Publications by authors named "Cheng-Yang Chou"

83 Publications

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy.

Pharmaceuticals (Basel) 2021 Jun 8;14(6). Epub 2021 Jun 8.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.
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http://dx.doi.org/10.3390/ph14060549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227247PMC
June 2021

COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells.

Oncogene 2021 Jul 11;40(26):4503-4519. Epub 2021 Jun 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-β3 activation. The CAF-cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-β3 antibody. Human tumors with high TGF-β3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-β3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.
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http://dx.doi.org/10.1038/s41388-021-01865-8DOI Listing
July 2021

Real-World Study of Adding Bevacizumab to Chemotherapy for Ovarian, Tubal, and Peritoneal Cancer as Front-Line or Relapse Therapy (ROBOT): 8-Year Experience.

Front Oncol 2020 14;10:1095. Epub 2020 Jul 14.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

This study aimed to determine the real-world, long-term prognostic impacts, and adverse effects (AEs) of bevacizumab (BEV) in Asian patients with ovarian/tubal/peritoneal cancers. We retrospectively reviewed the medical records of consecutive patients with ovarian/tubal/peritoneal cancer on front-line chemotherapy with or without BEV (Cohort 1) and those who relapsed following chemotherapy and/or BEV (Cohort 2) between 2011 and 2018 in a tertiary medical centre. Patient characteristics, BEV dosages, clinical outcomes, and AEs were analyzed. Hazard ratios for disease progression and death were analyzed using a cox proportional regression model. Benefits of BEV used throughout triweekly, in terms of improved progression-free survival (PFS) and overall survival (OS), were observed at a dosage of 7.5-15 mg/kg among advanced-stage Cohort 1 patients. A progression-free interval of <6 months was the strongest predictor of disease progression and death in advanced-stage patients. BEV throughout and optimal cytoreduction were independent predictors of reduced disease progression. No prognostic advantage was observed between serous and clear cell histologies when BEV was added. Moreover, BEV resulted in improved OS in Cohort 2 patients, especially in the platinum-sensitive subgroup. Most patients had a front-line BEV dosage <10 mg/kg per cycle with <10 treatment cycles. Low rates and grades of BEV-related AEs were observed in both cohorts. BEV used throughout effectively extended PFS and OS in advanced-stage patients with ovarian/tubal/peritoneal cancer. Patients with platinum-sensitive carcinoma, treated with BEV, had a significant improvement in OS and extended PFS. Therefore, BEV can safely be added to chemotherapy for ovarian/tubal/peritoneal cancers.
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http://dx.doi.org/10.3389/fonc.2020.01095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372289PMC
July 2020

Comparing PI3K/Akt Inhibitors Used in Ovarian Cancer Treatment.

Front Pharmacol 2020 3;11:206. Epub 2020 Mar 3.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.
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http://dx.doi.org/10.3389/fphar.2020.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063971PMC
March 2020

Chemoresistant ovarian cancer enhances its migration abilities by increasing store-operated Ca entry-mediated turnover of focal adhesions.

J Biomed Sci 2020 Feb 21;27(1):36. Epub 2020 Feb 21.

Department of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan.

Background: Among gynecological cancers, ovarian carcinoma has the highest mortality rate, and chemoresistance is highly prevalent in this cancer. Therefore, novel strategies are required to improve its poor prognosis. Formation and disassembly of focal adhesions are regulated dynamically during cell migration, which plays an essential role in cancer metastasis. Metastasis is intricately linked with resistance to chemotherapy, but the molecular basis for this link is unknown.

Methods: Transwell migration and wound healing migration assays were used to analyze the migration ability of ovarian cancer cells. Real-time recordings by total internal reflection fluorescence microscope (TIRFM) were performed to assess the turnover of focal adhesions with fluorescence protein-tagged focal adhesion molecules. SOCE inhibitors were used to verify the effects of SOCE on focal adhesion dynamics, cell migration, and chemoresistance in chemoresistant cells.

Results: We found that mesenchymal-like chemoresistant IGROV1 ovarian cancer cells have higher migration properties because of their rapid regulation of focal adhesion dynamics through FAK, paxillin, vinculin, and talin. Focal adhesions in chemoresistant cells, they were smaller and exhibited strong adhesive force, which caused the cells to migrate rapidly. Store-operated Ca entry (SOCE) regulates focal adhesion turnover, and cell polarization and migration. Herein, we compared SOCE upregulation in chemoresistant ovarian cancer cells to its parental cells. SOCE inhibitors attenuated the assembly and disassembly of focal adhesions significantly. Results of wound healing and transwell assays revealed that SOCE inhibitors decreased chemoresistant cell migration. Additionally, SOCE inhibitors combined with chemotherapeutic drugs could reverse ovarian cancer drug resistance.

Conclusion: Our findings describe the role of SOCE in chemoresistance-mediated focal adhesion turnover, cell migration, and viability. Consequently, SOCE might be a promising therapeutic target in epithelial ovarian cancer.
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http://dx.doi.org/10.1186/s12929-020-00630-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033940PMC
February 2020

A Dose Escalation Study of Trientine Plus Carboplatin and Pegylated Liposomal Doxorubicin in Women With a First Relapse of Epithelial Ovarian, Tubal, and Peritoneal Cancer Within 12 Months After Platinum-Based Chemotherapy.

