Table S1. Target sequence of STAT3 shRNAs Table S2. Primers sequence of miR-92a and pre-miR-92a Q... more Table S1. Target sequence of STAT3 shRNAs Table S2. Primers sequence of miR-92a and pre-miR-92a QPCR Table S3, Clinicopathologic characteristics of patients with epithelial ovarian cancer Fig.S1. STAT3 silencing by shRNA in EOC cell lines inhibits the cell viability in 3-dimensional cultures. Fig.S2. Immunoblot analysis of SKOV3/SKOV3 STAT3-KD cells for the expression of cleaved-PARP, Bcl-xL, and xIAP. b-actin was used as a loading control. Fig.S3. Top, representative spheroids formed by ES2 scramble/ES2 STAT3-KD cells treated with or without paclitaxel (PTX). Bottom, plot of the number of spheroids formed per 1000 cells in selected cells. Error bars represent the SD from triplicate cultures.
Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that contr... more Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that controls growth factor receptor stability. Histone deacetylase 6 expression and its pathogenic role in the uterine leiomyoma have not been studied. Here, we demonstrated that there was a consistent pattern of increasing HDAC6 and estrogen receptor (ER) a expression in leiomyoma samples. For all individual cases, expression of HDAC6 in the normal myometrium or leiomyoma positively correlated with ERa expression. The spearman's rho (r) was .53 (P ¼ .008) between HDAC6 and ERa in normal myometrium and, more significantly, the spearman rho was .80 (P < .001) between HDAC6 and ERa in leiomyoma. In ELT-3 leiomyoma cells, silencing HDAC6 expression substantially reduced ERa expression, lowered estrogen response, and inhibited ELT-3 cell growth. Our results, taken together, are the first to provide experimental evidence suggesting that HDAC6 may be an essential molecular therapeutic target in controlling leiomyoma growth.
Uterine fibroids (leiomyomas) are the most common benign tumours in women during their reproducti... more Uterine fibroids (leiomyomas) are the most common benign tumours in women during their reproductive age. Hyperplasia of uterine smooth muscle cells and abnormal deposition of extracellular matrix (ECM) are responsible for the development of uterine fibroids. Studies have shown that food rich in phytochemicals can prevent or treat leiomyoma. Therefore, the purpose of this study is to demonstrate the inhibitory effects of resveratrol on uterine fibroid cell growth and ECM-associated protein expression. We found that resveratrol inhibited the proliferation of leiomyoma cell line (ELT3) and uterine smooth muscle cell line (UtSMC) and affected the cell morphology of both cell lines, induced cell cycle arrest at S and G2/M phase, regulated cell apoptosis associated protein expression and induced cell apoptosis, and affected ECM-associated mRNA and protein expression. Our results suggest that resveratrol is potentially effective in preventing the hyperplasia of leiomyoma and uterine smooth muscle cells.
The Second Asian and Pacific Rim Symposium on Biophotonics, 2004. APBP 2004.
ABSTRACT Summary form only given. Photodynamic therapy (PDT) is a promising treatment modality th... more ABSTRACT Summary form only given. Photodynamic therapy (PDT) is a promising treatment modality that is being tested in the clinic for use in oncology. PDT requires three elements: light, a photosensitizer and oxygen. PDT-mediated oxidative stress elicits direct tumor cell damage and microvascular injury within exposed tumor. Microvasculature damage following PDT leads to a significant decrease in blood flow as well as severe and persistent tumor tissue hypoxia. Subsequently, tissue hypoxia can induce a plethora of molecular and physiological responses, including an adaptive response associated with gene activation. A primary step in hypoxia-mediated gene activation is the formation of the hypoxia-inducible factor (HIF-1) transcription factor complex. Hypoxia induces the stabilization of the HIF-1α, which in turn allows for the formation of the transcriptionally active protein complex. Up to date, the HIF-1-responsive genes that can modulate the PDT response have not been well identified. In the current study, we employed 5-aminolevulinic acid as a photosensitizer, 630 nm wavelength light-emitting diode (LED) manufactured by the Industrial Technology Research Institute as a light source. The experimental results demonstrated that cancer cells are more resistant to PDT under hypoxic status. PDT can transcriptionally induce or enhance HIF-1α expression in different cervical cancer cell lines (SiHa, HeLa, Caski, C33A, HT-3), immortalized cervical epithelium cell line 183 A, and human umbilical vein endothelial cells (HUVECs). Pharmacological and genetic inhibition assays revealed that PI3K/Akt signaling critically involves in the activation of HIF-1α by PDT in SiHa cells. When SiHa cells was treated with antisense HIF-1α (20μM), PDT activated HIF-1α protein expression was markedly inhibited, and subsequently sensitized SiHa cells to PDT. Currently, pharmaceutical companies actively develop novel compounds targeting HIF-1α as a promising cancer therapy. The results of this study will, therefore, provide important information to improve the therapeutic efficacy of PDT and have great clinical applicable potential.
Purpose: To evaluate the correlation between maximum standardized uptake value (SUV max) and mini... more Purpose: To evaluate the correlation between maximum standardized uptake value (SUV max) and minimum apparent diffusion coefficient (ADC min) of endometrial cancer derived from an integrated positron emission tomography / magnetic resonance (PET/MR) system and to determine their correlation with pathological prognostic factors. Materials and Methods: This prospective study was approved by the Institutional Review Board of the hospital, and informed consent was obtained. Between April and December 2014, 47 consecutive patients with endometrial cancer were enrolled and underwent simultaneous PET/MR examinations before surgery. Thirty-six patients with measurable tumors on PET/MR were included for image analysis. Pearson's correlation coefficient was used to evaluate the correlation between SUV max and ADC min of the tumors. The Mann-Whitney U-test was utilized to evaluate relationships between these two imaging biomarkers and pathological prognostic factors. Results: The mean SUV max and ADC min were 14.7 6 7.1 and 0.48 6 0.13 3 10 23 mm 2 /s, respectively. A significant inverse correlation was found between SUV max and ADC min (r 5-0.53; P 5 0.001). SUV max was significantly higher in tumors with advanced stage, deep myometrial invasion, cervical invasion, lymphovascular space involvement, and lymph node metastasis (P < 0.05). ADC min was lower in tumors with higher grade, advanced stage, and cervical invasion (P < 0.05). The ratio of SUV max to ADC min was higher in tumors with higher grade, advanced stage, deep myometrial invasion, cervical invasion, lymphovascular space involvement, and lymph node metastasis (P < 0.05). Conclusion: SUV max and ADC min of endometrial cancer derived from integrated PET/MR are inversely correlated and are associated with pathological prognostic factors.
