Yang Ming Branch of Taipei City Hospital

Taipei, Taiwan

Yang Ming Branch of Taipei City Hospital

Taipei, Taiwan
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Liu C.-Y.,Taipei Veterans General Hospital | Liu C.-Y.,National Yang Ming University | Chen K.-F.,National Taiwan University Hospital | Chen K.-F.,National Taiwan University | And 19 more authors.
Journal of Molecular Medicine | Year: 2017

Abstract: Triple negative breast cancer (TNBC) is an aggressive cancer for which prognosis remains poor. Combination therapy is a promising strategy for enhancing treatment efficacy. Blockade of STAT3 signaling may enhance the response of cancer cells to conventional chemotherapeutic agents. Here we used a SHP-1 agonist SC-43 to dephosphorylate STAT3 thereby suppressing oncogenic STAT3 signaling and tested it in combination with docetaxel in TNBC cells. We first analyzed messenger RNA (mRNA) expression of SHP-1 gene (PTPN6) in a public TNBC dataset (TCGA) and found that higher SHP-1 mRNA expression is associated with better overall survival in TNBC patients. Sequential combination of docetaxel and SC-43 in vitro showed enhanced anti-proliferation and apoptosis associated with decreased p-STAT3 and decreased STAT3-downstream effector cyclin D1 in the TNBC cell lines MDA-MB-231, MDA-MB-468, and HCC-1937. Ectopic expression of STAT3 reduced the increased cytotoxicity induced by the combination therapy. In addition, this sequential combination showed enhanced SHP-1 activity compared to SC-43 alone. Furthermore, the combination treatment-induced apoptosis was attenuated by small interfering RNA (siRNA) against SHP-1 or by ectopic expression of SHP-1 mutants that caused SC-43 to lose its SHP-1 agonist capability. Moreover, combination of docetaxel and SC-43 showed enhanced tumor growth inhibition compared to single-agent therapy in mice bearing MDA-MB-231 tumor xenografts. Our results suggest that the novel SHP-1 agonist SC-43 enhanced docetaxel-induced cytotoxicity by SHP-1 dependent STAT3 inhibition in human triple negative breast cancer cells. TNBC patients with high SHP-1 expressions show better survival. Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3. SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination. Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3. Key messages: TNBC patients with high SHP-1 expressions show better survival.Docetaxel combined with SC-43 enhances cell apoptosis and reduces p-STAT3.Enhanced prolyl-hydroxylase inhibition increases mainly CXCR4+/CD11b+ cells.SHP-1 inhibition reduces the enhanced effect of docetaxel-SC-43 combination.Docetaxel-SC-43 combination suppresses xenograft tumor growth and reduces p-STAT3. © 2017 Springer-Verlag Berlin Heidelberg

Liu C.-Y.,Taipei Veterans General Hospital | Liu C.-Y.,National Yang Ming University | Hung M.-H.,Taipei Veterans General Hospital | Hung M.-H.,National Yang Ming University | And 13 more authors.
Breast Cancer Research | Year: 2014

Introduction: Tamoxifen, a selective estrogen receptor (ER) modulator, may affect cancer cell survival through mechanisms other than ER antagonism. In the present study, we tested the efficacy of tamoxifen in a panel of ER-negative breast cancer cell lines and examined the drug mechanism.Methods: In total, five ER-negative breast cancer cell lines (HCC-1937, MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3) were used for in vitro studies. Cellular apoptosis was examined by flow cytometry and Western blot analysis. Signal transduction pathways in cells were assessed by Western blot analysis. The in vivo efficacy of tamoxifen was tested in xenograft nude mice. Results: Tamoxifen induced significant apoptosis in MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3 cells, but not in HCC-1937 cells. Tamoxifen-induced apoptosis was associated with inhibition of cancerous inhibitor of protein phosphatase 2A (CIP2A) and phospho-Akt (p-Akt) in a dose-dependent manner. Ectopic expression of either CIP2A or Akt protected MDA-MB-231 cells from tamoxifen-induced apoptosis. In addition, tamoxifen increased protein phosphatase 2A (PP2A) activity, and tamoxifen-induced apoptosis was attenuated by the PP2A antagonist okadaic acid in the sensitive cell lines, but not in resistant HCC-1937 cells. Moreover, silencing CIP2A by small interfering RNA sensitized HCC-1937 cells to tamoxifen-induced apoptosis. Furthermore, tamoxifen regulated CIP2A protein expression by downregulating CIP2A mRNA. Importantly, tamoxifen inhibited the in vivo growth of MDA-MB-468 xenograft tumors in association with CIP2A downregulation, whereas tamoxifen had no significant effect on CIP2A expression and anti-tumor growth in HCC-1937 tumors. Conclusions: Inhibition of CIP2A determines the effects of tamoxifen-induced apoptosis in ER-negative breast cancer cells. Our data suggest a novel "off-target" mechanism of tamoxifen and suggest that CIP2A/PP2A/p-Akt signaling may be a feasible anti-cancer pathway. © 2014 Liu et al.; licensee BioMed Central Ltd.

Huang C.-T.,Taipei Veterans General Hospital | Lee Y.-H.,Taipei Veterans General Hospital | Chow K.-C.,Yang Ming Branch of Taipei City Hospital | Yang C.-F.,Taipei Veterans General Hospital | And 10 more authors.
Internal Medicine Journal | Year: 2014

Background: The diagnosis of Adult T-cell leukaemia/lymphoma (ATL) in non-endemic regions is challenging. Aim: This study analyses the clinicopathologic features and diagnostic processes of ATL patients in Taiwan. Methods: ATL patients diagnosed and treated at Taipei Veterans General Hospital from 1998 through 2010 were retrospectively identified. The diagnosis of ATL was confirmed by in situ detection of human T-cell leukaemia virus type 1 (HTLV-1) when necessary. Patients' data were reviewed and analysed. Results: Fourteen ATL patients were identified, among whom six (42.9%) had an antecedent diagnosis of other malignant lymphomas before the ATL diagnosis, including two diagnosed with Hodgkin disease (HD), one with peripheral T-cell lymphoma, two with chronic lymphocytic leukaemia and one with angioimmunoblastic T-cell lymphoma. Of the 14 patients, eight (57%) were subclassified as the acute type, three (21.4%) as the lymphoma type, and three (21.4%) as the chronic type ATL. Five of six (83.3%) patients with initial non-ATL misdiagnosis were diagnosed with non-acute type ATL. In particular, a patient with an antecedent diagnosis of HD presented with typical Reed-Sternberg (RS)-like cells harbouring Epstein-Barr virus genomes in affected lymph nodes. The patient progressed to acute type ATL 3 years after the initial diagnosis, and HTLV-1 genomes were identified in the previous RS-like cells. Conclusion: In non-endemic areas, such as Taiwan, ATL, particularly the non-acute type, may mimic other lymphomas and easily be misdiagnosed. HTLV-1 serology should be routinely screened in all malignant lymphoma patients. In situ detection of HTLV-1 is helpful in cases with diagnostic dilemmas. © 2014 Royal Australasian College of Physicians.

Liu C.-Y.,Taipei Veterans General Hospital | Liu C.-Y.,National Yang Ming University | Hu M.-H.,Cardinal Tien Hospital | Hu M.-H.,Fu Jen Catholic University | And 16 more authors.
Oncotarget | Year: 2016

We tested the efficacy of lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, in a panel of triple-negative breast cancer (TNBC) cells, and examined the drug mechanism. Lapatinib showed an anti-proliferative effect in HCC 1937, MDA-MB-468, and MDA-MB-231 cell lines. Lapatinib induced significant apoptosis and inhibited CIP2A and p-Akt in a dose and time-dependent manner in the three TNBC cell lines. Overexpression of CIP2A reduced lapatinib-induced apoptosis in MDA-MB-468 cells. In addition, lapatinib increased PP2A activity (in relation to CIP2A inhibition). Moreover, lapatinib-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, lapatinib indirectly decreased CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter. Importantly, lapatinib showed anti-tumor activity in mice bearing MDA-MB-468 xenograft tumors, and suppressed CIP2A as well as p-Akt in these xenografted tumors. In summary, inhibition of CIP2A determines the effects of lapatinib-induced apoptosis in TNBC cells. In addition to being a dual tyrosine kinase inhibitor of HER2 and EGFR, lapatinib also inhibits CIP2A/PP2A/p-Akt signaling in TNBC cells.

Wu M.-P.,Yang Ming Branch of Taipei City Hospital | Wu S.-F.V.,National Taipei University of Nursing and Health Sciences | Wang T.-C.,Main Taipei City Hospital | Kao M.-J.,Yang Ming Branch of Taipei City Hospital | Yang W.-L.,Yang Ming Branch of Taipei City Hospital
Nursing and Health Sciences | Year: 2012

The purpose of this study was to evaluate the effectiveness of a community-based health promotion program targeting people with hypertension and high cholesterol. A pre-experimental study was conducted. A total of 60 residents were recruited to participate. Participants were assessed at baseline and at a 6month follow up at a regional hospital in northern Taiwan. The questionnaires used for data collection consisted of an assessment of self-efficacy, self-care activities, health outcomes, and physical fitness. Several teaching resources were used, including a DVD, a self-care booklet, group support (exercise and counseling sessions), and telephone follow up. A significant decrease in waist circumference (t=2.20, P=0.03) and high density lipoprotein-cholesterol level (t=4.71, P<0.00) was found at follow up. Moreover, the level of physical fitness activity, and sit-ups specifically (t=3.10, P<0.00), was increased. Participants also showed significant increases between baseline and 6month follow up in their efficacy expectation score (t=-5.81, P<0.00), outcome expectation scores (t=-4.76, P<0.00) and self-care behavior scores (t=-2.78, P=0.007). The community-based health promotion program is an effective means of helping people with hypertension and high cholesterol and should be instituted regularly and evaluated in clinical practice. © 2012 Blackwell Publishing Asia Pty Ltd.

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