Front Oncol 2019 24;9:437. Epub 2019 May 24.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related deaths worldwide. Preclinical studies found that copper-lowering agents could re-sensitize platinum-resistant cancer cells by enhancing the human copper transporter 1 (hCtr1)-mediated uptake of platinum. In the clinic, re-sensitization of platinum-resistance in relapsed EOC has been discovered by the application of trientine plus platinum (NCT01178112). However, no pharmacokinetic data of trientine has been reported in cancer patients. Our study aimed to explore the safety and activity of trientine combined with carboplatin and pegylated liposomal doxorubicin (PLD) in patients with EOC, tubal, and peritoneal cancer who experienced disease progression during platinum-based chemotherapy or showed relapse <12 months after completing first-line chemotherapy. Also, we aimed to demonstrate pharmacokinetic parameters and to discover potential biomarkers in our EOC patients. In this dose escalation study, 18 Asian patients in six dosing cohorts received fixed doses of carboplatin (AUC 4) and PLD (LipoDox®, TTY Biopharm Co. Ltd., Taipei, Taiwan) (40 mg/m, day 1 per 4-week cycle), and escalated daily trientine doses (range: 300-1800 mg; initiated 7 days before the 1st combination cycle) according to a 3 + 3 design. No dose-limiting toxicity or treatment-related death was observed. Four patients (22.2%) developed grade 3 drug-related adverse events (AEs), whereas no grade 4 AEs were encountered. Anemia and grade 2 dizziness were the most common hematological toxicity and neurotoxicity, respectively. In a pharmacokinetics comparison with healthy volunteers in the literature, our patients achieved greater absorption after oral trientinem, and more rapid elimination of triethylenetetramine dihydrochloride at high doses. The clinical benefit rate was 33.3 and 50.0% in the platinum-resistant and the partially platinum-sensitive group, respectively. A high baseline serum iron level and low serum copper level might help differentiate subgroups of patients with different clinical responses. Nevertheless, no associations of the clinical response with the levels of serum hCtr1, ceruloplasmin, or copper were observed. Combination therapy with carboplatin, trientine, and PLD was well-tolerated and safe. Our results encourage the development of a future phase II trial. ClinicalTrials.gov # NCT03480750.
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http://dx.doi.org/10.3389/fonc.2019.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544081PMC
May 2019

Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.

Cell Death Dis 2019 04 11;10(4):322. Epub 2019 Apr 11.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL11A1 expression levels, as well as resistance to cisplatin or paclitaxel. SC66 inhibited phosphorylation of Akt and its downstream effectors 4EBP1 and p70S6 kinase. SC66 also attenuated expression of TWIST1 and Mcl-1, factors important in cell invasiveness and anti-apoptosis, respectively. SC66-sensitized chemoresistant cells to cisplatin and paclitaxel treatment, and promoted apoptosis. In addition, SC66 inhibited COL11A1 expression via decreased binding of CCAAT/enhancer-binding protein beta (c/EBPβ), reducing chemoresistance and decreasing binding of nuclear transcription factor Y (NF-YA) to COL11A1. A mouse xenograft experiment demonstrated that SC66 treatment caused a reduction in tumor formation and enhanced the therapeutic efficacy of cisplatin. This study demonstrates the role of Akt in ovarian tumor progression and chemoresistance, and supports the application of SC66 as a therapy for ovarian cancer.
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http://dx.doi.org/10.1038/s41419-019-1555-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459878PMC
April 2019

Contribution of Human papillomavirus in neuroendocrine tumors from a series of 10,575 invasive cervical cancer cases.

Papillomavirus Res 2018 06 17;5:134-142. Epub 2018 Mar 17.

Hospital del Mar, Parc de Salut Mar, Barcelona, Spain.

Aims: Neuroendocrine tumors (NET) of the cervix are rare tumors with a very aggressive course. The human papillomavirus (HPV) has been linked to its etiology. The objective of this study is to describe HPV prevalence and genotype distribution of NET.

Methods And Results: Forty-nine tumors with histological neuroendocrine features were identified among 10,575 invasive cervical cancer (ICC) cases from an international study. HPV DNA detection was done using SPF10/DEIA /LiPA system. Immunohistochemical (IHC) staining for neuroendocrine markers (chromogranin A, synaptophysin, CD56) and for p16 as a surrogate for HPV transforming infection was performed. In 13 samples with negative IHC for all 3 neuroendocrine markers studied, it was possible to conduct electron microscopy (EM). NET represented 0.5% of the total ICC series and HPV was detected in 42 out of 49 samples (85.7%, 95%CI:72.8%,94.1%). HPV16 was the predominant type (54.8%), followed by HPV18 (40.5%). p16 overexpression was observed in 38/44 cases (86.4%). Neuroendocrine IHC markers could be demonstrated in 24/37 (64.9%) cases. EM identified neuroendocrine granules in 8 samples with negative IHC markers.

Conclusions: Our data confirms the association of cervical NET with HPV and p16 overexpression. Specifically, HPV16 and 18 accounted together for over 95% of the HPV positive cases. Current HPV vaccines could largely prevent these aggressive tumors.
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http://dx.doi.org/10.1016/j.pvr.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909066PMC
June 2018

Vitamin D-Binding Protein Enhances Epithelial Ovarian Cancer Progression by Regulating the Insulin-like Growth Factor-1/Akt Pathway and Vitamin D Receptor Transcription.

Clin Cancer Res 2018 07 23;24(13):3217-3228. Epub 2018 Feb 23.

