Fengxia Xue

Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy

In eukaryotic cells, control mechanisms have developed that restrain cell-cycle transitions in response to stress. These regulatory pathways are termed cell-cycle checkpoints. The G2/M checkpoint prevents cells from entering mitosis when DNA is damaged in order to afford these cells an opportunity to repair the damaged DNA before propagating genetic defects to the daughter cells. If the damage is irreparable, checkpoint signaling might activate pathways that lead to apoptosis. Since alteration of cell-cycle control is a hallmark of tumorigenesis, cell-cycle regulators represent potential targets for therapy. The centrosome has recently come into focus as a critical cellular organelle that integrates G2/M checkpoint control and repairs signals in response to DNA damage. A growing number of G2/M checkpoint regulators have been found in the centrosome, suggesting that centrosome has an important role in G2/M checkpoint function. In this review, we discuss centrosome-associated regulators of the G2/M checkpoint, the dysregulation of this checkpoint in cancer, and potential candidate targets for cancer therapy.

CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks.

Increasing evidence indicates that the tumor microenvironment has critical roles in all aspects of cancer biology, including growth, angiogenesis, metastasis and progression. Although chemokines and their receptors were originally identified as mediators of inflammatory diseases, it is being increasingly recognized that they serve as critical communication bridges between tumor cells and stromal cells to create a permissive microenvironment for tumor growth and metastasis. Thus, an important therapeutic strategy for cancer is to break this communication channel and isolate tumor cells for long-term elimination. Cytokine CXCL12 (also known as stromal-derived factor 1α) and its receptor CXCR4 represent the most promising actionable targets for this strategy. Both are overexpressed in various cancer types, and this aberrant expression strongly promotes proliferation, migration and invasion through multiple signal pathways. Several molecules that target CXCL12 or CXCR4 have been developed to interfere with tumor growth and metastasis. In this article, we review our current understanding of the CXCL12/CXCR4 axis in cancer tumorigenesis and progression and discuss its therapeutic implications.

Insulin resistance: A significant risk factor of endometrial cancer

OBJECTIVE To review the role played by insulin resistance in the development of endometrial cancer. METHODS Relevant manuscripts and studies were searched on Medline using the terms endometrial cancer, insulin resistance, obesity, adipokine, C-peptide, leptin, adiponectin, plasminogen activator inhibitor-1, insulin, PI3K/Akt, Ras/MAPK and metformin alone or in combination. RESULTS Epidemiological studies have shown that insulin resistance is an important potential risk factor of endometrial cancer, and several research studies have been undertaken to determine the mechanism underlying its link to this malignant disease. Risk factors of insulin resistance, such as the inflammatory mediators, adipokines adiponectin, leptin and plasminogen activator inhibitor-1 and excessive androgen are also risk factors of endometrial cancer. High levels of insulin induced by insulin resistance have been found to exert direct and indirect effects that contribute to the development of endometrial cancer. Insulin directly promotes cell proliferation and survival through the PI3K/Akt and Ras/MAPK pathways. Moreover, the network among insulin, estrogen and insulin-like growth factor-1 also contributes to the development of endometrial cancer. Indirectly, insulin leads to changes in sex hormone levels, including increases in the levels of estrogen. Additionally, a small number of studies suggested that metformin, an insulin-sensitizing agent, has therapeutic potential for endometrial cancer. CONCLUSIONS This evidence suggests that insulin resistance plays a central role in endometrial cancer development. Understanding the relationship between insulin resistance and endometrial cancer may supply new ideas to fight this malignancy. Furthermore, combating insulin resistance may be a useful preventive and therapeutic strategy for endometrial cancer.

Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions

Epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), play important roles in embryogenesis, stem cell biology, and cancer progression. EMT can be regulated by many signaling pathways and regulatory transcriptional networks. Furthermore, post-transcriptional regulatory networks regulate EMT; these networks include the long non-coding RNA (lncRNA) and microRNA (miRNA) families. Specifically, the miR-200 family, miR-101, miR-506, and several lncRNAs have been found to regulate EMT. Recent studies have illustrated that several lncRNAs are overexpressed in various cancers and that they can promote tumor metastasis by inducing EMT. MiRNA controls EMT by regulating EMT transcription factors or other EMT regulators, suggesting that lncRNAs and miRNA are novel therapeutic targets for the treatment of cancer. Further efforts have shown that non-coding-mediated EMT regulation is closely associated with epigenetic regulation through promoter methylation (e.g., miR-200 or miR-506) and protein regulation (e.g., SET8 via miR-502). The formation of gene fusions has also been found to promote EMT in prostate cancer. In this review, we discuss the post-transcriptional regulatory network that is involved in EMT and MET and how targeting EMT and MET may provide effective therapeutics for human disease.

MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer

Ovarian carcinoma is the most lethal gynaecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR‐506 has anti‐tumour activity, but its function has yet to be elucidated. We found that deregulation of miR‐506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic over‐expression of miR‐506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that CDK4 and CDK6 are direct targets of miR‐506, and that miR‐506 can inhibit CDK4/6–FOXM1 signalling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR‐506–CDK4/6–FOXM1 axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent. Copyright

Augmentation of Response to Chemotherapy by microRNA-506 Through Regulation of RAD51 in Serous Ovarian Cancers

BACKGROUND Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers. METHODS We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided. RESULTS MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8-12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P < .001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P = .045, respectively), thus recapitulating the clinical observation. CONCLUSIONS MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy.

miR-101 suppresses the epithelial-to-mesenchymal transition by targeting ZEB1 and ZEB2 in ovarian carcinoma

Ovarian carcinoma is the most lethal gynecologic malignancy; the majority of patients succumb to the disease within 5 years of diagnosis. The poor survival rate is attributed to diagnosis at advanced stage, when the tumor has metastasized. The epithelial-to-mesenchymal transition (EMT) is a necessary step toward metastatic tumor progression. Through integrated computational analysis, we recently identified a master microRNA (miRNA) network that includes miR-101 and regulates EMT in ovarian carcinoma. In the present study, we characterized the functions of miR-101. Using reporter gene assays, we demonstrated that miR-101 suppressed the expression of the E-cadherin repressors ZEB1 and ZEB2 by directly targeting the 3′-untranslated region (3′UTR) of both ZEB1 and ZEB2. Introduction of miR-101 significantly inhibited EMT and cell migration and invasion. Introducing cDNAs of ZEB1 and ZEB2 without 3′UTR abrogated miR-101-induced EMT alteration, respectively. Our findings showed that miR-101 represents a redundant mechanism for the miR-200 family that regulates EMT through two major E-cadherin transcriptional repressors.

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.