[show abstract][hide abstract] ABSTRACT: The present study was designed to investigate the role of vascular endothelial growth factor receptor (VEGFR)-3/Flt-4 in the early stages of cervical cancer. VEGFR-3/Flt-4 expression, vascular endothelial growth factor (VEGF)-C and VEGF-D in the early stages (Ia-IIa) of cervical cancer in 41 patients was examined by immunohistochemical analysis. Additionally, the VEGFR-3/Flt-4-marked vascular density (MVD) was examined and the relationship of these factors with clinicopathological factors was analyzed. VEGFR-3/Flt-4 was found to be expressed in lymphatic endothelial cells and, to a certain extent, in vascular endothelial cells. The VEGFR-3/Flt-4-positive vessels were largely distributed in the stroma surrounding the tumor tissues, and these vessels were morphologically divided into blood and lymphatic vessels, respectively. Cancer cells were found to express VEGF-C, VEGF-D and VEGFR-3/Flt-4, and their positive expression rate was 48.7% (20/41), 58.5% (24/41) and 63.4% (26/41), respectively. VEGFR-3/Flt-4 expression in the cancer cells of the cervical cancer patients in our study was found to be correlated to the clinical stage, lymph node metastasis, lymphatic invasion and expression of VEGF-C and VEGF-D. However, this expression was unrelated to menstrual status, histological grade and histological classification. MVD was correlated to the clinical stage and expression of VEGF-C and VEGF-D, but was unrelated to menstrual status, histological grade, histological classification, lymph node metastasis and lymphatic invasion. In conclusion, VEGFR-3/Flt-4 plays an important role in the early stages of cervical cancer.
[show abstract][hide abstract] ABSTRACT: To observe mRNA expression of tumor-specific antigen MAGE, BAGE and GAGE in epithelial ovarian cancer tissues and cell lines, to explore the relationship between gene expression and diagnosis, treatment and prognosis of ovarian cancer, and to evaluate the feasibility of their gene products as markers, and an immunotherapy target for ovarian cancer.
mRNA expression of MAGE-1, MAGE-3, GAGE-1/2 and BAGE were determined by reverse transcription polymerase chain reaction (RT-PCR) in 14 cases of normal ovarian tissue, 20 cases of ovarian benign tumor specimens, 41 cases of ovarian cancer specimens, and ovarian cancer cell lines SKOV3, A2780, and COC1.
MAGE, GAGE and BAGE genes were not expressed in normal ovarian tissue. In benign tumors, only the MAGE gene was expressed; the expression rate of this gene in benign tumors was 15% (3/20). In ovarian cancer tissues, MAGE-1 and MAGE-3 was highly expressed, with expression rates of 53.7% (22/41) and 36.6% (15/41), while GAGE-1/2 and BAGE had relatively low expression, with rates of 26.8% (11/41) and 14.6% (6/41). In metastatic lesions of ovarian cancer, only MAGE-1 and BAGE were expressed, with expression rates of 28.6% (2/7) and 14.3% (1/7). The positive expression rates of MAGE-1 and MAGE-3 in serous cystadenocarcinoma were significantly higher than that in other types of ovarian cancer (P < 0.05). Gene expression rate was not correlated with menopause or lymph node metastasis. Positive expression of MAGE-1 and MAGE-3 was positively correlated with tumor differentiation and the clinical stage of the ovarian cancer. In addition, the positive expression rate of BAGE was significantly higher in ovarian cancer patients with ascites (P < 0.05). The mRNA expression profiles of MAGE, GAGE and BAGE in ovarian carcinoma cell lines SKOV3, A2780 and COC1 varied, but there was at least one gene expressed in each cell line.
Tumor-specific antigen MAGE, BAGE and GAGE may play a role in the occurrence and development of ovarian cancer. These genes can be used as one of the important indicators for early diagnosis, efficacy evaluation and prognostic determination of ovarian cancer.
