Xueqiong Zhu

Proteomic identification of differentially-expressed proteins in squamous cervical cancer.

OBJECTIVE To identify candidate biomarkers for squamous cervical cancer as well as reveal the molecular mechanism underlying this disease by a proteomic approach. METHODS Proteins from 10 pairs of human squamous cervical cancer and matching adjacent normal cervical tissues were separated by two-dimensional gel electrophoresis and the differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Then, some of the interesting proteins obtained were confirmed by Western blotting in the other 20 pairs of tissues. RESULTS A comparison of protein patterns revealed 55 protein spots significantly changed, of which 24 protein spots with concordantly increased and 31 protein spots with concordantly decreased intensity in squamous cervical cancer compared with adjacent normal cervical tissues. Thirty-two of these proteins were identified by mass spectrometry. The overexpression of the Tyk2, S100A9, and Zinc finger protein 217 in squamous cervical cancer was confirmed by immunoblotting. CONCLUSIONS Our study suggested that a proteomics-based approach is useful for developing a more complete picture of the protein profile of squamous cervical cancer. Further ongoing analysis of these differential proteins will determine their potential applicability to squamous cervical cancer-specific diagnosis and therapeutics.

Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis

OBJECTIVE To conduct a meta-analysis of the studies assessing the effects of mifepristone on the uterus, uterine leiomyoma, and leiomyoma-related symptoms in premenopausal women. DESIGN Meta-analysis. SETTING Centers for reproductive care. PATIENT(S) Premenopausal women who suffered from leiomyoma. INTERVENTION(S) We identified all of the studies published before December 2012 that compared the status of patients with leiomyoma before and after treatment with mifepristone. MAIN OUTCOME MEASURE(S) Leiomyoma-related symptoms, uterine or leiomyoma volume, changes in endometrial thickness. RESULT(S) A meta-analytic technique was used to study 11 randomized controlled trials involving 780 women with symptomatic uterine leiomyomas. The subjects received 2.5-25 mg/d of mifepristone for 3-6 months. Mifepristone could effectively reduce uterine and leiomyoma volume and alleviate leiomyoma symptoms, including hypermenorrhea, the mean menstrual blood loss, pelvic pain, pelvic pressure, anemia, and dysmenorrhea. There was no significant difference in the rate of atypical endometrial hyperplasia between the mifepristone treatment group and the placebo group. CONCLUSION(S) Mifepristone significantly reduced uterine and leiomyoma volume and alleviated leiomyoma-related symptoms. We recommend 2.5 mg of mifepristone administered daily for 3 or 6 months as the optimum clinical treatment for leiomyoma. There is insufficient evidence that mifepristone treatment led to atypical endometrial hyperplasia.

Chlamydia Trachomatis Infection-Associated Risk of Cervical Cancer: A Meta-Analysis