Arsenic apparently affects numerous intracellular signal transduction pathways and causes many al... more Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations leading to apoptosis and differentiation in malignant cells. We and others have demonstrated that arsenic inhibits the metastatic capacity of cancer cells. Here we present additional mechanistic studies to elucidate the potential of arsenic as a promising therapeutic inhibitor of metastasis. The effects of arsenic trioxide (ATO) on human cervical cancer cell lines migration and invasion were observed by transwell assays. In experimental metastasis assays, cancer cells were injected into tail veins of severe combined immunodeficient mice for modeling metastasis. The mechanisms involved in ATO regulation of CXCR4 were analyzed by immunoblot, real-time polymerase chain reaction, and luciferase reporter assays. Immunohistochemistry was utilized to identify PP2A/C and CXCR4 protein expressions in human cervical cancer tissues. ATO inhibited CXCR4-mediated cervical cancer cell invasion in vitro and distant metastasis in vivo. We determined that ATO modulates the pivotal nuclear factor-kappa B (NF-κB)/CXCR4 signaling pathway that contributes to cancer metastasis. Substantiating our findings, we demonstrated that ATO activates PP2A/C activity by downregulating miR-520h, which results in IKK inactivation, IκB-dephosphorylation, NF-κB inactivation, and, subsequently, a reduction in CXCR4 expression. Furthermore, PP2A/C was reduced during cervical carcinogenesis, and the loss of PP2A/C expression was closely associated with the nodal status of cervical cancer patients. Our results indicate a functional link between ATO-mediated PP2A/C regulation, CXCR4 expression, and tumor-suppressing ability. This information will be critical in realizing the potential for synergy between ATO and other anti-cancer agents, thus providing enhanced benefit in cancer therapy.
Background: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related dea... more Background: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. Method: The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. Results: We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. Conclusion: We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.
The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia, a... more The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia, and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase (CA) XII is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation, and enhanced expression is often present in several types of tumors. However, CA XII expression in oral squamous cell carcinoma (OSCC) and its correlation with patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; prognosis have not been investigated so far. In this study, we detected the expression of CA XII in 264 patients with OSCC using tissue microarrays (TMAs), and evaluated its correlation with clinicopathologic factors and disease prognosis. CA XII expression was present in 185/264 (70%) cases and was associated with more-advanced clinical stages (p=0.003), a larger tumor size (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), and postoperative recurrence (p=0.047), but was not associated with positive lymph node metastasis or distal metastasis. Importantly, CA XII expression was correlated with a poorer patient prognosis in a univariate (p=0.034, log-rank test) survival analysis. According to our results, the expression of CA XII in OSCC samples can predict the progression of OSCC and survival of OSCC patients.
To evaluate vascular endothelial growth factor (VEGF) as a marker for predicting lymph node metas... more To evaluate vascular endothelial growth factor (VEGF) as a marker for predicting lymph node metastasis and an independent prognostic factor of early-stage cervical carcinoma. One hundred thirty-five women with stage IB-IIA cervical carcinoma had radical abdominal hysterectomies and pelvic lymph node dissections. Intratumoral cytosol VEGF concentrations were assayed with enzyme immunoassay. Histopathologic items and cytosol VEGF-influencing clinical outcomes were compared. Twenty-two women (16.3%) who had disease recurrence had higher levels of cytosol VEGF (1020 versus 112 pg/mg protein, P &lt;.001) than those without recurrence. Using a cutoff value of 400 pg/mg protein resulted in best sensitivity of 75%, best specificity of 70%, positive predictive value of 41%, and negative predictive value of 92%. Only overexpressed cytosol VEGF (hazard ratio 6.44, P &lt;.001) was an independent prognostic factor of disease-free survival. The overexpressed cytosol VEGF (hazard ratio 4.50, P =.021) and positive lymphovascular emboli (hazard ratio 4.11, P =.045) were independent prognostic factor of overall survival. Cytosol VEGF might be a biomarker for the status of pelvic lymph nodes in early-stage cervical carcinoma and an independent prognostic indicator of its outcome.
Background and Objectives: Hepatocellular carcinoma (HCC) is one of the most frequent malignant n... more Background and Objectives: Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and the second leading cause of death from cancer in Taiwan. Interleukin-8 (IL-8) is an angiogenic chemokine with important roles in the development and progression of many human malignancies including HCC. This study investigates the effects of single-nucleotide polymorphisms (SNPs) in the IL-8 gene on the susceptibility and clinicopathological characteristics of HCC. Methods: One hundred thirty-one HCC patients and 340 control subjects were analyzed for four IL-8 SNPs (À251 T/A, þ781 C/T, þ1633 C/T, and þ2767 A/T) using PCR-RFLP genotyping analysis. Results: After adjusting for other confounders, results show that individuals with the IL-8 þ781 T/T polymorphic genotype had a significantly lower risk of developing HCC than those with the wild-type (C/C) genotype (AOR ¼ 0.346; 95% CI: 0.132-0.909). Multiple regression analysis showed that the presence of T/A or A/A at IL-8 À251 may indicate higher potential risk of hepatitis B infection (AOR ¼ 2.847; 95% CI: 1.083-8.656). Additionally, these four IL-8 SNPs did not associate with liver-related clinicopathological markers in serum. Conclusions: Genetic polymorphism at IL-8 þ781 is an important factor in determining susceptibility to HCC in the Taiwanese population.
