Zhongqiu Lin

Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in cervical cancer.

BackgroundMultiple studies proved that miRNAs have a causal role in tumorigenesis. Some miRNAs are regulated by epigenetic alterations in their promoter regions and can be activated by chromatin- modifying drugs.MethodsWe treated cervical cancer cells with 5-aza-2’-deoxycytidine and get a microarray analysis. Dysregulation of miRNAs was measured by qPCR in cervical cell lines and methylation status of them in cervical cancer tissue were performed with MeDIP-qPCR assay.ResultsWe found hypermethylation of miR-432, miR-1286, miR-641, miR-1290, miR-1287 and miR-95 may have some relationship with HPV infection in cervical cell lines. In primary tumors of cervix with paired normal tissue, expression levels of miRNAs were inversely correlated with their DNA methylation status in the cervical cancer cell lines treated with 5-AZA.ConclusionsOur results indicate that miRNAs might play a role in the pathogenesis of human cervical cancer with HPV and identify altered miRNA methylation as a possible epigenetic mechanism involved in their aberrant expression.

The functional reconstruction of fertility-sparing radical abdominal trachelectomy for early stage cervical carcinoma.

OBJECTIVE To study the feasibility and outcome of functional reconstruction during radical abdominal trachelectomy in the treatment of early stage cervical carcinoma. STUDY DESIGN Ten cervical cancer patients (FIGO stage IA2 or IB1 with tumours less than 2 cm in diameter) who desired to preserve their fertility underwent abdominal radical trachelectomy with functional reconstruction, including preserving the ascending uterine artery, placing a stent to avoid intrauterine adhesions and using three pieces of mesh to prevent cervical incompetence and uterine prolapse. RESULTS The mean age of the patients was 29 years (range 28-30). The average operative time was 261 min (range 204-345), with a mean blood loss of 370 ml (range 150-500). The mean time to remove the urinary catheter was 12 days (range 8-14) after surgery and the mean time to remove pelvic drainage was 4 days (range 2-8). During the follow-up (range 4-68 months), no recurrence was detected and a normal menstrual pattern resumed within 8 weeks after surgery. No abnormality was noted in the preserved ascending branches of the uterine arteries, and no intrauterine adhesion was found. One patient successfully conceived without reproductive assistance and another patient conceived with in vitro fertilization. There was no cervical incompetence or premature rupture of membrane in their pregnancies, and cesarean sections were done as in normal women at a gestation of 38(+5) weeks and 34(+3) weeks, respectively. CONCLUSION We conclude that the functional reconstruction is a good choice of fertility-sparing surgery for patients with early stage cervical carcinoma.

Expression and Functional Role of ALDH1 in Cervical Carcinoma Cells

Tumor formation and growth is dictated by a very small number of tumor cells, called cancer stem cells, which are capable of self-renewal. The genesis of cancer stem cells and their resistance to conventional chemotherapy and radiotherapy via mechanisms such as multidrug resistance, quiescence, enhanced DNA repair abilities and anti-apoptotic mechanisms, make it imperative to develop methods to identify and use these cells as diagnostic or therapeutic targets. Aldehyde dehydrogenase 1 (ALDH1) is used as a cancer stem cell marker. In this study, we evaluated ALDH1 expression in CaSki, HeLa and SiHa cervical cancer cells using the Aldefluor method to isolate ALDH1-positive cells. We showed that higher ALDH1 expression correlated with significantly higher rates of cell proliferation, microsphere formation and migration. We also could demonstrate that SiHa-ALDH1- positive cells were significantly more tumorigenic compared to SiHa-ALDH1-negative cells. Similarly, SiHa cells overexpressing ALDH1 were significantly more tumorigenic and showed higher rates of cell proliferation and migration compared to SiHa cells where ALDH1 expression was knocked down using a lentivirus vector. Our data suggested that ALDH1 is a marker of cervical cancer stem cells and expand our understanding of its functional role.

Overexpression of hypoxia-inducible factor-1α is a predictor of poor prognosis in cervical cancer: a clinicopathologic study and a meta-analysis.

