Keng-Fu Hsu

National Cheng Kung University, 臺南市, Taiwan, Taiwan

Are you Keng-Fu Hsu?

Claim your profile

Publications (41)159.58 Total impact

  • Yih-Fung Chen · Keng-Fu Hsu · Meng-Ru Shen
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cell migration and invasion are essential steps in the metastatic cascade that has great impact on patient outcomes. Spatial and temporal organization of Ca(2+) signaling regulates the multiple aspects of migration machinery, including cytoskeletal reorganization, traction force generation, and focal adhesion dynamics. Stromal interaction molecules (STIM) and Orai proteins, recently identified as critical constituents of store-operated Ca(2+) entry (SOCE), have been implicated in cancer cell migration and tumor metastasis. The clinical significance of STIM proteins and Orai Ca(2+) channels in tumor progression and their diagnostic and prognostic potentials have also been demonstrated in different types of cancers. Here we review the recent advances in understanding the important roles and regulatory mechanisms of STIM/Orai-mediated SOCE in cancer spread. The clinical implications and the emergence as a selective target for cancer therapeutics are also discussed.(1).
    No preview · Article · Nov 2015 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The goal of this study was to investigate the impact of ovarian preservation on the survival of women with early-stage endometrial cancer, particularly young women. Materials and methods: A study cohort of 64 patients with histologically confirmed early-stage endometrial cancer was retrospectively collected from 10 member hospitals of the Taiwanese Gynecologic Oncology Group between 1998 and 2009. Survivorship and overall survival were compared between these two groups using a log-rank test. Results: All patients who underwent surgery were adult women with a mean age of 40.4 ± 9.2 years (range 24-63 years). Ovary-preserving surgery was performed in 38 (59.4%) patients who desired to preserve their ovaries, incidentally in 19 (29.7%) patients with a preoperative diagnosis other than endometrial carcinoma, and in seven patients (10.9%) with unknown reasons. The 5-year recurrence-free survival rate was 98.3% with a median follow up of 44.6 months (range 1.0-126.9 months). Eight patients required adjuvant treatment (12.5%); one patient had documented local recurrence (1.6%); and no metachronous ovarian malignancy occurred during follow up. Conclusion: Preservation of bilateral ovaries does not increase cancer-related mortality. A more conservative approach to surgical staging may be considered in premenopausal women with early-stage endometrial cancer without risk factors.
    No preview · Article · Oct 2015 · Taiwanese Journal of Obstetrics and Gynecology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.
    Full-text · Article · Dec 2014 · Oncotarget
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report the clinical and pathological findings of two cases of Bowen's disease (BD) with features resembling myrmecia wart, and tried to find evidence of human papillomavirus (HPV) infection in such lesions by immunohistological staining, genotyping systems, polymerase chain reaction (PCR) and electron microscopy. Both cases manifested unique barnacle-like hyperkeratotic nodules or plaques clinically, and microscopically proliferation of atypical keratinocytes involving the entire thickness of the epidermis, hypergranulosis with eosinophilic and/or basophilic inclusion bodies, features that mimicked myrmecia wart. Electron microscopy revealed myrmecia inclusion-like large intranuclear and cytoplasmic electron-dense bodies. Immunohistological staining with anti-HPV antibody, genotyping systems for HPV infection and specific PCR designed to detect HPV-1 L1 sequences failed to detect evidence of HPV infection. P16(INK4a) was overexpressed in the atypical keratinocytes of both cases. This finding suggests that the pathogenesis of these two BD may involve certain unknown or undetectable HPV, or reflect disturbances of the Rb signaling pathway unrelated to HPV infection. The unique "myrmecioid" clinicopathological features in our cases suggest that this type of lesion may be a new variant of BD.