[show abstract][hide abstract] ABSTRACT: Methylation plays an important role in the regulation of gene expression in many cancer tissues. RUNX3 is an important tumor suppressor gene located on human chromosome 1p36.1, and many tumors do not express it due to methylation of the promoter region of the CpG island. The molecular mechanisms involved in RUNX3 gene expression and epithelial ovarian cancer are not fully understood. This study investigates the relationship between RUNX3 methylation and expression in ovarian cancer. The methylation of the RUNX3 gene promoter region was measured in 32 primary epithelial ovarian cancer samples and corresponding nonmalignant ovarian tissues, 36 benign epithelial ovarian tumor tissues, and 10 normal ovarian tissues by methylation-specific PCR (MSP) and RT-PCR. The relationships between RUNX3 methylation status, expression, and clinicopathologic characteristics were analyzed. RUNX3 methylation was further assessed by MSP and RT-PCR before and after 5-aza-2'-deoxycytidine (5-aza-dc) treatment in normal and cancer cell lines. We detected RUNX3 methylation in 53.1% of primary ovarian cancer tumors, 16.7% of benign ovarian tumors, and 28% of nonmalignant tissues surrounding ovarian cancers. No methylation was detected in normal ovarian tissues. No significant correlation between RUNX3 methylation and clinicopathological characteristics was observed. The RT-PCR results found RUNX3 expression in all normal ovarian tissues (10/10) and in most of the unmethylated ovarian cancer tissues (12/15); in contrast, it was not detected in most of the RUNX3-methylated ovarian cancer tissues (16/17). Our data suggest that methylation plays a critical role in the regulation of RUNX3 repression, and that it is significantly correlated with RUNX3 mRNA expression in ovarian cancer tissues (p = 0.006).
Omics: a journal of integrative biology 09/2009; 13(4):307-11. · 2.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cervical cancer is the most common malignant gynecological cancer, and lymphatic metastasis can occur in the early stage of tumor growth. Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a marker for lymphatic endothelium, provides powerful tools for studying tumor lymphangiogenesis. The purpose of this study is to investigate the clinical implications of lymphangiogenesis in the metastasis of early-stage invasive cervical carcinoma.
We used immunohistochemical (IHC) staining with the antibody against LYVE-1 to measure lymph vessel density in 41 cases of early-stage invasive cervical carcinoma and 12 cases of normal cervical samples. We then analyzed the correlation between lymph vessel density and clinicopathological features of the tumors.
(1) The majority of peritumoral lymphatics were enlarged, dilated, and irregular. In contrast, intratumoral lymph vessels were small and collapsed. The peritumoral lymphatic vessel density (PLVD) was significantly higher than the intratumoral lymphatic vessel density (ILVD) (P < 0.01). (2) Both ILVD and PLVD were significantly higher than the LVD of the control cervixes (P < 0.01). (3) Both ILVD and PLVD were significantly associated with lymph node metastasis (ILVD, P < 0.05; PLVD, P < 0.01) and lymphatic vessel invasion (ILVD, P < 0.05; PLVD, P < 0.01). Both the ILVD and PLVD in patients with histological grade HG2 and HG3 were significantly higher than those with HG1 (P < 0.05).
Tumor lymphangiogenesis in early-stage invasive cervical carcinoma may play an important role in the process of lymphatic metastasis.
[show abstract][hide abstract] ABSTRACT: To investigate the role of vascular endothelial growth factors (VEGF)-C/D and their receptor Flt-4 in the lymphatic metastasis of early-stage invasive cervical carcinoma.
Immunohistochemical (IHC) staining with the antibodies against VEGF-C, VEGF-D, and Flt-4 was used to examine the expression of them in 97 cases of early-stage cervical carcinoma (Ia-IIa). Meanwhile, the lymphatic vessel density (LVD) was measured using the antibody against lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). We then analyzed the correlation between Flt-4-positive vessel density (FVD), LVD and clinicopathological features of the tumors.
(1) The positive rates of VEGF-C, VEGF-D, and Flt-4 were 57.7%, 60.8%, and 52.6% in the cervical tumor samples, respectively. (2) The expression levels of VEGF-C, VEGF-D, and Flt-4 were significantly correlated with lymphatic metastasis and lymphatic vessel invasion. LVD was significantly associated with lymph node metastasis and lymphatic vessel invasion. On the other hand, FVD was strongly associated with clinical staging. (3) The expression levels of VEGF-C and VEGF-D were significantly correlated with LVD and FVD, while Flt-4 levels showed no correlation with LVD or FVD.