Background Published data on the prognostic value of hypoxia-inducible factor-1&agr; (HIF-1&agr;) expression in cervical cancer are conflicting and heterogeneous. We aimed to derive a more precise estimation of them. Methods We conducted a clinicopathologic study in 74 patients with early-stage cervical cancer treated through surgery and performed a meta-analysis among patients with cervical cancer of all stages to estimate the prognostic importance of HIF-1&agr; expression for disease-free survival (DFS) and overall survival (OS). Expression of HIF-1&agr; was evaluated through immunohistochemistry. Results A positive nuclear expression of HIF-1&agr; was found in 94.6% of all specimens. There were significant associations between HIF-1&agr; expression and International Federation of Gynecology and Obstetrics stage (P = 0.024), tumor size (P = 0.003), and anemia (P = 0.010), respectively. Log-rank tests revealed significant correlations between HIF-1&agr; expression, International Federation of Gynecology and Obstetrics stages, tumor grade, tumor size and DFS/OS, respectively. The multivariate Cox regression analyses revealed HIF-1&agr; overexpression and high tumor grade to be independent predictors for impaired DFS (HIF-1&agr; overexpression: hazard ratio [HR], 2.67; 95% confidence interval [CI], 1.10–6.47; high tumor grade: HR, 5.56; 95% CI, 1.47–21.13) and OS (HIF-1&agr; overexpression: HR, 2.57; 95% CI, 1.06–6.23; high tumor grade: HR, 6.23; 95% CI, 1.49–25.97). The results of 10 studies indicated that HIF-1&agr; overexpression predicted poor DFS (HR, 1.98; 95% CI, 1.22–3.21) and OS (HR, 2.58; 95% CI, 1.86–3.56) for cervical cancer. Conclusions The present clinicopathologic study and meta-analysis showed that HIF-1&agr; overexpression is associated with poor survival of cervical cancer and emphasized the importance of HIF-1&agr; as a predictor for cervical cancer.

Galectin-3 regulates metastatic capabilities and chemotherapy sensitivity in epithelial ovarian carcinoma via NF-κB pathway.

Galectin-3 (Gal-3) has been found to be involved in the tumor progression and chemoresistance of epithelial ovarian cancer (EOC). Some studies have shown that Gal-3 may interact with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). However, it is unclear whether the effects of Gal-3 on the metastasis and chemosensitivity of EOC are related to NF-κB. In this study, we aimed to explore whether Gal-3 promoted progression and carboplatin resistance in EOC via NF-κB pathway. Plasmid transfection and RNA interference were used to upregulate or downregulate the expression of Gal-3 in ovarian cancer cell lines. Then, the expression of Gal-3 and the protein expressions of phosphorylation NF-κB pathway molecules were further detected by Western blot. Transwell migration assay was employed to detect the effects of Gal-3 on the migration and invasion of ovarian cancer cell lines. After treatment with carboplatin, flow cytometry (FCM) was employed to detect the effects of Gal-3 on carboplatin-induced apoptosis. Immunofluorescence technique was used to examine the translocation of phosphorylated P65 into the nucleus in ovarian cancer cells after the upregulation of Gal-3. After the knockdown of Gal-3 by small interfering RNA (siRNA), the migration and the invasion of cancer cells were significantly inhibited while the apoptosis and the sensitivities to carboplatin increased. Western blot showed reduction in the phosphorylation components of the NF-κB pathway: inhibitor of kappa B (IκB), IκB kinase (IKK), and P65. However, after the Gal-3 upregulation by plasmid transfection, the capabilities of migration and invasion of cancer cells were significantly promoted while the apoptosis and the sensitivities to carboplatin decreased. Immunofluorescence showed increased nuclear translocation of P65. Inhibitors of the NF-κB pathway did not affect the Gal-3 expression level in ovarian cancer cells. Gal-3 may affect the migratory and invasive capabilities of cancer cells as well as the chemosensitiviy to carboplatin in EOC by acting through the NF-κB pathway.