    No preview · Article · Nov 2014 · The Journal of Dermatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To understand the mechanisms of postpartum uterine involution, we investigated the uterine myometrial changes during pregnancy and the postpartum period. Materials and methods Nine groups of uterine myometrial samples from mice (n = 4) were collected on gestational Day 0 (nonpregnant), Day 1, Day 2, Day 7, Day 14, and Day 21 and on postpartum Day 1, Day 2, and Day 7. Human samples of uterine myometrium on term (n = 1) and postpartum Day 1 (n = 2) were also collected. Ki-67 immunostaining was used to determine myometrial proliferation. For cell hypertrophy analysis, organelle proteins, β-actin, prohibin, calnexin, and golgin-97 were analyzed by Western blotting. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and evaluation of activated caspase-3 expression by Western blot analysis assay were used to detect apoptosis. Autophagy was assayed via the evaluation of LC3 expression by Western blotting, immunohistochemistry, and autophagosomes by electron microscopy. Results Uterine myocytes proliferated during the early stage of gestation with a peak at Day 2, whereas myocyte hypertrophy with increased cellular organelle production occurred gradually in later stages of pregnancy. Postpartum autophagy developed abruptly in uterine myocytes without obvious apoptosis. Conclusion Autophagy of myocytes may play an important role in uterine involution. These results have implications for our understanding of myometrial functional adaptations during pregnancy and the physiological role of autophagy in the uterine remodeling events in the postpartum period.
    No preview · Article · Sep 2014 · Taiwanese Journal of Obstetrics and Gynecology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ovarian cancer (OvCa) is the second most common type of gynecological cancer. More seriously, the prognosis for survival is relatively poor if an early OvCa diagnosis is not achieved. However, it is extremely challenging to diagnose very early stage OvCa, when treatments are the most effective, because of the lack of specific and sensitive biomarkers. Therefore, in order to achieve early detection of OvCa, screening and identifying biomarkers with high specificity and affinity are greatly needed. In this study, an integrated microfluidic system capable of performing cell-based systematic evolution of ligands by an exponential enrichment (Cell-SELEX) process was developed for automatic, high-throughput screening of multiple cell lines to competitively select aptamer-based biomarkers for OvCa. This on-chip Cell-SELEX process only required five rounds of aptamer selection, which is much faster than using a conventional SELEX process (22 rounds). Using this on-chip process, 13 aptamers specific to OvCa cells were successfully screened and three of them showed high affinity towards target cells with dissociation constants of 1.8 nM, 8.3 nM, and 1.3 nM. Analysis of stained fluorescence images and competitive testing against multiple cancer cell lines (cervical cancer, breast cancer, lung cancer, and liver cancer) were performed to verify the specificity of these selected aptamers. The results demonstrated that this developed system could perform the on-chip Cell-SELEX selection successfully and could be applied for personalized aptamer screening or targeted therapy monitoring in the near future.
    Full-text · Article · Aug 2014 · Lab on a Chip
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The aim of this study was to investigate the clinical and pathological characteristics of uterine clear cell carcinoma (UCCC) and the treatment of this disease in relation to patient outcomes. Methods: The clinicopathological data for and the management of all patients with UCCC who presented between 1991 and 2010 at 11 member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed. Results: There were no significant differences in 5-year overall survival (OS) rates between patients with pure UCCC (n=100) and non-pure UCCC (n=53) at the same surgical stage, with OS rates of 92.6%, and 87.7% for stage I; 83.3% and 83.3% for stage II; 64.0% and 67.8% for stage III; and 16.7% and 0% for stage IV (n=1), respectively. Tumor stage and age independently influenced the OS rate of UCCC. For the patients with early stage UCCC, the adjuvant therapy modality was the only significant prognostic factor for recurrence-free survival. The patients with early stage UCCC who received adjuvant therapy had excellent 5-year recurrence-free survival and OS rates compared to those who received radiotherapy (100% vs. 74%, p=0.01; 100% vs. 72%, p=0.03). Conclusions: The 5-year survival rates of patients with pure UCCC and non-pure UCCC were similar. The prognosis for surgical staging of patients with stage I/II UCCC was encouraging. Postoperative adjuvant platinum-based chemotherapy is recommended for patients with early stage UCCC who are at a high risk of recurrence.