Department of Obstetrics & Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Malignant ascites of epithelial ovarian cancer (EOC) helps identify prognostic biomarkers or mechanisms of tumor progression. Vitamin D-binding protein (DBP) was revealed to be upregulated in EOC ascites in our previous proteomic study. Here, we examined the role of DBP in EOC. We analyzed ascites, serum, and tissue samples of patients with newly diagnosed EOC to determine the prognostic effects of DBP. We verified DBP function using orthotopic animal models and DBP regulation in ovarian cancer cell lines. Elevated ascitic DBP was significantly associated with poor response to chemotherapy, short progression-free interval, increased cancer progression, and death. Ascitic DBP overexpression was an independent unfavorable biomarker for progression-free survival; DBP overexpression in cancerous tissue was significantly related to chemoresistance. and investigations demonstrated an important role for DBP in ovarian cancer progression. Orthotopic model mice inoculated with DBP knockdown ovarian cancer cells displayed a significant reduction in tumor formation, malignant cell number, ascitic DBP levels, invasiveness, and metastasis, and increased survival compared with controls. In presence of vitamin D receptor (VDR), DBP promoted cell aggression (invasion and doubling time) via activation of the insulin-like growth factor-1/insulin-like growth factor-binding protein-2/Akt axis, and induced suppression of vitamin D-responsive genes. A NF-κB p65-binding site in the promoter was identified as a major determinant of DBP-dependent promoter activation. This study highlights the importance of DBP in ovarian tumor progression and the potential application of DBP as a therapeutic target for EOC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2943DOI Listing
July 2018

Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF-κB-mediated IKKβ expression.

Int J Cancer 2017 12 30;141(11):2305-2317. Epub 2017 Aug 30.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

We have shown that collagen type XI alpha 1 (COL11A1) promotes ovarian cancer progression and is associated with chemoresistance to cisplatin and paclitaxel in ovarian cancer cells. Here, we demonstrate how COL11A1 regulates twist family basic helix-loop-helix transcription factor 1-related protein 1 (TWIST1) to induce chemoresistance and inhibit apoptosis in ovarian cancer cells. Small interfering RNA-mediated reduction in COL11A1 protein levels increased the chemosensitivity to cisplatin and paclitaxel via downregulated TWIST1 expression. TWIST1 messenger RNA levels positively associated with COL11A1 messenger RNA expression levels in ovarian tumors. High TWIST1 expression levels were significantly associated with a progression-free interval of ≤ 6 months (p = 0.001) and death (p = 0.040). In addition, patients with high TWIST1 mRNA levels had significantly shorter 5-year overall-survival (p = 0.004) and progression-free survival (p = 0.009) rates, compared to patients with low TWIST1 levels. Increased TWIST1 expression caused by COL11A1-induced transcription of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) gene occurred via increased SP1 phosphorylation and binding to the IKKβ promoter. COL11A1-mediated nuclear factor-kappa B activation, via transcriptional activation of IKKβ, promoted TWIST1, Mcl-1, and GAS6 expression, which were associated with chemoresistance and anti-apoptosis in ovarian cancer cells. We suggest that IKKβ and TWIST1 can potentially be targeted in patients with COL11A1-positive ovarian cancer.
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http://dx.doi.org/10.1002/ijc.30932DOI Listing
December 2017

Case report: term birth after fertility-sparing treatments for stage IB1 small cell neuroendocrine carcinoma of the cervix.

BMC Womens Health 2017 07 28;17(1):56. Epub 2017 Jul 28.

Department of Obstetrics & Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng-Li Rd. Northern District, Tainan, 70403, Taiwan.

Background: Advances in cervical cancer management for childbearing women have led to less radical approaches. Use of fertility-sparing treatment to treat small cell neuroendocrine carcinoma (SCNEC) is challenging owing to the aggressive nature of the disease, even in early stage disease.

Case Presentation: A 25-year-old nulligravida woman presented with malodorous vaginal discharge and was diagnosed to have an exophytic cervical SCNEC. A magnetic resonance image scan showed no evidence of parametrial invasion or distant metastasis. Clinical staging allocated her to stage IB1 disease. She underwent radical abdominal trachelectomy for reproductive purpose. Preoperative and postoperative chemotherapy with ifosfamide/etoposide/cisplatin combining gonadotropin-releasing hormone agonist were administered. She had a spontaneous, uneventful pregnancy and successfully delivered a term baby via cesarean section 7 years after treatment.

Conclusion: To our knowledge, we describe the first success in offering a fertility-preserving multimodality strategy to present favorable oncologic, reproductive, and obstetric outcomes in a fertile woman of stage I SCNEC. Individualized multimodality therapy may be utilized in specific patients with early-stage cervical cancer to preserve their fertility.
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http://dx.doi.org/10.1186/s12905-017-0404-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534099PMC
July 2017

Inducement of apoptosis by cucurbitacin E, a tetracyclic triterpenes, through death receptor 5 in human cervical cancer cell lines.

Cell Death Discov 2017 24;3:17014. Epub 2017 Apr 24.

Graduate Institute of Medical Science, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan.