Vascular endothelial growth factor C (VEGF-C) is an important growth factor that governs lymphati... more Vascular endothelial growth factor C (VEGF-C) is an important growth factor that governs lymphatic spread and the development of intraperitoneal tumors associated with epithelial ovarian cancer; however, its regulation is not yet understood. Overexpression of Her-2/neu is related to poor survival in advanced epithelial ovarian carcinoma patients. Accordingly, this study attempted to analyze the association between the Her-2/neu oncogene and VEGF-C in ovarian carcinoma and to elucidate the molecular mechanism of VEGF-C induction by Her-2/ neu. Immunohistochemistry was used to determine the expression of Her-2/neu and VEGF-C in tissues from 41 patients with epithelial ovarian carcinoma. Several Her-2/neu-stably-transfected Caov-3 ovarian carcinoma cells were used to evaluate the effect of Her-2/neu on VEGF-C, the possible regulation mechanism, and the biological function of VEGF-C. Our experimental results identified a significant association between the Her-2/ neu oncogene and VEGF-C expression in both epithelial ovarian cancer patients (p < 0.05; Fisher's exact test) and in vitro cell lines. The overexpression of Her-2/neu in Caov-3 ovarian cancer cells resulted in induction of a considerable amount of VEGF-C mRNA and protein; this process was dose-dependently inhibited by herceptin. The generation of VEGF-C significantly increased endothelial permeability. Pharmacological and genetic inhibition assays revealed that the cytoplasmic signaling molecule, p38 MAPK, and the transcriptional factor, NF-KB, are critically involved in the transcriptional activation of the VEGF-C gene by Her-2/neu. In conclusion, this work clearly establishes that the Her-2/neu oncogene is essential for the regulation of VEGF-C in ovarian carcinoma. It may be possible to use the monoclonal antibody targeting Her-2/neu receptor to limit the formation of malignant ascites and lymphatic spread in ovarian carcinoma.
International Journal of Gynecological Cancer, 2001
Carcinosarcoma is a rare neoplasm which, in the female genital tract, arises mainly in the endome... more Carcinosarcoma is a rare neoplasm which, in the female genital tract, arises mainly in the endometrium. Although the pathogenesis remains obscure, there is an apparent association between pelvic irradiation and uterine sarcomas. There have been sporadic case reports of the development of carcinosarcomas of the cervix, vagina, and extragenital areas, but not of the ovary, after previous pelvic irradiation. We describe a case of ovarian carcinosarcoma arising in a 74-year-old female who had pelvic irradiation 33 years previously. Exploratory laparotomy showed a 25 × 18 × 9 cm left ovarian tumor with adjacent organ invasion including periuterine serosa and rectum. The patient was treated by optimal cytoreduction, followed by chemotherapy with adriamycin and cisplatin. However, acute hepatitis caused by reactivation of hepatitis B virus infection developed just before the fifth course of chemotherapy. She died of hepatic failure two weeks later.
The aim of this study was to evaluate whether vascular endothelial growth factor (VEGF) could be ... more The aim of this study was to evaluate whether vascular endothelial growth factor (VEGF) could be a marker for disease-free survival in endometrial carcinoma patients. Fifty-three patients with endometrial carcinoma undergoing surgery were enrolled. Clinical and pathologic items were recorded. Cytosol VEGF was quantified by enzyme immunoassay. The microvessel density (MVD) of the excised tumors was immunohistochemically assessed. The relationship among MVD, cytosol VEGF concentration of the tumor tissues, and clinicopathologic parameters was analyzed. The risk factors influencing clinical outcome were tested. Higher cytosol VEGF concentrations and MVD values were noted in tumors with advanced stage (more than stage I) (917 versus 125 pg/mg, P = 0.03; 94.1 +/- 37.8 versus 60.8 +/- 38.9, P = 0.008), lymphovascular emboli (917 versus 102 pg/mg, P = 0.001; 94.4 +/- 33.2 versus 62.4 +/- 40.7, P = 0.009), and lymph node metastasis (1032 versus 95 pg/mg, P &amp;amp;lt; 0.001; 116.5 +/- 30.8 versus 56.7 +/- 33.3, P &amp;amp;lt; 0.001). The cytosol VEGF and MVD showed a positive linear correlation (VEGF versus MVD, r = 0.41, P = 0.003). Grade 3 tumor and overexpressed cytosol VEGF (&amp;amp;gt; 800 pg/mg) are independent risk factors for recurrence. There was a trend that patients with grade 1 or 2 tumors and normal-expressed VEGF had the highest probability of disease-free survival, and patients with grade 3 tumors and overexpressed cytosol VEGF had the poorest probability of disease-free survival. Cytosol VEGF had a good correlation with the disease progression and metastasis in endometrial carcinoma, and it might also be an independent prognostic factor for disease-free survival of endometrial carcinoma patients.
To evaluate the efficacy and safety of a distearoylphosphatidylcholine pegylated liposomal doxoru... more To evaluate the efficacy and safety of a distearoylphosphatidylcholine pegylated liposomal doxorubicin, Lipo-Dox, in platinum-resistant or refractory epithelial ovarian cancer. A multicenter phase II trial enrolled women with platinum-resistant or refractory epithelial ovarian carcinoma and naïve to anthracycline. Eligible patients had either measurable tumor(s) or elevated serum CA 125 titer. Lipodox was initiated with a dose of 45 mg/m2 at a 4-week interval with subsequent escalation or reduction. A total of six cycles were scheduled. 29 patients, 20 with platinum-resistant and 9 with platinum refractory tumors, were enrolled. Lipo-Dox was given for an average of 4.6 cycles per patient with a total of 134 cycles. Among the 26 evaluable patients, one achieved CR, 5 PR and 9 SD. The overall response rate was 23.1% (95% CI, 6.8%-39.3%) with a median response duration of 11.6 weeks. 5 of the 6 responses were in patients with resistant disease. The median progression-free duration in the SD patients was 25.7 weeks. With a median follow-up of 13.8 months, the median progression-free and median overall survivals in the 26 patients were 5.4 months and 13.8 months, respectively. Hand-foot skin reaction occurred in 4.5% and skin pigmentation in 11.2% of all treatment cycles, all were Grade 1/2. Nausea and vomiting occurred in 14.2%, while anemia, leukopenia and thrombocytopenia occurred in 20.9%, 32.8% and 9% of cycle, respectively, and were mostly Grade 1 or 2. Lipo-Dox, the third liposome encapsulated doxorubicin, at 45 mg/m2 every 4 weeks, is effective against recurrent, platinum-resistant epithelial ovarian cancers.