The association between XRCC1 genetic polymorphisms and the risk of endometrial carcinoma in Chinese

Accumulated evidences report that X-ray repair cross-complementing group 1 gene (XRCC1) genetic polymorphisms play an important role in the development of endometrial carcinoma (EC). This study aims to evaluate the association of XRCC1 c.1161G>A and c.1804C>A genetic polymorphisms with the risk of EC. A total of 218 EC patients and 243 cancer-free controls were included in this study. The genotypes of XRCC1 genetic polymorphisms were determined by the created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. We found that these two genetic polymorphisms were statistically associated with the risk of EC. As for c.1161G>A, in comparison with GG wild genotype, the AA genotype was significantly associated with the increased risk of EC (OR=2.36, 95% CI 1.28-4.37, χ(2)=7.71, P=0.005). As for c.1804C>A, the CC genotype significantly increased the risk of EC in comparison with CC wild genotype (OR=2.77, 95% CI 1.38-5.58, χ(2)=8.54, P=0.003). Our data indicate that the A allele of c.1161G>A and c.1804C>A genetic polymorphisms could contribute to increase the risk of EC (for c.1161G>A: A versus (vs.) G, OR=1.34, 95% CI 1.02-1.76, χ(2)=4.56, P=0.033; for c.1804C>A: A vs. C, OR=1.34, 95% CI 1.01-1.77, χ(2)=4.03, P=0.045). Our results indicate that the XRCC1 c.1161G>A and c.1804C>A genetic polymorphisms significantly influenced the risk of EC in Chinese populations, and might be used as molecular markers for evaluating EC risk.

Aldehyde dehydrogenase 1 (ALDH1) positivity correlates with poor prognosis in cervical cancer

Objective To analyse the associations between aldehyde dehydrogenase 1 (ALDH1) tumour immunopositivity and disease-free survival in cervical carcinoma. Methods ALDH1 immunohistochemistry was performed on formalin-fixed, paraffin wax-embedded cervical tumour tissue samples obtained from hospital archives. Data regarding disease-free survival were obtained. Kaplan–Meier survival analyses and Cox proportional hazards regression models were performed. Results Patients with ALDH1-positive tumours (n = 31) had significantly shorter disease-free survival than those with ALDH1-negative tumours (n = 167; 41.99 ± 0.90 vs 53.64 ± 2.67 months). ALDH1 positivity was associated with poor prognosis (relative risk 2.727; 95% confidence intervals 1.253, 5.914). Conclusions ALDH1 positivity is associated with poor prognosis of cervical carcinoma, and may be an independent predictor of prognosis.

Impact of Hyperglycemia on Outcomes among Patients Receiving Neoadjuvant Chemotherapy for Bulky Early Stage Cervical Cancer.

Background The impact of hyperglycemia on survival of patients undergoing neoadjuvant chemotherapy (NACT) for bulky early stage cervical cancer (BESCC) has not been explored. Method Records of patients who received NACT and radical hysterectomy in our institution between January 2005 and June 2010 were reviewed. Results In total, 347 patients were included. The median follow-up time was 37 months (range: 4–65). Patients with hyperglycemia (fasting blood glucose ≥ 100 mg/dl) had shorter recurrence-free survival (RFS) (univariate hazard ratio [HR] = 1.95, 95% confidence interval [CI] [1.16, 3.28], P = 0.010) and cancer-specific survival (CSS) (univariate HR = 2.24, 95% CI [1.33, 3.78], P = 0.002) compared with those with euglycemia (fasting blood glucose <100 mg/dl). In multivariate analysis, positive surgical margins, parametrium invasion, node metastasis, hyperglycemia and complete response to NACT independently predicted recurrence and cancer-specific death. To further validate the prognostic value of hyperglycemia, we conducted a subgroup analysis based on patient baseline characteristics and prognostic effect of hyperglycemia remained significant in all subgroups. On multivariable logistic regression analysis, euglycemia before NACT, squamous cell tumor and pre-treatment squamous cell carcinoma antigen levels < 3.5 ng/ml were identified as independent predictors of complete response after NACT. Conclusions FBG ≥100 mg/dl is a negative prognostic predictor for cervical cancer patients receiving NACT for BESCC. Patients with hyperglycemia are less likely to achieve complete response after NACT. Our findings underscore the clinical utility of hyperglycemia screening of for cervical cancer patients.