Cervical cancer is the most common malignancy in women, for which conization or hysterectomy are the main therapy. Curcubitacin E (Cu E) is a natural compound-based drug which from the Guadi (climbing stem of ). Previously shown to be an anti-tumor as well as a potent chemopreventive agent against several types of tumors. The present study, investigated anti-proliferation and apoptosis induced by Cu E in cervical cancer cell lines (HeLa and Ca Ski). The results indicate that the cytotoxicity is associated with accumulation in apoptosis but not necrosis. Cu E produced apoptosis as well as the up-regulation the expression of death receptor 5 (DR5). In addition, the DR5 gene activation in apoptosis, both effects increased proportionally with the dose of Cu E; however, mitosis delay was also dependant on the amount of Cu E treatment in the cancer cells. These results indicate that Cu E may delay cancer cell growth by apoptosis via upregulation of DR5 gene expression.
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http://dx.doi.org/10.1038/cddiscovery.2017.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402524PMC
April 2017

Seeking new surgical predictors of mesh exposure after transvaginal mesh repair.

Int Urogynecol J 2016 Oct 18;27(10):1547-55. Epub 2016 Mar 18.

Department of Obstetrics & Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan.

Introduction And Hypothesis: The purpose of this study was to explore new preventable risk factors for mesh exposure.

Methods: A retrospective review of 92 consecutive patients treated with transvaginal mesh (TVM) in the urogynecological unit of our university hospital. An analysis of perioperative predictors was conducted in patients after vaginal repairs using a type 1 mesh. Mesh complications were recorded according to International Urogynecological Association (IUGA) definitions. Mesh-exposure-free durations were calculated by using the Kaplan-Meier method and compared between different closure techniques using log-rank test. Hazard ratios (HR) of predictors for mesh exposure were estimated by univariate and multivariate analyses using Cox proportional hazards regression models.

Results: The median surveillance interval was 24.1 months. Two late occurrences were found beyond 1 year post operation. No statistically significant correlation was observed between mesh exposure and concomitant hysterectomy. Exposure risks were significantly higher in patients with interrupted whole-layer closure in univariate analysis. In the multivariate analysis, hematoma [HR 5.42, 95 % confidence interval (CI) 1.26-23.35, P = 0.024), Prolift mesh (HR 5.52, 95 % CI 1.15-26.53, P = 0.033), and interrupted whole-layer closure (HR 7.02, 95 % CI 1.62-30.53, P = 0.009) were the strongest predictors of mesh exposure.

Conclusion: Findings indicate the risks of mesh exposure and reoperation may be prevented by avoiding hematoma, large amount of mesh, or interrupted whole-layer closure in TVM surgeries. If these risk factors are prevented, hysterectomy may not be a relative contraindication for TVM use. We also provide evidence regarding mesh exposure and the necessity for more than 1 year of follow-up and preoperative counselling.
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http://dx.doi.org/10.1007/s00192-016-2996-6DOI Listing
October 2016

Targeting FXYD2 by cardiac glycosides potently blocks tumor growth in ovarian clear cell carcinoma.

Oncotarget 2016 Sep;7(39):62925-62938

Institute of Basic Medical Sciences, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ovarian clear cell carcinoma (OCCC) is an aggressive neoplasm with a high recurrence rate that frequently develops resistance to platinum-based chemotherapy. There are few prognostic biomarkers or targeted therapies exist for patients with OCCC. Here, we identified that FXYD2, the modulating subunit of Na+/K+-ATPases, was highly and specifically expressed in clinical OCCC tissues. The expression levels of FXYD2 were significantly higher in advanced-stage of OCCC and positively correlated with patients' prognoses. Silencing of FXYD2 expression in OCCC cells inhibited Na+/K+-ATPase enzyme activity and suppressed tumor growth via induction of autophagy-mediated cell death. We found that high FXYD2 expression in OCCC was transcriptionally regulated by the transcriptional factor HNF1B. Furthermore, up-regulation of FXYD2 expression significantly increased the sensitivity of OCCC cells to cardiac glycosides, the Na+/K+-ATPase inhibitors. Two cardiac glycosides, digoxin and digitoxin, had a great therapeutic efficacy in OCCC cells in vitro and in vivo. Taken together, our results demonstrate that FXYD2 is functionally upregulated in OCCC and may serve as a promising prognostic biomarker and therapeutic target of cardiac glycosides in OCCC.
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http://dx.doi.org/10.18632/oncotarget.7497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325337PMC
September 2016

Parental intention regarding the administration of the HPV vaccine for adolescent daughters in Taiwan.

Women Health 2016 23;56(4):361-75. Epub 2015 Oct 23.

d Department of Nursing , College of Medicine, National Cheng Kung University , Tainan , Taiwan.

This study aimed to investigate parental intention regarding the human papilloma virus (HPV) vaccination for adolescent daughters. Parents or guardians of adolescent girls, aged 12-14 years, from junior high schools in Taiwan participated and completed a HPV vaccination intention survey based on the Theory of Planned Behavior. The survey was conducted from October to November, 2009. Most, 78%, of the respondents reported a high intention to vaccinate daughters against HPV. A high intention of vaccination was associated with a family history of gynecological tumors (adjusted odds ratio [OR]: 2.22, 95% confidence interval [CI]: 1.10-4.51) and HPV awareness (adjusted OR: 2.33, 95% CI: 1.45-3.76). Higher parental intention was reported by respondents with a positive attitude toward the HPV vaccine (adjusted OR: 6.83, 95% CI: 4.16-11.22), perceived greater influence of subjective norms (adjusted OR: 121.23, 95% CI: 42.69-344.21), greater perceived behavioral control (adjusted OR: 67.69, 95% CI: 16.40-279.41), and perceived that the vaccine had limited influence on adolescent sexual behavior (adjusted OR: 2.24, 95% CI: 1.41-3.78). Health-care professionals must be knowledgeable about the HPV and actively promote vaccination among adolescent girls. Improvements in vaccination can be achieved through recommendations by physicians and nurses.
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http://dx.doi.org/10.1080/03630242.2015.1101740DOI Listing
September 2016

Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells.