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumo... more G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-C...
BJOG: An International Journal of Obstetrics and Gynaecology, 1999
To investigate the pathological significance of intra-tumoural blood flow signals detected by col... more To investigate the pathological significance of intra-tumoural blood flow signals detected by colour Doppler ultrasound and their association with angiogenesis in cervical carcinoma. A prospective cross-sectional study. University hospital. One hundred and four women with Stage IB-IIA cervical carcinoma. All women underwent radical hysterectomy and pelvic lymph node dissection. Transvaginal colour Doppler ultrasound was performed before surgery to search for arterial blood flow signals within the tumours. Tumours with a measurable intra-tumoural resistance index were defined as tumour with detectable blood flow and the others as tumour with undetectable blood flow. The microvessel density of the excised tumour was assessed immunohistochemically. The women&amp;amp;#39;s clinical and pathologic data were recorded. There were 60 tumours (58%) exhibiting detectable intra-tumoural blood flow signals. Tumours with detectable blood flow were larger, had deeper cervical stromal invasion, a higher incidence of parametrial invasion and pelvic lymph node metastases, and a higher microvessel density, when compared with those without detectable blood flow. Cervical cancers with deep cervical stromal invasion, parametrial invasion, and pelvic lymph node metastasis had higher microvessel density than those with superficial stromal invasion, no parametrial invasion, or no lymph node metastasis. Microvessel density correlated well with lymph node metastases and parametrial invasion by multiple regression analysis, while intra-tumoural blood signals only showed correlation with parametrial invasion. In the prediction of pelvic lymph node metastases and parametrial invasion, colour flow Doppler had a sensitivity of 0.80 and specificity of 0.48 in predicting lymph node metastases, and sensitivity of 0.91 and specificity of 0.57 in predicting parametrial invasion. The characteristics of blood flow signals in cervical carcinoma detected by colour Doppler ultrasound are associated with tumour angiogenesis and could reflect the likelihood of parametrial invasion and lymph node metastases in cervical carcinoma. The intra-tumoural blood flow signals might be used as a screening test in predicting parametrial invasion and pelvic lymph node metastases. These findings may be helpful in planning treatment for women with Stage I and II cervical carcinoma.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014
High-level expression of vascular endothelial growth factor (VEGF)-C is associated with chemoresi... more High-level expression of vascular endothelial growth factor (VEGF)-C is associated with chemoresistance and adverse prognosis in acute myeloid leukemia (AML). Our previous study has found that VEGF-C induces cyclooxygenase-2 (COX-2) expression in AML cell lines and significant correlation of VEGF-C and COX-2 in bone marrow specimens. COX-2 has been reported to mediate the proliferation and drug resistance in several solid tumors. Herein, we demonstrated that the VEGF-C-induced proliferation of AML cells is effectively abolished by the depletion or inhibition of COX-2. The expression of endothelin-1 (ET-1) rapidly increased following treatment with VEGF-C. We found that ET-1 was also involved in the VEGF-C-mediated proliferation of AML cells, and that recombinant ET-1 induced COX-2 mRNA and protein expressions in AML cells. Treatment with the endothelin receptor A (ETRA) antagonist, BQ 123, or ET-1 shRNAs inhibited VEGF-C-induced COX-2 expression. Flow cytometry and immunoblotting revealed that VEGF-C induces S phase accumulation through the inhibition of p27 and the upregulation of cyclin E and cyclin-dependent kinase-2 expressions. The cell-cycle-related effects of VEGF-C were reversed by the depletion of COX-2 or ET-1. The depletion of COX-2 or ET-1 also suppressed VEGF-C-induced increases in the bcl-2/bax ratio and chemoresistance against etoposide and cytosine arabinoside in AML cells. We also demonstrated VEGF-C/ET-1/COX-2 axis-mediated chemoresistance in an AML xenograft mouse model. Our findings suggest that VEGF-C induces COX-2-mediated resistance to chemotherapy through the induction of ET-1 expression. Acting as a key regulator in the VEGF-C/COX-2 axis, ET-1 represents a potential target for ameliorating resistance to chemotherapy in AML patients.
Sacrospinous ligament fixation (SSLF) is one of the most utilized surgeries in the management of ... more Sacrospinous ligament fixation (SSLF) is one of the most utilized surgeries in the management of pelvic organ prolapse (POP). We conducted a large-series study of SSLF in a tertiary center by an experienced urogynecologic team. The 453 women with POP who underwent SSLF at National Taiwan University Hospital in the period from 2002 to 2015 are reviewed. All patients received unilateral SSLF with Veronikis ligature carrier. Concomitant anterior colporrhaphy was performed in 75.3% of the cases and posterior colporrhaphy in 78.6%. The mean operation time was 92.3 ± 31.5 minutes. The intraoperative blood loss was 92.3 ± 91.4 ml. The objective cure rate was 82.5%, and 79 (17.5%) patients recurred. The Kaplan-Meier recurrence-free analysis showed a steep decline during the first postoperative year, and the yearly number of recurrent patients decreased as the follow-up period proceeded. A comparison of the site of recurrence found that anterior compartment prolapse was the most common with ...
Table S1. Target sequence of STAT3 shRNAs Table S2. Primers sequence of miR-92a and pre-miR-92a Q... more Table S1. Target sequence of STAT3 shRNAs Table S2. Primers sequence of miR-92a and pre-miR-92a QPCR Table S3, Clinicopathologic characteristics of patients with epithelial ovarian cancer Fig.S1. STAT3 silencing by shRNA in EOC cell lines inhibits the cell viability in 3-dimensional cultures. Fig.S2. Immunoblot analysis of SKOV3/SKOV3 STAT3-KD cells for the expression of cleaved-PARP, Bcl-xL, and xIAP. b-actin was used as a loading control. Fig.S3. Top, representative spheroids formed by ES2 scramble/ES2 STAT3-KD cells treated with or without paclitaxel (PTX). Bottom, plot of the number of spheroids formed per 1000 cells in selected cells. Error bars represent the SD from triplicate cultures.
Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that contr... more Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that controls growth factor receptor stability. Histone deacetylase 6 expression and its pathogenic role in the uterine leiomyoma have not been studied. Here, we demonstrated that there was a consistent pattern of increasing HDAC6 and estrogen receptor (ER) a expression in leiomyoma samples. For all individual cases, expression of HDAC6 in the normal myometrium or leiomyoma positively correlated with ERa expression. The spearman's rho (r) was .53 (P ¼ .008) between HDAC6 and ERa in normal myometrium and, more significantly, the spearman rho was .80 (P < .001) between HDAC6 and ERa in leiomyoma. In ELT-3 leiomyoma cells, silencing HDAC6 expression substantially reduced ERa expression, lowered estrogen response, and inhibited ELT-3 cell growth. Our results, taken together, are the first to provide experimental evidence suggesting that HDAC6 may be an essential molecular therapeutic target in controlling leiomyoma growth.
Uterine fibroids (leiomyomas) are the most common benign tumours in women during their reproducti... more Uterine fibroids (leiomyomas) are the most common benign tumours in women during their reproductive age. Hyperplasia of uterine smooth muscle cells and abnormal deposition of extracellular matrix (ECM) are responsible for the development of uterine fibroids. Studies have shown that food rich in phytochemicals can prevent or treat leiomyoma. Therefore, the purpose of this study is to demonstrate the inhibitory effects of resveratrol on uterine fibroid cell growth and ECM-associated protein expression. We found that resveratrol inhibited the proliferation of leiomyoma cell line (ELT3) and uterine smooth muscle cell line (UtSMC) and affected the cell morphology of both cell lines, induced cell cycle arrest at S and G2/M phase, regulated cell apoptosis associated protein expression and induced cell apoptosis, and affected ECM-associated mRNA and protein expression. Our results suggest that resveratrol is potentially effective in preventing the hyperplasia of leiomyoma and uterine smooth muscle cells.
The Second Asian and Pacific Rim Symposium on Biophotonics, 2004. APBP 2004.
ABSTRACT Summary form only given. Photodynamic therapy (PDT) is a promising treatment modality th... more ABSTRACT Summary form only given. Photodynamic therapy (PDT) is a promising treatment modality that is being tested in the clinic for use in oncology. PDT requires three elements: light, a photosensitizer and oxygen. PDT-mediated oxidative stress elicits direct tumor cell damage and microvascular injury within exposed tumor. Microvasculature damage following PDT leads to a significant decrease in blood flow as well as severe and persistent tumor tissue hypoxia. Subsequently, tissue hypoxia can induce a plethora of molecular and physiological responses, including an adaptive response associated with gene activation. A primary step in hypoxia-mediated gene activation is the formation of the hypoxia-inducible factor (HIF-1) transcription factor complex. Hypoxia induces the stabilization of the HIF-1α, which in turn allows for the formation of the transcriptionally active protein complex. Up to date, the HIF-1-responsive genes that can modulate the PDT response have not been well identified. In the current study, we employed 5-aminolevulinic acid as a photosensitizer, 630 nm wavelength light-emitting diode (LED) manufactured by the Industrial Technology Research Institute as a light source. The experimental results demonstrated that cancer cells are more resistant to PDT under hypoxic status. PDT can transcriptionally induce or enhance HIF-1α expression in different cervical cancer cell lines (SiHa, HeLa, Caski, C33A, HT-3), immortalized cervical epithelium cell line 183 A, and human umbilical vein endothelial cells (HUVECs). Pharmacological and genetic inhibition assays revealed that PI3K/Akt signaling critically involves in the activation of HIF-1α by PDT in SiHa cells. When SiHa cells was treated with antisense HIF-1α (20μM), PDT activated HIF-1α protein expression was markedly inhibited, and subsequently sensitized SiHa cells to PDT. Currently, pharmaceutical companies actively develop novel compounds targeting HIF-1α as a promising cancer therapy. The results of this study will, therefore, provide important information to improve the therapeutic efficacy of PDT and have great clinical applicable potential.
Purpose: To evaluate the correlation between maximum standardized uptake value (SUV max) and mini... more Purpose: To evaluate the correlation between maximum standardized uptake value (SUV max) and minimum apparent diffusion coefficient (ADC min) of endometrial cancer derived from an integrated positron emission tomography / magnetic resonance (PET/MR) system and to determine their correlation with pathological prognostic factors. Materials and Methods: This prospective study was approved by the Institutional Review Board of the hospital, and informed consent was obtained. Between April and December 2014, 47 consecutive patients with endometrial cancer were enrolled and underwent simultaneous PET/MR examinations before surgery. Thirty-six patients with measurable tumors on PET/MR were included for image analysis. Pearson's correlation coefficient was used to evaluate the correlation between SUV max and ADC min of the tumors. The Mann-Whitney U-test was utilized to evaluate relationships between these two imaging biomarkers and pathological prognostic factors. Results: The mean SUV max and ADC min were 14.7 6 7.1 and 0.48 6 0.13 3 10 23 mm 2 /s, respectively. A significant inverse correlation was found between SUV max and ADC min (r 5-0.53; P 5 0.001). SUV max was significantly higher in tumors with advanced stage, deep myometrial invasion, cervical invasion, lymphovascular space involvement, and lymph node metastasis (P < 0.05). ADC min was lower in tumors with higher grade, advanced stage, and cervical invasion (P < 0.05). The ratio of SUV max to ADC min was higher in tumors with higher grade, advanced stage, deep myometrial invasion, cervical invasion, lymphovascular space involvement, and lymph node metastasis (P < 0.05). Conclusion: SUV max and ADC min of endometrial cancer derived from integrated PET/MR are inversely correlated and are associated with pathological prognostic factors.