Is Ovarian Preservation Feasible in Early-Stage Adenocarcinoma of the Cervix?

Background In cervical adenocarcinoma, surgical treatment involves bilateral oophorectomy, which affects the long-term quality of life. The aim of our study was to access the incidence of ovarian metastasis in early-stage cervical adenocarcinoma and to suggest an algorithm for the triage of these patients to preserve the ovaries. Material/Methods A total 101 patients with cervical adenocarcinoma who had undergone radical hysterectomy with pelvic lymphadenectomy and bilateral oophorectomy were included in this study. Data on the clinicopathologic characteristics of the cases were collected and low risk factors for ovarian metastasis in early-stage cervical adenocarcinoma were analyzed. Results The ovary metastasis rate of cervical adenocarcinoma in this study was 4.95%, while it is only 2% in stage IB1. Pathological grade, LSVI, lymph node status, tumor size, depth of stromal invasion, and involvement of the junction of the cervix and the body of the uterus were associated with ovarian metastasis, while LSVI, lymph node status, depth of stromal invasion, and involvement of the junction of the cervix and the body of the uterus were associated with ovarian metastasis in stage IB. Multivariate analysis revealed that LVSI and lymph node metastasis were independent risk factors for ovarian metastasis in all stages of cervical adenocarcinoma, but involvement of the junction of the cervix and the body of the uterus was an independent risk factor for ovarian metastasis in stage IB. Conclusions The incidence of ovarian metastasis in cervical adenocarcinoma is low. Our study suggests that ovarian preservation is safe and feasible in patients with no risk factors for ovarian metastasis. Further prospective studies are warranted.

Impact of the care provided by gynecologic oncologists on outcomes of cervical cancer patients treated with radical hysterectomy

For many malignant diseases, specialized care has been reported to be associated with better outcomes. The purpose of this study is to investigate the influence of gynecologic oncologists on treatment outcomes for cervical cancer patients treated by radical hysterectomy. Records of patients who received radical hysterectomy between January 2005 and June 2010 were reviewed. Perioperative morbidity, recurrence-free survival, and cancer-specific survival were assessed. Cox regression model was used to evaluate gynecologic oncologists as an independent predictor of survival. A total of 839 patients were included. Of these patients, 553 were treated by gynecologic oncologists, while 286 were treated by other subspecialties. With regard to operative outcomes, significant differences in favor of operation by gynecologic oncologists were found in number of patients receiving para-aortic node sampling and dissection (P=0.038), compliance with surgical guidelines (P=0.003), operative time (P<0.0001), estimated blood loss (P<0.0001), transfusion rate (P=0.046), number of removed nodes (P=0.033), and incidences of ureteric injury (P=0.027), cystotomy (P=0.038), and fistula formation (P=0.002). Patients who were operated on by gynecologic oncologists had longer recurrence-free survival (P=0.001; hazard ratio [HR] =0.64; 95% confidence interval [CI] [0.48, 0.84]) and cancer-specific survival (P=0.005; HR=0.64; 95% CI [0.47, 0.87]), and this association remained significant in patients with locally advanced disease. Care by gynecologic oncologists was an independent predictor for improved recurrence-free survival (P<0.0001; HR=0.57; 95% CI [0.42, 0.76]) and cancer-specific survival (P=0.001; HR=0.58; 95% CI [0.42, 0.81]), which was still significant among patients with locally advanced cancer. Given the results, we believe for cervical cancer patients receiving radical hysterectomy, operation by gynecologic oncologists results in significantly improved surgical and survival outcomes. The importance of the subspecialty of a gynecologist for cervical cancer patients should be addressed in clinical practice, especially for those in developing countries.