VEGF-C/D and Flt-4 may play an important role in the process of lymphatic metastasis of early-stage invasive cervical carcinoma through paracrine and autocrine mechanisms.
Journal of Experimental & Clinical Cancer Research 02/2009; 28:98. · 3.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this study is to determine the relationship between methylation and loss of hMLH1 and hMSH2 expression in ovarian cancer.
We examined the methylation status of hMLH1 and hMSH2 promoter region by methylation-specific polymerase chain reaction (MSP) in 56 primary ovarian cancer tissues and 20 normal ovarian tissues, the relationship between the methylation status of these two genes and clinicopathological characteristics were analysed. We then treated SKOV3 and 3AO ovarian cancer cell lines with the demethylating agent 5-aza-2'-deoxycytidine (5-aza-dc). The hMLH1 and hMSH2 methylation was further assessed by MSP, and their mRNA expression was compared by reverse transcription polymerase chain reaction (RT-PCR) before and after 5-aza-dc treatment in these two cell lines.
The methylation frequency of hMLH1 and hMSH2 was 30.4% (17 of 56) and 51.7% (29 of 56) in ovarian cancers, respectively, while no methylation was detected in normal ovarian tissues (P=0.015). There is a significant correlation between hMLH1 promoter hypermethylation and histological grade (P=0.028) as well as lymphatic metastasis (P=0.003). Methylation of hMSH2 correlated with histological grade (P=0.035) and lymphatic metastasis (P=0.015). Besides, the methylation rates of hMSH2 were significantly higher in endometrioid adenocarcinoma tissues than in other pathological types of ovarian cancer. After 5-aza-dc treatment, the expression of hMLH1 and hMSH2 was reversed in two cell lines.
Our results indicate that promoter hypermethylation is an important mechanism for loss of hMLH1 and hMSH2 expression in human ovarian cancer and may be a potential prognostic factor in ovarian cancer.
Australian and New Zealand Journal of Obstetrics and Gynaecology 11/2008; 48(5):505-9. · 1.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate expression of elastin, lysyl oxidase (LOX) and elafin in cardinal ligament of women with pelvic organ prolapse (POP) so as to determine their contributions to POP.
The cardinal ligament samples were obtained from 60 POP subjects and 60 non-POP control women undergoing hysterectomy. RT-PCR was used to verify the mRNA level of elastin, LOX and elafin. The protein concentration of the three genes was determined by western blotting technique, electrophoretic separation and quantification.
The premenopausal and postmenopausal POP groups demonstrated significantly decreased expressions of elastin in cardinal ligament both in mRNA and protein levels than control group (mRNA 0.42 +/- 0.22, 0.26 +/- 0.20 versus 0.79 +/- 0.30, 0.63 +/- 0.23; protein 0.44 +/- 0.32, 0.20 +/- 0.19 versus 0.89 +/- 0.27, 0.78 +/- 0.25; P < 0.05). There was an identical tendency in the expression of LOX (mRNA 0.37 +/- 0.18, 0.20 +/- 0.14 versus 0.65 +/- 0.22, 0.53 +/- 0.20; protein 0.45 +/- 0.27, 0.26 +/- 0.21 versus 0.85 +/- 0.39, 0.69 +/- 0.31; P < 0.05). In POP group, the mRNA and protein levels of elastin and LOX in postmenopausal patients were significantly lower than premenopausal patients (P < 0.05). Inversely, POP group demonstrated an increased expression of elafin in cardinal ligament both in mRNA and protein levels than corresponding control group (mRNA 1.33 +/- 0.35, 1.47 +/- 0.37 versus 0.62 +/- 0.25, 0.55 +/- 0.24; protein 0.85 +/- 0.30, 0.76 +/- 0.35 versus 0.21 +/- 0.15, 0.29 +/- 0.22; P < 0.05). There was no significant difference in the expression of elafin between premenopausal and postmenopausal POP groups either in mRNA or protein levels (P > 0.05). There was a positive correlation between elastin and LOX both in mRNA and protein levels in POP group(r = 0.9959, 0.9708; P < 0.05), but there was no correlation between elastin and elafin (r = -0.0402, -0.0365; P > 0.05).
The results suggest that the decreased expression of elastin and LOX and the increased expression of elafin in the cardinal ligaments may contribute to POP.