Wenyan Tian

Visfatin, a potential biomarker and prognostic factor for endometrial cancer

OBJECTIVE Visfatin, a newly discovered adipocytokine, is thought to play a role in the pathogenesis of metabolic-syndrome-related cancers. The aim of this study was to assess the clinical significance of serum levels and tissue expression of visfatin in relation to endometrial cancer (EC). METHODS A total of 234 EC patients were included in this study. Serum visfatin, metabolic and anthropometric parameters were measured in EC patients and controls. Serum visfatin levels were detected using ELISA. Tissue expression of visfatin was analyzed using immunohistochemistry in tissue microarrays. The correlation between clinicopathological variables and visfatin in EC tissues and the prognostic value of visfatin for overall survival was evaluated. RESULTS Serum levels of visfatin were significantly higher in EC patients than in controls (P<0.05). In univariate and multivariate logistic regression models, a positive association between EC and serum visfatin, BMI, waist-to-hip ratio, diabetes, and hypertension was evident (P<0.05). Visfatin expression was significantly higher in EC tissue than in normal endometrial tissue (P=0.001). Moreover, serum visfatin levels were significantly positively correlated with tissue expression of visfatin in EC patients (P<0.05). High visfatin expression in EC tissues was significantly associated with advanced FIGO stage (P=0.016) and myometrial invasion ≥1/2 (P=0.023). The overall survival rate of EC patients was significantly higher in the group with negative visfatin expression than with positive visfatin expression (P=0.035). CONCLUSIONS Visfatin is a potential serum biomarker and prognostic factor for EC that may indicate high risk for EC and EC progression. It may also be a novel potential therapeutic target for EC.

Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent

OBJECTIVE To determine serum insulin levels, expression and phosphorylation of InsR, IRS-1 and Akt in endometrial cancer (EC) tissues, and to explore the correlation between them. To investigate if insulin-induced mitogenic and anti-apoptotic effects are PI3K-dependent in EC cells. METHODS Serum insulin levels were measured by radioimmunoassay. We performed RT-PCR and western blotting to evaluate the expression and activation of key proteins of PI3K/Akt pathway in 63 EC tissues. The proliferation and apoptosis rates were determined with MTT, BrdU and annexin V/PI assays. RESULTS Serum insulin levels and InsR, IRS-1 and Akt expression and phosphorylation were significantly elevated in patients with EC compared to those without EC. Additionally, levels of p-InsR, p-IRS-1, and p-Akt were significantly higher in patients with high-grade, advanced stage, deep myometrial invasion, and lymph-node metastasis. The expression and activation of InsR, IRS-1, and p-Akt were positively related with the levels of serum insulin. The insulin-induced mitogenic and anti-apoptotic effects in EC cells were blocked when cells were pre-incubated with LY294002. Ishikawa 3-H-12 cells showed increased p-Akt levels after treatment with insulin at 10(-8)M for 15min. The insulin-induced Akt activation was inhibited by LY294002 in a dose-dependent manner. CONCLUSION Insulin played an essential role in EC tumorigenesis. Activation of InsR, IRS-1, and Akt was associated with features of aggressive EC. Insulin was a mitogenic and anti-apoptotic agent for EC cells, and these effects were dependent on PI3K/Akt pathway. Decreasing insulin level and blocking the InsR-IRS-PI3K-Akt pathway could be viable preventive and therapeutic strategies for EC.

Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis

BackgroundCancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC.MethodsStromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry.ResultsCAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC.ConclusionsOur data indicated that CAFs derived from EC tissues promoted EC progression via the SDF-1/CXCR4 axis in a paracrine- or autocrine-dependent manner. SDF-1α is a novel independent poor prognostic factor for EC patients’ survival. Targeting the SDF-1/CXCR4 axis might provide a novel therapeutic strategy for EC treatment.

Prognostic significance of thrombocytosis, platelet parameters and aggregation rates in epithelial ovarian cancer

The aim of this study is to investigate the impact of preoperative platelet counts, parameters and aggregation rates (maximal aggregation rate: MAR) on prognosis in patients with epithelial ovarian cancer (EOC).

Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway

The involvement of insulin in endometrial carcinoma (EC) was investigated using radioimmunoassay, Western blot, immunoprecipitation, MTT, and Annexin V-FITC/PI assays in tissue samples and cultured cells. Serum levels of insulin, p-p52Shc, p-p46Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1 were elevated in patients with EC. Expression of key proteins in the MEK/ERK pathway, including p-p52Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1, was significantly higher in patients with advanced FIGO stage, high grade, and lymph-node metastasis and correlated positively with serum insulin concentration. Insulin promotes Ishikawa 3-H-12 cell proliferation, survival, and invasion, and these effects induced by insulin were significantly blocked by MEK inhibitor PD98059. Insulin thus promotes EC cell proliferation, survival, and invasion via the MEK/ERK pathway.

The therapeutic significance of aromatase inhibitors in endometrial carcinoma

OBJECTIVE To review recent studies about the application of aromatase inhibitors in endometrial carcinoma and the benefits and challenges of aromatase inhibitors in this regard. METHODS Relevant studies and manuscripts were searched for in Pubmed using the following terms, either alone or in combination: aromatase, aromatase inhibitors, letrozole, anastrozole, endometrial cancer, breast cancer, endocrine, therapy, and side effects. RESULTS Endometrial carcinoma is one of the most pervasive gynecological malignancies. Type I endometrial carcinoma is estrogen-dependent. Recent studies have demonstrated that aromatase inhibitors, which interfere with estrogen biosynthesis by inhibiting the activity of aromatase, can be used to treat endometrial carcinoma and its precancerous lesions to some extent. In early-stage endometrial carcinoma or atypical hyperplasia, a precancerous lesion of endometrial carcinoma, the effects of aromatase inhibitors were promising. However, in advanced or recurrent endometrial carcinoma, the application of aromatase inhibitors cannot solve the problem evidently. In addition, these inhibitors have limitations, like side effects and drug resistance. The need for a new generation of inhibitors with higher specificity and fewer side effects should be studied further. CONCLUSIONS Aromatase inhibitors show promise in the therapy of endometrial carcinoma, especially the early stage. Further studies should be conducted to develop next-generation aromatase inhibitors with higher specificity and fewer side effects.

Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways

OBJECTIVE Endometrial carcinoma is one of the most common malignancies of the female reproductive system, but the aetiology and pathogenesis are not well understood, although adipokines such as visfatin may be involved. Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrial carcinoma. METHODS We investigated the effect of visfatin on endometrial carcinoma cell proliferation, cell cycle, and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells. We also assessed the effect of visfatin on tumour growth in vivo. RESULTS Visfatin stimulated the proliferation of both Ishikawa and KLE cells, and visfatin treatment promoted G1/S phase progression and inhibited endometrial carcinoma cell apoptosis. Visfatin promoted endometrial carcinoma tumour growth in BALB/c-nu mice. Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining, which revealed much stronger positive signals for Ki-67 with over-abundant visfatin. Western blot analysis revealed that insulin receptor (IR), insulin receptor substrate (IRS)1/2 and key components of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin. Treated cells showed increased C-MYC and cyclin D1 and reduced caspase-3 expression. The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the PI3K inhibitor LY294002 and MEK inhibitor U0126. CONCLUSIONS Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and PI3K/Akt and MAPK/ERK signalling. Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma.

Contrast-enhanced MRI in preoperative assessment of myometrial and cervical invasion, and lymph node metastasis: diagnostic value and error analysis in endometrial carcinoma

To determine the ability of contrast‐enhanced magnetic resonance imaging to predict myometrial invasion, cervical invasion, and pelvic lymph node metastasis in endometrial carcinoma and to analyze factors that lead to errors in this identification.

Van Wyk and Grumbach syndrome: two case reports and review of the published work.

Van Wyk and Grumbach syndrome is characterized by a long‐standing history of hypothyroidism, high levels of thyroid‐stimulating hormone, uni‐ or bilateral ovarian cysts, isosexual precocity and a delayed bone age. All of the features can be reversed with treatment of the underlying hypothyroidism. Here, we describe two cases of Van Wyk and Grumbach syndrome presenting with bilateral multicystic ovaries and enlargement of the pituitary gland. One patient suffered from ovarian cyst and hypophysoma resection, the other patient promptly responded to L‐thyroxine with complete regression of the ovarian cyst and other symptoms.

Androgen insensitivity syndrome with gynandroblastoma and vulvar leiomyoma: case report and literature review.

Objective This study aimed to describe a rare case of androgen insensitivity syndrome (AIS) in association with gynandroblastoma and vulvar leiomyomata. Materials and Methods The patient was a 64-year-old phenotypically female person with 46 XY chromosomal karyotypes who presented with a chief complaint of abdominal distension of 1-month duration. She had 2 vulvar masses for more than 20 years and had experienced life-long (untreated) amenorrhea. History and physical examination findings showed the patient to be 175 cm in height, with normal breast development, and a lack of pubic or axillary hair. Serum levels were as follows: testosterone, 1,980 ng/dL; estradiol, 1,380.8 pg/mL. Results In combination with clinical findings, a diagnosis of complete AIS was made. The patient subsequently underwent surgery, during which the bilateral vulvar masses and the rudimentary uterus, right sex gland, and left side of the tumor were resected. Histological examination of the tumor revealed a mass composed primarily of juvenile-type granulosa cells, admixed with a Sertoli cell component that comprised less than 50% of the tumor. The right side of the gonad had an ovarian-like cortex and was considered to be an undeveloped ovary. The left and right side of the vulvar masses were diagnosed with leiomyomas. Conclusions Patients with AIS should be monitored closely because these patients may also experience gonadal tumors. When confronted with gynandroblastoma, close attention should be paid to the patient’s endocrinologic status, and comprehensive endocrinologic analyses should be conducted to make correct treatment decisions.