Arsenic apparently affects numerous intracellular signal transduction pathways and causes many al... more Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations leading to apoptosis and differentiation in malignant cells. We and others have demonstrated that arsenic inhibits the metastatic capacity of cancer cells. Here we present additional mechanistic studies to elucidate the potential of arsenic as a promising therapeutic inhibitor of metastasis. The effects of arsenic trioxide (ATO) on human cervical cancer cell lines migration and invasion were observed by transwell assays. In experimental metastasis assays, cancer cells were injected into tail veins of severe combined immunodeficient mice for modeling metastasis. The mechanisms involved in ATO regulation of CXCR4 were analyzed by immunoblot, real-time polymerase chain reaction, and luciferase reporter assays. Immunohistochemistry was utilized to identify PP2A/C and CXCR4 protein expressions in human cervical cancer tissues. ATO inhibited CXCR4-mediated cervical cancer cell invasion in vitro and distant metastasis in vivo. We determined that ATO modulates the pivotal nuclear factor-kappa B (NF-κB)/CXCR4 signaling pathway that contributes to cancer metastasis. Substantiating our findings, we demonstrated that ATO activates PP2A/C activity by downregulating miR-520h, which results in IKK inactivation, IκB-dephosphorylation, NF-κB inactivation, and, subsequently, a reduction in CXCR4 expression. Furthermore, PP2A/C was reduced during cervical carcinogenesis, and the loss of PP2A/C expression was closely associated with the nodal status of cervical cancer patients. Our results indicate a functional link between ATO-mediated PP2A/C regulation, CXCR4 expression, and tumor-suppressing ability. This information will be critical in realizing the potential for synergy between ATO and other anti-cancer agents, thus providing enhanced benefit in cancer therapy.
Background: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related dea... more Background: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. Method: The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. Results: We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. Conclusion: We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.
The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia, a... more The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia, and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase (CA) XII is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation, and enhanced expression is often present in several types of tumors. However, CA XII expression in oral squamous cell carcinoma (OSCC) and its correlation with patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; prognosis have not been investigated so far. In this study, we detected the expression of CA XII in 264 patients with OSCC using tissue microarrays (TMAs), and evaluated its correlation with clinicopathologic factors and disease prognosis. CA XII expression was present in 185/264 (70%) cases and was associated with more-advanced clinical stages (p=0.003), a larger tumor size (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), and postoperative recurrence (p=0.047), but was not associated with positive lymph node metastasis or distal metastasis. Importantly, CA XII expression was correlated with a poorer patient prognosis in a univariate (p=0.034, log-rank test) survival analysis. According to our results, the expression of CA XII in OSCC samples can predict the progression of OSCC and survival of OSCC patients.
To evaluate vascular endothelial growth factor (VEGF) as a marker for predicting lymph node metas... more To evaluate vascular endothelial growth factor (VEGF) as a marker for predicting lymph node metastasis and an independent prognostic factor of early-stage cervical carcinoma. One hundred thirty-five women with stage IB-IIA cervical carcinoma had radical abdominal hysterectomies and pelvic lymph node dissections. Intratumoral cytosol VEGF concentrations were assayed with enzyme immunoassay. Histopathologic items and cytosol VEGF-influencing clinical outcomes were compared. Twenty-two women (16.3%) who had disease recurrence had higher levels of cytosol VEGF (1020 versus 112 pg/mg protein, P &lt;.001) than those without recurrence. Using a cutoff value of 400 pg/mg protein resulted in best sensitivity of 75%, best specificity of 70%, positive predictive value of 41%, and negative predictive value of 92%. Only overexpressed cytosol VEGF (hazard ratio 6.44, P &lt;.001) was an independent prognostic factor of disease-free survival. The overexpressed cytosol VEGF (hazard ratio 4.50, P =.021) and positive lymphovascular emboli (hazard ratio 4.11, P =.045) were independent prognostic factor of overall survival. Cytosol VEGF might be a biomarker for the status of pelvic lymph nodes in early-stage cervical carcinoma and an independent prognostic indicator of its outcome.
Background and Objectives: Hepatocellular carcinoma (HCC) is one of the most frequent malignant n... more Background and Objectives: Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and the second leading cause of death from cancer in Taiwan. Interleukin-8 (IL-8) is an angiogenic chemokine with important roles in the development and progression of many human malignancies including HCC. This study investigates the effects of single-nucleotide polymorphisms (SNPs) in the IL-8 gene on the susceptibility and clinicopathological characteristics of HCC. Methods: One hundred thirty-one HCC patients and 340 control subjects were analyzed for four IL-8 SNPs (À251 T/A, þ781 C/T, þ1633 C/T, and þ2767 A/T) using PCR-RFLP genotyping analysis. Results: After adjusting for other confounders, results show that individuals with the IL-8 þ781 T/T polymorphic genotype had a significantly lower risk of developing HCC than those with the wild-type (C/C) genotype (AOR ¼ 0.346; 95% CI: 0.132-0.909). Multiple regression analysis showed that the presence of T/A or A/A at IL-8 À251 may indicate higher potential risk of hepatitis B infection (AOR ¼ 2.847; 95% CI: 1.083-8.656). Additionally, these four IL-8 SNPs did not associate with liver-related clinicopathological markers in serum. Conclusions: Genetic polymorphism at IL-8 þ781 is an important factor in determining susceptibility to HCC in the Taiwanese population.
Vascular endothelial growth factor C (VEGF-C) is an important growth factor that governs lymphati... more Vascular endothelial growth factor C (VEGF-C) is an important growth factor that governs lymphatic spread and the development of intraperitoneal tumors associated with epithelial ovarian cancer; however, its regulation is not yet understood. Overexpression of Her-2/neu is related to poor survival in advanced epithelial ovarian carcinoma patients. Accordingly, this study attempted to analyze the association between the Her-2/neu oncogene and VEGF-C in ovarian carcinoma and to elucidate the molecular mechanism of VEGF-C induction by Her-2/ neu. Immunohistochemistry was used to determine the expression of Her-2/neu and VEGF-C in tissues from 41 patients with epithelial ovarian carcinoma. Several Her-2/neu-stably-transfected Caov-3 ovarian carcinoma cells were used to evaluate the effect of Her-2/neu on VEGF-C, the possible regulation mechanism, and the biological function of VEGF-C. Our experimental results identified a significant association between the Her-2/ neu oncogene and VEGF-C expression in both epithelial ovarian cancer patients (p < 0.05; Fisher's exact test) and in vitro cell lines. The overexpression of Her-2/neu in Caov-3 ovarian cancer cells resulted in induction of a considerable amount of VEGF-C mRNA and protein; this process was dose-dependently inhibited by herceptin. The generation of VEGF-C significantly increased endothelial permeability. Pharmacological and genetic inhibition assays revealed that the cytoplasmic signaling molecule, p38 MAPK, and the transcriptional factor, NF-KB, are critically involved in the transcriptional activation of the VEGF-C gene by Her-2/neu. In conclusion, this work clearly establishes that the Her-2/neu oncogene is essential for the regulation of VEGF-C in ovarian carcinoma. It may be possible to use the monoclonal antibody targeting Her-2/neu receptor to limit the formation of malignant ascites and lymphatic spread in ovarian carcinoma.
International Journal of Gynecological Cancer, 2001
Carcinosarcoma is a rare neoplasm which, in the female genital tract, arises mainly in the endome... more Carcinosarcoma is a rare neoplasm which, in the female genital tract, arises mainly in the endometrium. Although the pathogenesis remains obscure, there is an apparent association between pelvic irradiation and uterine sarcomas. There have been sporadic case reports of the development of carcinosarcomas of the cervix, vagina, and extragenital areas, but not of the ovary, after previous pelvic irradiation. We describe a case of ovarian carcinosarcoma arising in a 74-year-old female who had pelvic irradiation 33 years previously. Exploratory laparotomy showed a 25 × 18 × 9 cm left ovarian tumor with adjacent organ invasion including periuterine serosa and rectum. The patient was treated by optimal cytoreduction, followed by chemotherapy with adriamycin and cisplatin. However, acute hepatitis caused by reactivation of hepatitis B virus infection developed just before the fifth course of chemotherapy. She died of hepatic failure two weeks later.
The aim of this study was to evaluate whether vascular endothelial growth factor (VEGF) could be ... more The aim of this study was to evaluate whether vascular endothelial growth factor (VEGF) could be a marker for disease-free survival in endometrial carcinoma patients. Fifty-three patients with endometrial carcinoma undergoing surgery were enrolled. Clinical and pathologic items were recorded. Cytosol VEGF was quantified by enzyme immunoassay. The microvessel density (MVD) of the excised tumors was immunohistochemically assessed. The relationship among MVD, cytosol VEGF concentration of the tumor tissues, and clinicopathologic parameters was analyzed. The risk factors influencing clinical outcome were tested. Higher cytosol VEGF concentrations and MVD values were noted in tumors with advanced stage (more than stage I) (917 versus 125 pg/mg, P = 0.03; 94.1 +/- 37.8 versus 60.8 +/- 38.9, P = 0.008), lymphovascular emboli (917 versus 102 pg/mg, P = 0.001; 94.4 +/- 33.2 versus 62.4 +/- 40.7, P = 0.009), and lymph node metastasis (1032 versus 95 pg/mg, P &amp;amp;lt; 0.001; 116.5 +/- 30.8 versus 56.7 +/- 33.3, P &amp;amp;lt; 0.001). The cytosol VEGF and MVD showed a positive linear correlation (VEGF versus MVD, r = 0.41, P = 0.003). Grade 3 tumor and overexpressed cytosol VEGF (&amp;amp;gt; 800 pg/mg) are independent risk factors for recurrence. There was a trend that patients with grade 1 or 2 tumors and normal-expressed VEGF had the highest probability of disease-free survival, and patients with grade 3 tumors and overexpressed cytosol VEGF had the poorest probability of disease-free survival. Cytosol VEGF had a good correlation with the disease progression and metastasis in endometrial carcinoma, and it might also be an independent prognostic factor for disease-free survival of endometrial carcinoma patients.
To evaluate the efficacy and safety of a distearoylphosphatidylcholine pegylated liposomal doxoru... more To evaluate the efficacy and safety of a distearoylphosphatidylcholine pegylated liposomal doxorubicin, Lipo-Dox, in platinum-resistant or refractory epithelial ovarian cancer. A multicenter phase II trial enrolled women with platinum-resistant or refractory epithelial ovarian carcinoma and naïve to anthracycline. Eligible patients had either measurable tumor(s) or elevated serum CA 125 titer. Lipodox was initiated with a dose of 45 mg/m2 at a 4-week interval with subsequent escalation or reduction. A total of six cycles were scheduled. 29 patients, 20 with platinum-resistant and 9 with platinum refractory tumors, were enrolled. Lipo-Dox was given for an average of 4.6 cycles per patient with a total of 134 cycles. Among the 26 evaluable patients, one achieved CR, 5 PR and 9 SD. The overall response rate was 23.1% (95% CI, 6.8%-39.3%) with a median response duration of 11.6 weeks. 5 of the 6 responses were in patients with resistant disease. The median progression-free duration in the SD patients was 25.7 weeks. With a median follow-up of 13.8 months, the median progression-free and median overall survivals in the 26 patients were 5.4 months and 13.8 months, respectively. Hand-foot skin reaction occurred in 4.5% and skin pigmentation in 11.2% of all treatment cycles, all were Grade 1/2. Nausea and vomiting occurred in 14.2%, while anemia, leukopenia and thrombocytopenia occurred in 20.9%, 32.8% and 9% of cycle, respectively, and were mostly Grade 1 or 2. Lipo-Dox, the third liposome encapsulated doxorubicin, at 45 mg/m2 every 4 weeks, is effective against recurrent, platinum-resistant epithelial ovarian cancers.