    No preview · Article · Jul 2014 · Gynecologic Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective To investigate the clinical and pathological characteristics and the management of uterine papillary serous carcinoma (UPSC) in relation to patients’ outcomes. Methods Clinicopathological data and the management of patients treated between 1991 and 2010 at 11 member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed. The Kaplan-Meier method was used to generate survival curves, and factors predictive of outcome were compared using the log-rank test and Cox regression analysis. Results A total of 119 pure UPSC patients were recruited. Stages I, II, III, and IV were identified in 34.5%, 2.5%, 36.1%, and 26.9% of the patients, respectively. The recurrence rate was 20.5% in FIGO stage I/II disease and 55.2% in FIGO stage III/IV disease. The 5-year overall survival rates for the patients with stage I, II, III, and IV disease were 92.0%, 66.7%, 34.2%, and 17.3%, respectively. Multivariate analysis showed that tumor stage (stages III/IV hazard ratio [HR] 8.65, 95% confidence interval [CI] 3.00-24.9) and optimal cytoreduction (HR 0.40, 95%CI 0.22-0.73) independently influenced the overall survival rate of UPSC patients. In addition, optimal cytoreduction (HR 0.36, 95%CI 0.17-0.78) and the combination of chemotherapy and radiation (HR 0.11, 95%CI 0.04-0.37) improved the overall survival of the advanced stage (FIGO stages III/IV) UPSC patients. Conclusions UPSC represents an aggressive subtype of endometrial cancer commonly accompanied by extra-uterine disease. Comprehensive surgical staging with cytoreductive surgery is mandatory and beneficial for UPSC patients. Systemic chemotherapy combined with radiation should be considered as adjuvant therapy for advanced stage UPSC patients.
    No preview · Article · May 2014 · Gynecologic Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aggressive epithelial ovarian cancers (EOCs) frequently progress and become fatal, even when cytoreduction surgery plus platinum-based chemotherapy is performed. Thus, the early detection of high-risk subgroups is important to provide opportunities for better treatment outcomes, using alternative therapeutic strategies. This study aimed to explore the expression of circulating insulin-like growth factor (IGF) system components and their relationship with treatment outcome in EOC. We included 228 patients with median follow-up time of 44 months at 2 tertiary centers. There were 68 cancer deaths and 108 cases of cancer progression in the cohort. Preoperative serum levels of total IGF1, IGF2, IGF binding protein 2 (IGFBP2), and IGFBP3 were analyzed using an enzyme-linked immunosorbent assay and were then converted into an IGF1/IGFBP3 molar ratio. The risks of mortality and progression were estimated using Cox regression models in univariate and multivariate analyses. Our results showed that high IGF1, IGF2, and IGFBP3 levels were significantly associated with an early cancer stage, non-serous histology, and optimal cytoreduction. High IGFBP2 levels were associated with an advanced stage and serous histology. Overall and progression-free survival durations were significantly better among patients with high IGF1, IGF2, or IGFBP3 levels. In multivariate analysis, serum IGFBP2 levels were significantly associated with increased risk of mortality (hazard ratio = 1.84, 95% confidence interval: 1.07-3.18, p = 0.03), indicating that IGFBP2 could be used as an early predictor of EOC-related mortality. The combination of elevated IGFBP2 and reduced IGF1 levels at diagnosis could further facilitate the identification of a patient subgroup with the worst prognosis.
    Preview · Article · Nov 2013 · Endocrine Related Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early and accurate diagnosis of cancer plays a very important role in favorable clinical outcomes. DNA methylation of tumor suppressor genes has been recognized as a diagnostic biomarker for early carcinogenesis. The presence of 5-methylcytosine in the CpG islands in the promoter region of a tumor suppressor gene is an important indicator of DNA methylation. However, the standard detection assay utilizing a bisulfite treatment and HpaII/MspI endonuclease digestion is a tedious and lengthy process and requires a relatively large amount of DNA for testing. In this study, the methylated DNAs of various tumor suppressor genes, HAAO, HOXA9 and SFRP5, were chosen as candidates for detection of ovarian cancer cells. The entire experimental process for the DNA methylation assay, including target DNA isolation, HpaII/MspI endonuclease digestion, and nucleic acid amplification has been realized in an integrated microfluidic system. The limit of detection using this developed system has been experimentally determined to be 102 cells/reaction. The entire process from sample loading to analysis of the results only took 3 h which is much faster than the existing protocols. Different sources of biosamples, such as cells, ascites and serums, could be detected with the methylated DNA, indicating that this developed microfluidic system could be adapted for clinical use. Thus, this developed microsystem may be a promising platform for the rapid and early diagnosis of cancers.
    No preview · Article · Nov 2013 · Microfluidics and Nanofluidics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ovarian cancer is the second most common of the gynecological cancers in Taiwan. It is challenging to diagnose at an early stage when proper treatment is the most effective. It is well recognized that the detection of tumor cells (TCs) is critical for determining cancer growth stages and may provide important information for accurate diagnosis and even prognosis. In this study, a new microfluidic platform integrated with a moving-wall micro-incubator, a micro flow cytometer and a molecular diagnosis module performed automated identification of ovarian cancer cells. By efficiently mixing the cells and immunomagnetic beads coated with specific antibodies, the target TCs were successfully isolated from the clinical samples. Then counting of the target cells was achieved by a combination of the micro flow cytometer and an optical detection module and showed a counting accuracy as high as 92.5 %. Finally, cancer-associated genes were amplified and detected by the downstream molecular diagnosis module. The fluorescence intensity of specific genes (CD24 and HE4) associated with ovarian cancer was amplified by the molecular diagnosis module and the results were comparable to traditional slab-gel electrophoresis analysis, with a limit of detection around 10 TCs. This integrated microfluidic platform realized the concept of a "lab-on-a-chip" and had advantages which included automation, disposability, lower cost and rapid diagnosis and, therefore, may provide a promising approach for the fast and accurate detection of cancer cells.
    No preview · Article · Jan 2013 · Biomedical Microdevices
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the clinical outcome and parameters related to coexisting endometrial carcinoma in women with tissue-diagnosed endometrial hyperplasia. Between January 1991 and December 2009, three hundred and eighty-six patients with the presumptive diagnosis of endometrial hyperplasia were retrieved. Among these, one hundred and twenty-five patients were identified as having coexisting endometrial carcinoma in hysterectomy specimens. The three hundred and eighty-six patients were divided into two groups: the hyperplasia-benign group (261 cases) and the hyperplasia-malignant group (125 cases). Several clinical parameters including age, menopausal status, history of abnormal uterine bleeding, obstetrical history, medical history of diabetes and hypertension, BMI, and preoperative pathologic results were investigated. Age ≥53 (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.26 to 4.57), menopausal status (OR, 2.07; 95% CI, 1.14 to 3.76), diabetes history (OR, 7.33; 95% CI, 2.79 to 19.26), abnormal uterine bleeding (OR, 3.99; 95% CI, 1.22 to 13.02), atypical endometrial hyperplasia (OR, 7.38; 95% CI, 4.03 to 13.49), and body mass index ≥27 (OR, 3.24; 95% CI, 1.76 to 5.97) were independent risk factors for prediction of endometrial hyperplasia coexisting with endometrial carcinoma. The diagnostic efficacy of atypical endometrial hyperplasia to predict the endometrial hyperplasia coexisting with endometrial carcinoma was better than or similar to those of other independent factors and combinations of these factors. Coexisting malignancy should be considered when examining endometrial hyperplasia patients with the related risk factors, especially atypical endometrial hyperplasia.
    Full-text · Article · Jan 2013 · Journal of Gynecologic Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate, using three-dimensional power Doppler ultrasound (3D-PDU), alterations in cervical intratumoral vascularization during and after radiotherapy. Between 2004 and 2009 we enrolled into the study 37 patients with FIGO Stages IB1–IIB cervical carcinoma who were undergoing radiotherapy. Serial 3D-PDU scans were performed during treatment, providing ultrasonographic measurement of tumor size, vascularization index, flow index and vascularization flow index, as well as monthly for 3 months post-treatment and tri-monthly thereafter, until vascularity was undetectable on two consecutive occasions. Physical examination, cervical cytology and serum marker evaluation were performed every 3–6 months for the first 5 years following treatment. Patients evaluated after a 2-year tumor-free interval and those with clinically assessed positive findings at follow-up underwent 3D-PDU to detect possible local disease. A total of 329 3D-PDU scans were performed in the 37 women. Cervical tumors and intratumoral vascularization disappeared within 3 months following radiotherapy, except in one patient with persistent disease. Nine patients had disease relapse, in four of whom the recurrence was local. In three of these four, there was recurrence of tumor and vascularization after a complete response. At follow-up, 3D-PDU detected local disease with 75.0% sensitivity and 98.5% specificity, while serum markers detected local disease among 34 patients with squamous cell carcinoma with 20.0% sensitivity and 77.3% specificity. Compared with serum markers in cervical squamous cell carcinoma, 3D-PDU has higher sensitivity and specificity for detecting local recurrence or persistence in cervical carcinoma. Thus, 3D-PDU combined with clinical assessment may be a new and safe method for monitoring radiotherapy treatment response and detecting local recurrence. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.
    No preview · Article · Jun 2012 · Ultrasound in Obstetrics and Gynecology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early and accurate diagnosis of cancer plays a very important role in cancer treatment. The DNA methylation of tumor suppressor genes has been used as a diagnostic biomarker of early carcinogenesis. The 5-methylcytosine of CpG islands in the promoter region has been demonstrated as an evidence of DNA methylation. In this study, the entire process for performing DNA methylation assay including capturing of target DNA, HpaII and MspI endonuclease digestion and nucleic acid amplification have been realized in an integrated microfluidic system. The limit of detection in the microfluidic system was experimentally found to be 102 cells/reaction. The entire process from sample loading to results observed only takes 3 hrs. Rapid diagnosis of ovarian cancer cells in the integrated microfluidic system has been demonstrated by using cell lines and clinical samples. The developed micro system may be promising for early diagnosis of cancers.
    No preview · Article · Jan 2012 · Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS)
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human papilloma virus (HPV) has been implicated in the carcinogenesis and prognosis of certain head and neck cancers. Whether it also has a role in the pathogenesis of nasopharyngeal carcinoma (NPC) in Taiwan is unclear. Detection and genotyping of HPVs were performed in 43 primary NPCs (one WHO-I and 42 WHO-II/III) and 40 nasopharyngeal controls using PCR-based HPV genotyping arrays. Localisation of high-risk HPV and Epstein-Barr virus genomes was performed in another 46 primary NPCs (five WHO-I and 41 WHO-II/III) and seven paired metastatic WHO-II/III NPCs using in situ hybridisation. In the HPV genotyping cohort, oncogenic HPVs were detected equally in WHO-II/III NPCs (31%, 13/42) and nasopharyngeal controls (35%, 14/40). Tumour high-risk HPV status did not correlate with the prognosis of patients with NPC. In the high-risk HPV in situ hybridisation cohort, 14 (88%) of the 16 oncogenic HPV-positive WHO-II/III NPCs showed a unique cytoplasmic/perinuclear staining pattern, which is distinct from the typical dot/punctate nuclear staining pattern indicating HPV genome integration. In addition, oncogenic HPVs were not always retained in NPC cells during the process of metastasis. This study does not support an association between oncogenic HPV and the carcinogenesis or prognosis of WHO-II/III NPCs in Taiwan.