J Cancer 2015 22;6(10):1011-9. Epub 2015 Aug 22.

1. Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan.

Solanum incanum extract (SR-T100), containing the active ingredient solamargine, can induce apoptosis via upregulation of tumor necrosis factor receptor expression and activation of the mitochondrial apoptosis pathway, and has therapeutic effects in patients with actinic keratosis. Here, we evaluate the novel molecular mechanisms underlying SR-T100-regulated stemness and chemoresistance. The concentration of SR-T100 that inhibited 50% cell viability (IC50) was lower in ovarian cancer cells than in nonmalignant cells. Furthermore, the SR-T100 IC50 in chemoresistant cells was similar to the IC50 in chemosensitive cells. Additionally, SR-T100 increased cisplatin and paclitaxel sensitivity in chemoresistant cells. SR-T100 downregulated the expression of stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), Notch1, and FoxM1, and reduced sphere formation in ovarian cancer cells. Using microarray analyses, immunoblotting, luciferase activity, and chromatin immunoprecipitation (ChIP) assays, we showed that SR-T100 suppressed the expression of c/EBPβ and COL11A1, and its promoter activity, in resistant cells, but not sensitive cells. SR-T100, paclitaxel, and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, as compared to the vehicle control, and the combination of cisplatin and SR-T100 was more effective than either treatment alone. SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment.
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http://dx.doi.org/10.7150/jca.12738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565851PMC
September 2015

IL17a and IL21 combined with surgical status predict the outcome of ovarian cancer patients.

Endocr Relat Cancer 2015 Oct 6;22(5):703-11. Epub 2015 Jul 6.

College of MedicineGraduate Institute of Anatomy and Cell Biology, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, TaiwanDepartment of Obstetrics and GynecologyGynecologic Cancer Center, Cathay General Hospital, Taipei, TaiwanDepartment of Obstetrics and GynecologyCollege of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, TaiwanDepartment of Obstetrics and GynecologyCollege of Medicine and the Hospital, National Cheng Kung University, Tainan, TaiwanCollege of MedicineGraduate Institute of OncologyCollege of MedicineGraduate Institute of Clinical Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan College of MedicineGraduate Institute of Anatomy and Cell Biology, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, TaiwanDepartment of Obstetrics and GynecologyGynecologic Cancer Center, Cathay General Hospital, Taipei, TaiwanDepartment of Obstetrics and GynecologyCollege of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, TaiwanDepartment of Obstetrics and GynecologyCollege of Medicine and the Hospital, National Cheng Kung University, Tainan, TaiwanCollege of MedicineGraduate Institute of OncologyCollege of MedicineGraduate Institute of Clinical Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan College of MedicineGraduate Institute of Anatomy and Cell Biology, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, TaiwanDepartment of Obstetrics and GynecologyGynecologic Cancer Center, Cathay General Hospital, Taipei, TaiwanDepartment of Obstetrics and GynecologyCollege of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, TaiwanDepartment of Obstetrics and GynecologyCollege of Medicine and the Hospital, National Cheng Kung University, Tainan, TaiwanCollege of MedicineGraduate Institute of OncologyCollege of MedicineGraduate Institute of Clinical Medicine, National Taiwan Univer

Aside from tumor cells, ovarian cancer-related ascites contains the immune components. The aim of this study was to evaluate whether a combination of clinical and immunological parameters can predict survival in patients with ovarian cancer. Ascites specimens and medical records from 144 ovarian cancer patients at our hospital were used as the derivation group to select target clinical and immunological factors to generate a risk-scoring system to predict patient survival. Eighty-two cases from another hospital were used as the validation group to evaluate this system. The surgical status and expression levels of interleukin 17a (IL17a) and IL21 in ascites were selected for the risk-scoring system in the derivation group. The areas under the receiver operating characteristic (AUROC) curves of the overall score for disease-free survival (DFS) of the ovarian cancer patients were 0.84 in the derivation group, 0.85 in the validation group, and 0.84 for all the patients. The AUROC curves of the overall score for overall survival (OS) of cases were 0.78 in the derivation group, 0.76 in the validation group, and 0.76 for all the studied patients. Good correlations between overall risk score and survival of the ovarian cancer patients were demonstrated by sub-grouping all participants into four groups (P for trend <0.001 for DFS and OS). Therefore, acombination of clinical and immunological parameters can provide a practical scoring system to predict the survival of patients with ovarian carcinoma. IL17a and IL21 can potentially be used as prognostic and therapeutic biomarkers.
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http://dx.doi.org/10.1530/ERC-15-0145DOI Listing
October 2015

COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization.

Oncotarget 2015 Sep;6(27):23748-63

Department of Obstetrics and Gynaecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan.