AbstractAs whether Chlamydia trachomatis infection increases the risk of cervical cancer is controversial in the literature, we performed a meta-analysis.Based on a comprehensive search of publications in the Medline, Cochrane, and EMBASE databases, we identified and extracted data from all relevant articles examining C. trachomatis infection and the risk of cervical cancer. The quality of each included study was assessed according to the 9-star Newcastle–Ottawa scale. The strength of association between the C. trachomatis and risk of cervical cancer was estimated by odds ratio (OR) and 95% confidence intervals (CIs). This review was registered at PROSPERO with registration No. CRD42014015672.A total of 22 studies with 4291 cervical cancer cases and 7628 controls were identified. Overall, C. trachomatis was significantly linked to increased cervical cancer risk in prospective studies (OR = 2.21, 95% CI: 1.88–2.61, P < 0.001), as well as in retrospective studies (OR = 2.19, 95% CI: 1.74–2.74, P < 0.001). Additionally, with a multivariate logistic regression analysis adjusted for HPV and age, C. trachomatis infection was identified as an independent predictor of cervical cancer in 11 studies (OR = 1.76, 95% CI: 1.03–3.01, P = 0.04). Coinfection of human papilloma virus and C. trachomatis has a higher risk of cervical cancer (OR = 4.03, 95% CI: 3.15–5.16, P < 0.001). A subgroup analysis based on histological type indicated an elevated risk for both squamous cell carcinoma (OR = 2.21, 95% CI: 2.00–2.45, P < 0.001), and adenocarcinoma (OR = 1.61, 95% CI: 1.21–2.15, P = 0.001), in associated with C. trachomatis. Subgroup analysis by where C. trachomatis infection was detected showed a significantly higher risk of cervical cancer associated with C. trachomatis infection detected in serum (OR = 2.20, 95% CI: 2.01–2.42, P < 0.001), cervical tissue blocks (OR = 2.88, 95% CI: 1.21–6.83, P = 0.02), and cervical secretion (OR = 2.71, 95% CI: 1.41–5.20, P = 0.003), especially in serum with no obvious heterogeneity.In conclusion, our novel data demonstrate that individuals infected with C. trachomatis have a higher risk of cervical cancer. Therefore, it is necessary to expand C. trachomatis infection screening and treat women with C. trachomatis promptly, particularly those with human papilloma virus infections. This approach will not only protect against pelvic inflammatory disease and infertility, but may also prevent cervical cancer.

Expression of Aquaporin 1 and Aquaporin 3 in Fetal Membranes and Placenta in Human Term Pregnancies with Oligohydramnios

OBJECTIVE To explore the pathophysiology of oligohydramnios, the association between the expression of aquaporin 1 and aquaporin 3 in fetal membranes and placenta and oligohydramnios was investigated. METHODS Sixty patients underwent elective cesarean sections at term were studied, 30 patients with isolated oligohydramnios and the other 30 with normal amniotic fluid volume (AFV). Real-time polymerase chain reaction and immunohistochemistry were employed to determine expression and localization of aquaporin 1 and aquaporin 3 in amnion, chorion and placenta, respectively. RESULTS The expression of aquaporin 1 and aquaporin 3 was detected in amnion, chorion and placenta using real-time RT-PCR. By immunohistochemistry, aquaporin 1 and aquaporin 3 protein expressions in amnion epithelia and chorion cytotrophoblasts were identified. In placenta, aquaporin 1 was detected in placental vessels, while aquaporin 3 was found in trophoblast cells. In comparison to normal AFV group, there was a significant decrease of aquaporin 1 expression in amnion in oligohydramnios group, but no significant difference in chorion and placenta between the two groups. The expression of the aquaporin 3 in amnion and chorion in oligohydramnios group was significantly decreased, while expression in placenta was significantly increased compared with that in normal AFV group. CONCLUSIONS Alteration of aquaporin 1 and aquaporin 3 expression in fetal membranes and placenta may be important in the pathophysiology of isolated oligohydramnios.

The expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta in term pregnancies complicated by idiopathic polyhydramnios.

BACKGROUND Aquaporins are a family of membrane-bound water channel proteins that regulate the flow of water across a variety of biological membranes. The expression of aquaporin 8 and aquaporin 9 has been demonstrated in human chorioamniotic membrane and placenta. But their roles in the pathophysiology of polyhydramnios are unclear. AIMS To study the expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta in term pregnancies complicated by idiopathic polyhydramnios and to explore the association between aquaporin expressions and polyhydramnios. SUBJECTS The placentas were collected from 51 patients who underwent elective Cesarean sections at term, of which 21 cases had idiopathic polyhydramnios and the other 30 had normal amniotic fluid volume. OUTCOME MEASURES Real-time polymerase chain reaction and immunohistochemistry techniques were used to determine the expression and localization of aquaporin 8 and aquaporin 9 in the amnion, chorion and placenta. RESULTS Expression of aquaporin 8 and aquaporin 9 was detected in the amnion, chorion and placenta and located in amnion epithelia, chorion cytotrophoblasts and placental trophoblast. Compared to normal amniotic fluid volume group, the expression of aquaporin 8 in amnion, and aquaporin 9 in amnion and chorion, were significantly increased in idiopathic polyhydramnios group; however, their expression in the placenta was significantly decreased. CONCLUSIONS When polyhydramnios occurs, expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta is an adaptive change, which may be involved in the regulation of amniotic fluid volume. However, the modulation factors of the aquaporin 8 and aquaporin 9 expressions need further study.