    No preview · Article · Jul 2011 · Journal of clinical pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To assess knowledge and attitudes regarding cervical cancer and human papillomavirus (HPV) among undergraduate women in Taiwan. A descriptive cross-sectional design. Five universities in southern Taiwan. 953 undergraduate women aged 17-36 years. The self-administered HPV Belief questionnaire was used to collect data on knowledge and beliefs regarding cervical cancer, Pap testing, and HPV. Knowledge, beliefs, cervical cancer, Pap testing, HPV, likelihood of cervical cancer, and HPV infection. Seventy percent of participants agreed that cervical cancer could be prevented and was a severe disease, and 80% knew the purpose of Pap testing. Forty-nine percent were aware of HPV. Undergraduate women with an awareness of HPV were more likely to be older, studying a health-related major, have a higher class standing, have a personal history of gynecologic visits, and have had a Pap test. Neither family history of gynecologic cancer nor sexual experience predicted HPV awareness, although sexual experience had a significant association with the knowledge and beliefs of cervical cancer. Most of the undergraduate women believed themselves unlikely to acquire cervical cancer or HPV infection. Undergraduate women in Taiwan have limited knowledge of cervical cancer and HPV. Awareness of the likelihood of HPV infection is low among undergraduate women, even those who are sexually active. Educational campaigns focusing on cervical cancer screening and HPV infection are needed, particularly for sexually active undergraduate women.
    Preview · Article · Jul 2011 · Oncology Nursing Forum

  • No preview · Article · Jun 2011 · International Journal of Colorectal Disease
  • [Show abstract] [Hide abstract]
    ABSTRACT: Isolation and detection of tumor ceIJs (TCs) from a large amount of biological samples have been a major chaIJenge in clinical diagnosis. To tackle this problem, a three-dimensiona l micro incubator using deflecting membranes has been reported by our group previously. However, it requires a relatively complicated fabrication process, which involves bonding of multiple polydimethyl siloxane (PDMS) layers. In this study, a new micro incubator equipped with moving-wall structures is presented. Compared with our previous work, the new chip requires a simpler fabrication process and can be activated with ease. Experimental results showed that the developed micro incubator can be used for isolation of tumor cells when incorporated with magnetic beads. Furthermore, counting and detection of these cancer cells can be further performed when integrated with a micro flow cytometer and a micro nucleic acid module. Therefore, the developed device may be promising for further biomedical applications.
    No preview · Article · Jun 2011
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.
    Full-text · Article · May 2011 · The Journal of clinical investigation
  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study reports a new three-dimensional (3D) microfluidic platform capable of rapid isolation and detection of cancer cells from a large sample volume (e.g. ~1 mL) by utilizing magnetic microbead-based technologies. Several modules, including a 3D microfluidic incubator for the magnetic beads to capture cancer cells, a microfluidic control module for sample transportation and a nucleic acid amplification module for genetic identification, are integrated into this microsystem. With the incorporation of surface-modified magnetic beads, target cancer cells can be specifically recognized and conjugated onto the surface of the antibody-coated magnetic microbeads by utilizing a swirling effect generated by the new 3D microfluidic incubator, followed by isolating and purifying the magnetic complexes via the incorporation of an external magnet and a microfluidic control module, which washes away any unbound waste solution. Experimental results show that over 90% of the target cancer cells can be isolated from a large volume of bio-samples within 10 min in the 3D microfluidic incubator. In addition, the expressed genes associated with ovarian and lung cancer cells can also be successfully amplified by using the on-chip nucleic acid amplification module. More importantly, the detection limit of the developed system is found to be 5 × 10(1) cells mL(-1) for the target cancer cells, indicating that this proposed microfluidic system may be adapted for clinical use for the early detection of cancer cells. Consequently, the proposed 3D microfluidic system incorporated with immunomagnetic beads may provide a promising automated platform for the rapid isolation and detection of cancer cells with a high sensitivity.
    No preview · Article · Oct 2010 · Lab on a Chip

Publication Stats

578 Citations
159.58 Total Impact Points

Institutions

  • 2002-2015
    • National Cheng Kung University
      • • Department of Obstetrics and Gynecology
      • • Department of Physiology
      臺南市, Taiwan, Taiwan
  • 2005-2013
    • National Cheng Kung University Hospital
      • Department of Pediatrics
      臺南市, Taiwan, Taiwan
  • 2001
    • ՊԵՐԻՆԱՏՈԼՈԳԻԱՅԻ, ՄԱՆԿԱԲԱՐՁՈՒԹՅԱՆ ԵՎ ԳԻՆԵԿՈԼՈԳԻԱՅԻ ԻՆՍՏԻՏՈՒՏ
      Ayrivan, Yerevan, Armenia