Chemoresistance to anticancer drugs substantially reduces survival in epithelial ovarian carcinoma (EOC). Here, microarray analysis showed that collagen type XI alpha 1 (COL11A1) is a chemotherapy response-associated gene. Chemoresistant cells expressed higher COL11A1 and c/EBPβ than chemosensitive cells. COL11A1 or c/EBPβ downregulation suppressed chemoresistance, whereas COL11A1 overexpression attenuated sensitivity to cisplatin and paclitaxel.The c/EBPβ binding site in the COL11A1 promoter was identified as the major determinant of cisplatin- and paclitaxel-induced COL11A1 expression. Immunoprecipitation and immunofluorescence showed that in resistant cells, Akt and PDK1 were highly expressed and that anticancer drugs enhanced binding activity between COL11A1 and PDK1 binding and attenuated PDK1 ubiquitination and degradation. Conversely, chemosensitive cells showed decreased activity of COL11A1 binding to PDK1 and increased PDK1 ubiquitination, which were reversed by COL11A1 overexpression. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and clinical outcome.
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http://dx.doi.org/10.18632/oncotarget.4250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695149PMC
September 2015

Gene methylation profiles as prognostic markers in ovarian clear cell and endometrioid adenocarcinomas.

Am J Transl Res 2015 15;7(1):139-52. Epub 2015 Jan 15.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University Taipei, Taiwan ; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University Taipei, Taiwan ; Graduate Institute of Oncology, College of Medicine, National Taiwan University Taipei, Taiwan.

Ovarian cancer is a cancer of high mortality. Aberrant gene methylation of tumor suppressor genes has been shown to be related to the development of malignancy. This study aimed to investigate the methylation of various genes in ovarian clear cell adenocarcinoma (OCCA) and ovarian endometrioid adenocarcinoma (OEA) and evaluate methylation biomarkers in terms of patient chemo-response and outcome. Eight candidate genes from 66 OCCA and 51 OEA patients were evaluated by methylation-specific polymerase chain reaction and capillary electrophoresis. Clinico-pathological parameters and patient outcomes were analyzed. The frequencies of gene methylation in RASSF1A (79% vs. 59%, p=0.025), E-cadherin (30% vs. 10%, p=0.011), and DLEC1 (71% vs. 43%, p=0.003) were higher in the patients with OCCA than in those with OEA. The chemo-resistant group had a significantly higher percentage of E-cadherin methylation (36.7% vs. 16.1%, p=0.036) than the chemo-sensitive group. In multivariate analysis (log-rank test), advanced stage (4.79 [2.10-10.94], p<0.001) was the only risk factor for mortality. Those with methylation of more than two out of three genes (E-cadherin, DLEC1, and SFRP5) had a shorter disease-free survival (1.89 [1.07-3.32], p=0.028) and overall survival (3.29 [1.57-6.87], p=0.002) than those with methylation of one or no gene. In advanced-stage malignancies, those with more than two out of the three gene methylations also had a shorter overall survival (3.86 [1.63-9.09], p=0.002) than those with methylation of only one or no gene. Patients with OCCA have different patterns of gene methylation than those with OEA. Methylation of the E-cadherin, DLEC1 and SFRP5 genes can be a prognostic biomarker for OCCA and OEA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346531PMC
March 2015

All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells.

Carcinogenesis 2015 Apr 5;36(4):498-507. Epub 2015 Mar 5.

Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan 704, Taiwan

Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all-trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells.
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http://dx.doi.org/10.1093/carcin/bgv018DOI Listing
April 2015

FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells.

Oncotarget 2015 Feb;6(4):2349-65

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385856PMC
http://dx.doi.org/10.18632/oncotarget.2957DOI Listing
February 2015

Outcome of 3-day bleomycin, etoposide and cisplatin chemotherapeutic regimen for patients with malignant ovarian germ cell tumours: a Taiwanese Gynecologic Oncology Group study.

Eur J Cancer 2014 Dec;50(18):3161-7

Background: The combination of bleomycin, etoposide and cisplatin (BEP) is currently the most widely used treatment for malignant ovarian germ cell tumours (MOGCTs). The aim of this study was to evaluate the efficacy and adverse effects of the 3-day BEP regimen in Taiwan. The prognostic factors of the MOGCT patients were also analysed.

Patients And Methods: Two hundred and thirty-nine cases of MOGCTs were identified from the Taiwanese Gynecologic Oncology Group database, and 204 of those who received postoperative BEP chemotherapy were then analysed.

Results: The estimated rate of no evidence of disease was 94.0% for 204 patients with adjuvant BEP regimen. Seven grade 3/4 haematological adverse effects including four subjects with neutropenia, one with pancytopenia and two with neutropenic fever were recorded in the 853 total courses of chemotherapeutic cycles. The rates of haematological and non-haematological adverse effects were 0.82% and 2.3%, respectively. No treatment-related mortality was noted. In the analysis of prognostic factors, only tumour stage had a significant impact on disease recurrence (95% confidence interval (CI), 4.2–94.4, p < 0.001) and disease-related mortality (95% CI, 2.2–163.9, p = 0.007).

Conclusions: The current 3-day adjuvant BEP regimen was effective and safe for patients with MOGCTs.
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http://dx.doi.org/10.1016/j.ejca.2014.10.006DOI Listing
December 2014

Cell fate regulation by gelsolin in human gynecologic cancers.

Proc Natl Acad Sci U S A 2014 Oct 22;111(40):14442-7. Epub 2014 Sep 22.

Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6;

Chemoresistance is a major hurdle in cancer treatment. Down-regulation of apoptosis pathways is one of the key determinants for chemoresistance. Here, we report higher gelsolin (GSN) levels in chemoresistant gynecological cancer cells compared with their sensitive counterparts. cis-Diammine dichloroplatinium (II) (CDDP)-induced GSN down-regulation is associated with its cleavage and apoptosis. Although the C-terminal GSN fragment (C-GSN) sensitized chemoresistant cells to CDDP, intact GSN and its N-terminal fragment (N-GSN) attenuated this response. GSN silencing also facilitated CDDP-induced apoptosis in chemoresistant cells. In contrast, intact GSN (I-GSN) was prosurvival in the presence of CDDP through a FLICE-like inhibitory protein (FLIP)-Itch interaction. This interaction was colocalized in the perinuclear region that could be dissociated by CDDP in sensitive cells, thereby inducing FLIP ubiquitination and degradation, followed by apoptosis. In resistant cells, GSN was highly expressed and CDDP failed to abolish the I-GSN-FLIP-Itch interaction, resulting in the dysregulation of the downstream responses. In addition, we investigated the association between GSN expression in ovarian serous adenocarcinoma and progression free survival and overall survival, as well as clinical prognosis. GSN overexpression was significantly associated with more aggressive behavior and more cancer deaths and supported our hypothesis that high GSN expression confers chemoresistance in cancer cells by altering the GSN-FLIP-Itch interaction. These findings are in agreement with the notion that GSN plays an important role in the regulation of gynecological cell fate as reflected in dysregulation in chemosensitivity.
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http://dx.doi.org/10.1073/pnas.1401166111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209992PMC
October 2014

An on-chip Cell-SELEX process for automatic selection of high-affinity aptamers specific to different histologically classified ovarian cancer cells.

Lab Chip 2014 Oct;14(20):4017-28

Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan 30013.

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.
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http://dx.doi.org/10.1039/c4lc00587bDOI Listing
October 2014

SPAK mediates KCC3-enhanced cervical cancer tumorigenesis.

FEBS J 2014 May 7;281(10):2353-65. Epub 2014 Apr 7.

Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.

Ste20-related proline/alanine-rich kinase (SPAK) plays a role in regulating many biological activities, and interacts with K-Cl co-transporter 3 (KCC3); however, the importance of SPAK for KCC3 function has not been demonstrated. Here, we investigated the role of SPAK in KCC3-regulated cell invasiveness and tumor formation. We show that induction of KCC3 expression triggers activation of the NF-κB and SPAK signaling cascades, leading to activation of p38 mitogen-activated protein kinase (MAPK) and matrix metalloproteinase-2 (MMP2). A small interference RNA-mediated reduction in SPAK protein levels suppressed the invasive ability and oncogenic potential of cervical cancer cells, and decreased tumor formation in mouse xenografts. A combination of experimental approaches, including RT-PCR and real-time RT-PCR, gelatin zymography, NF-κB luciferase activity and chromatin immunoprecipitation assays, showed that the induction of KCC3 over-expression increased MMP2 expression and augmented binding of NF-κB to its putative SPAK promoter binding site, suggesting that the SPAK/MMP2 axis is up-regulated by NF-κB. Pharmacological inhibition of NF-κB or MMP2 abrogated KCC3-triggered, SPAK-dependent cell invasiveness. Furthermore, p38 MAPK was identified as the upstream regulator of KCC3-dependent MMP2 activation. We conclude that SPAK may promote KCC3-mediated tumor aggressiveness via the NF-κB/p38 MAPK/MMP2 axis.
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http://dx.doi.org/10.1111/febs.12787DOI Listing
May 2014

Surgical trends for benign ovarian tumors among hospitals of different accreditation levels: an 11-year nationwide population-based descriptive study in Taiwan.

Taiwan J Obstet Gynecol 2013 Dec;52(4):498-504

Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Objective: Using a population-based nationwide database, we describe the changing surgical trends for laparoscopy or laparotomy for benign ovarian tumors among hospitals of different accreditation levels in Taiwan (medical centers, regional hospitals, and local hospitals).

Materials And Methods: Women who had National Health Insurance and received either laparoscopy or laparotomy as the primary surgery for benign ovarian tumors in Taiwan during 1999-2009 were identified for analysis.

Results: In total, 135,793 women who received either laparotomic (39,779) or laparoscopic surgery (96,014) for benign ovarian pathology were identified. The increase in annual laparoscopy number from 7176 in 1999 to 11,046 in 2009 was significant according to a log-linear regression test (p < 0.0001). The decrease in laparotomies from 3845 to 3567 was not significant (p = 0.190). Service volume shifts from local hospitals to regional hospitals were noted, with a concomitant decrease in the numbers of local hospitals. Laparoscopy was used more often than laparotomy among all three hospital accreditation levels. An increasing trend for choosing laparoscopy was observed for medical centers and local hospitals (p < 0.0001), but not regional hospitals (p = 0.0745). Laparoscopy was used more often in younger patients, by younger surgeons, and by male surgeons among hospitals at all three accreditation levels.

Conclusion: Laparoscopy was preferentially used over laparotomy at all three hospital levels. An increasing trend for choosing laparoscopy was observed for medical centers and local hospitals, but not regional hospitals. Service volume shifts from local hospitals to regional hospitals were noted. Use of laparoscopy differed according to patient age, surgeon age, and surgeon gender among different hospital levels.
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http://dx.doi.org/10.1016/j.tjog.2013.10.008DOI Listing
December 2013

Circulating IGF system and treatment outcome in epithelial ovarian cancer.

Endocr Relat Cancer 2014 Apr 30;21(2):217-29. Epub 2014 Jan 30.

Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan.

Aggressive epithelial ovarian cancers (EOCs) frequently progress and become fatal, even when cytoreduction surgery plus platinum-based chemotherapy are performed. Thus, the early detection of high-risk subgroups is important in order to provide opportunities for better treatment outcomes, using alternative therapeutic strategies. This study aimed to explore the expression of circulating IGF system components and their relationship with treatment outcome in EOC. We included 228 patients with a median follow-up time of 44 months at two 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 ELISA 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 (P=0.003 and P=0.001), IGF2 (P=0.003 and P=0.02), or IGFBP3 levels (P=0.02 and P=0.008). In multivariate analysis, serum IGFBP2 levels were significantly associated with increased risk of mortality (hazard ratio=1.84, 95% CI: 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.
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http://dx.doi.org/10.1530/ERC-13-0274DOI Listing
April 2014

Lin28B is an oncofetal circulating cancer stem cell-like marker associated with recurrence of hepatocellular carcinoma.

PLoS One 2013 14;8(11):e80053. Epub 2013 Nov 14.

Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

By using an expressed sequence tag bioinformatic algorithm, we identified that Lin28 homolog B (Lin28B) may have an oncofetal expression pattern which may facilitate detecting cancer cells in adults. It is also reported to be a potential marker for cancer stem cells. Therefore, we sought to verify oncofetal-stemness characters of Lin28B and test its potential as a circulating cancer stem cell-like marker in adult HCC patients. Lin28B mRNA was examined in a panel of fetal tissue, adult tissue and tumors. Lin28B was over-expressed or knocked down in HepG2 cells to evaluate its potential as a stem cell-like marker. RT-qPCR for Lin28B was performed in the peripheral blood mononuclear cells from patients with HCC receiving surgery (n=96) and non-HCC controls (n=60) and analyzed its clinical significance. Lin28B showed an oncofetal expression pattern. Its overexpression could upregulate stemness markers (OCT4, Nanog and SOX2) and enhance tumorsphere formation in vitro. Lin28B knockdown had opposite effects. Circulating Lin28B was detected in peripheral blood mononuclear cells in 3 cases (5%) of non-HCC controls and 32 cases (33.3%) of HCC patients. In HCC patients, circulating Lin28B was associated with high tumor grade (P=0.046), large size (P=0.005), high AJCC stage (P=0.044) and BCLC stage (P=0.017). Circulating Lin28B was significantly associated with decreased recurrence-free survival (P<0.001). Circulating Lin28B separated early stage HCC into 2 recurrence-free survival curves (P=0.003). In multivariate analysis, circulating Lin28B was an independent variable associated with early recurrence (P=0.045) and recurrence in early stage HCC (P=0.006). In conclusion, the oncofetal gene Lin28B is a potential oncofetal cancer-stem-cell-like circulating tumor cell marker that correlates with HCC recurrence after hepatectomy. Circulating Lin28B could refine early AJCC stages. Our finding supports the possible use of a TNMC (C for circulating tumor cells) staging system in HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828221PMC
August 2014

Low Papanicolaou smear screening rate of women with HIV infection: a nationwide population-based study in Taiwan, 2000-2010.

J Womens Health (Larchmt) 2013 Dec 30;22(12):1016-22. Epub 2013 Aug 30.

1 Department of Nursing, National Cheng Kung University and Hospital , Tainan, Taiwan .

Background: Women infected by human immunodeficiency virus (HIV) have a higher risk of contracting cervical cancer. Recent guidelines recommend that all HIV-positive women should receive two Pap smears in the first year after their HIV diagnosis.

Methods: This was a population-based cohort study, and the National Health Insurance Research Database (NHIRD) in Taiwan was used to estimate the Pap smear screening rate for 1449 HIV-infected women aged 18 years and over from 2000 to 2010. A multiple logistic regression analysis was used to identify factors associated with HIV-infected women who had received Pap smears.

Results: Of 1449 women, 618 (43%) women received at least one Pap smear. Only 14.7% of the HIV-infected women received Pap smears within one year after being diagnosed with HIV. A logistic regression analysis showed that the factors associated with receiving at least one Pap smear after HIV diagnosis were increasing age (AOR 1.04, 95% CI 1.03-1.05), high monthly income (AOR 1.83, 95% CI 1.51-2.23), any history of antiretroviral therapy (AOR 1.78, 95% CI 1.38-2.29), retention in HIV care (AOR 1.36, 95% CI 1.04-1.77), a history of sexually transmitted diseases (AOR 1.96, 95% CI 1.50-2.56), and any history of treatment for opportunistic infections (AOR 2.46, 95% CI 1.91-3.16).

Conclusions: A great need exists to develop strategies for promoting receipt of Pap smear screening services that specifically target severely disadvantaged women with HIV, particularly younger, lower income women and those in an asymptomatic phase.
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http://dx.doi.org/10.1089/jwh.2012.4127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852610PMC
December 2013

Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva.

Eur J Cancer 2013 Nov 22;49(16):3450-61. Epub 2013 Jul 22.

Unit of Infections and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBER en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. Electronic address:

Background: Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions.

Methods: Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI).

Results: Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold).

Conclusion: Combined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide.
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http://dx.doi.org/10.1016/j.ejca.2013.06.033DOI Listing
November 2013
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