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumo... more G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-C...
BJOG: An International Journal of Obstetrics and Gynaecology, 1999
To investigate the pathological significance of intra-tumoural blood flow signals detected by col... more To investigate the pathological significance of intra-tumoural blood flow signals detected by colour Doppler ultrasound and their association with angiogenesis in cervical carcinoma. A prospective cross-sectional study. University hospital. One hundred and four women with Stage IB-IIA cervical carcinoma. All women underwent radical hysterectomy and pelvic lymph node dissection. Transvaginal colour Doppler ultrasound was performed before surgery to search for arterial blood flow signals within the tumours. Tumours with a measurable intra-tumoural resistance index were defined as tumour with detectable blood flow and the others as tumour with undetectable blood flow. The microvessel density of the excised tumour was assessed immunohistochemically. The women&amp;amp;#39;s clinical and pathologic data were recorded. There were 60 tumours (58%) exhibiting detectable intra-tumoural blood flow signals. Tumours with detectable blood flow were larger, had deeper cervical stromal invasion, a higher incidence of parametrial invasion and pelvic lymph node metastases, and a higher microvessel density, when compared with those without detectable blood flow. Cervical cancers with deep cervical stromal invasion, parametrial invasion, and pelvic lymph node metastasis had higher microvessel density than those with superficial stromal invasion, no parametrial invasion, or no lymph node metastasis. Microvessel density correlated well with lymph node metastases and parametrial invasion by multiple regression analysis, while intra-tumoural blood signals only showed correlation with parametrial invasion. In the prediction of pelvic lymph node metastases and parametrial invasion, colour flow Doppler had a sensitivity of 0.80 and specificity of 0.48 in predicting lymph node metastases, and sensitivity of 0.91 and specificity of 0.57 in predicting parametrial invasion. The characteristics of blood flow signals in cervical carcinoma detected by colour Doppler ultrasound are associated with tumour angiogenesis and could reflect the likelihood of parametrial invasion and lymph node metastases in cervical carcinoma. The intra-tumoural blood flow signals might be used as a screening test in predicting parametrial invasion and pelvic lymph node metastases. These findings may be helpful in planning treatment for women with Stage I and II cervical carcinoma.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014
High-level expression of vascular endothelial growth factor (VEGF)-C is associated with chemoresi... more High-level expression of vascular endothelial growth factor (VEGF)-C is associated with chemoresistance and adverse prognosis in acute myeloid leukemia (AML). Our previous study has found that VEGF-C induces cyclooxygenase-2 (COX-2) expression in AML cell lines and significant correlation of VEGF-C and COX-2 in bone marrow specimens. COX-2 has been reported to mediate the proliferation and drug resistance in several solid tumors. Herein, we demonstrated that the VEGF-C-induced proliferation of AML cells is effectively abolished by the depletion or inhibition of COX-2. The expression of endothelin-1 (ET-1) rapidly increased following treatment with VEGF-C. We found that ET-1 was also involved in the VEGF-C-mediated proliferation of AML cells, and that recombinant ET-1 induced COX-2 mRNA and protein expressions in AML cells. Treatment with the endothelin receptor A (ETRA) antagonist, BQ 123, or ET-1 shRNAs inhibited VEGF-C-induced COX-2 expression. Flow cytometry and immunoblotting revealed that VEGF-C induces S phase accumulation through the inhibition of p27 and the upregulation of cyclin E and cyclin-dependent kinase-2 expressions. The cell-cycle-related effects of VEGF-C were reversed by the depletion of COX-2 or ET-1. The depletion of COX-2 or ET-1 also suppressed VEGF-C-induced increases in the bcl-2/bax ratio and chemoresistance against etoposide and cytosine arabinoside in AML cells. We also demonstrated VEGF-C/ET-1/COX-2 axis-mediated chemoresistance in an AML xenograft mouse model. Our findings suggest that VEGF-C induces COX-2-mediated resistance to chemotherapy through the induction of ET-1 expression. Acting as a key regulator in the VEGF-C/COX-2 axis, ET-1 represents a potential target for ameliorating resistance to chemotherapy in AML patients.
Sacrospinous ligament fixation (SSLF) is one of the most utilized surgeries in the management of ... more Sacrospinous ligament fixation (SSLF) is one of the most utilized surgeries in the management of pelvic organ prolapse (POP). We conducted a large-series study of SSLF in a tertiary center by an experienced urogynecologic team. The 453 women with POP who underwent SSLF at National Taiwan University Hospital in the period from 2002 to 2015 are reviewed. All patients received unilateral SSLF with Veronikis ligature carrier. Concomitant anterior colporrhaphy was performed in 75.3% of the cases and posterior colporrhaphy in 78.6%. The mean operation time was 92.3 ± 31.5 minutes. The intraoperative blood loss was 92.3 ± 91.4 ml. The objective cure rate was 82.5%, and 79 (17.5%) patients recurred. The Kaplan-Meier recurrence-free analysis showed a steep decline during the first postoperative year, and the yearly number of recurrent patients decreased as the follow-up period proceeded. A comparison of the site of recurrence found that anterior compartment prolapse was the most common with ...
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Papers by Lin-hung Wei