Immunohistochemical expression of Annexin A2 and S100A proteins in patients with bulky stage IB–IIA cervical cancer treated with neoadjuvant chemotherapy

OBJECTIVE Abnormal expression of Annexin A2 and S100A proteins has been reported to induce sensitivity/resistance to chemotherapy in a variety of cancers. The aim of this study was to evaluate the significance of Annexin A2 and S100A protein expression to predict response to neoadjuvant chemotherapy and prognostic significance of these protein expressions in bulky stage IB-IIA cervical cancer patients. METHODS Paired tumor samples (pre- and post-chemotherapy) were obtained from 68 patients who were treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy at our hospital from 2006 to 2011. The expression of Annexin A2 and S100A proteins was analyzed by immunohistochemistry. RESULTS Thirty-six patients were identified as chemotherapy-response and 32 were non-response. (a). Protein expression in tumor cells: (1). Exposure of tumor cells to chemotherapy results in a change of Annexin A2 and S100A expression (P<0.05). (2). Annexin A2, S100A8 and S100A9 protein expression correlates with tumor response to chemotherapy (P<0.05). (b). Protein expression in stromal cells: (1). Expression of Annexin A2, S100A8 and S100A9 was increased, but S100A2 and S100A4 was decreased after exposure to chemotherapy (P<0.05). (2). Only S100A4 expression was associated with response to chemotherapy (P<0.05). Multivariate analysis revealed that tumor size (P=0.022), differentiation (P=0.000), Annexin A2 expression in stromal cells (P=0.009), and S100A8 expression in tumor cells (P=0.008) were independent prognostic factors for progression-free survival of cervical cancer patients. CONCLUSIONS Expression of some of the measured proteins in tumor and stromal cells correlates with chemotherapy exposure, response to therapy, and progression-free survival.

Molecular mechanisms of cisplatin resistance in cervical cancer

Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer.

Transforming growth factor-β1 in carcinogenesis, progression, and therapy in cervical cancer

Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-β1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-β signaling pathway, such as mutations or loss of expression of TGF-β receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-β1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-β1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-β1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

Effects of Laparoscopic Versus Minilaparotomic Myomectomy on Uterine Leiomyoma: A Meta-analysis

A meta-analysis was conducted to assess the effects of laparoscopic versus minilaparotomic myomectomy on uterine leiomyoma in premenopausal women. We performed a computerized search of MEDLINE, Embase, and the Cochrane Library from 1996 to 2104. From 711 studies, a total of 4 studies met our inclusion criteria, and a meta-analytic technique was used to study the 4 randomized controlled trials involving 577 women with symptomatic uterine leiomyoma. Compared with the minilaparotomic myomectomy group, the laparoscopic myomectomy group showed a significantly less hemoglobin drop and blood loss, lower postoperative analgesic use, shorter duration of postoperative ileus, shorter hospitalization days and recovery time, and higher levels in the pregnancy rate per cycle and the live birth rate per cycle. There was no significant difference between the 2 groups regarding the operating time, complications, laparotomic conversion rate, cumulative pregnancy rate, cumulative live birth rate, and abortion rates. When performed by experienced surgeons in selected patients (e.g., symptomatic leiomyoma women who have the indications for surgery), laparoscopic myomectomy is a better choice than minilaparotomic myomectomy.

PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer.

Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF-1α, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1α/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1α, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1α, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin-based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer.