona fide target repressed by let-7i. In the HNSCC cell line OECM-1, knockdown of BMP4 reduced mesenchymal-mode migration and invasion in 3D culture. In clinical HNSCC samples, let-7i expression was inversely correlated with BMP4 expression. Our results revealed that let-7i attenuates mesenchymal-mode migration of HNSCC cells through repression of a novel target, BMP4.
    Biochemical and Biophysical Research Communications 02/2013; · 2.28 Impact Factor
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    ABSTRACT: Chromosomal instability (CIN) is widely considered a hallmark of cancer but its precise roles in cancer stem cells (CSCs) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis and poor prognosis. Here we report that BMI1 mediates its diverse effects through upregulatiion of the mitotic kinase Aurora A which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed microRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exert several effects, including centrosomal amplification and aneuploidy, anti-apoptosis and cell cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that co-amplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT and CIN through the BMI1-AURKA axis and suggest therapeutic utility from inhibiting Aurora A in head and neck cancers which overexpress BMI1.
    Cancer Research 11/2012; · 9.28 Impact Factor

Publication Stats

2k Citations
398.00 Total Impact Points

Institutions

  • 2006–2014
    • National Yang Ming University
      • • Institute of Clinical Medicine
      • • Faculty of Medicine
      • • Institute of Biochemistry and Molecular Biology
      T’ai-pei, Taipei, Taiwan
  • 2000–2013
    • Taipei Veterans General Hospital
      • Department of Medicine
      Taipei, Taipei, Taiwan
  • 2011
    • University of Texas Health Science Center at Houston
      • Division of Gastroenterology, Hepatology and Nutrition (Internal Medicine)
      Houston, TX, United States
  • 2009
    • National Chung Hsing University
      • Institute of Biochemistry
      臺中市, Taiwan, Taiwan
  • 2007–2008
    • Chia-Yi Christian Hospital
      Chia-i-hsien, Taiwan, Taiwan