NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition.

Metastasis of tumor cells is a complex challenge and significantly diminishes the overall survival and prognosis of cancer patients. The epithelial-to-mesenchymal transition (EMT) is a well-known mechanism responsible for the invasiveness of tumor cells. A number of molecular pathways can regulate the EMT mechanism in cancer cells and nuclear factor-kappaB (NF-κB) is one of them. The nuclear translocation of NF-κB p65 can induce the transcription of several genes involved in EMT induction. The present review describes NF-κB and EMT interaction in cancer cells and their association in cancer progression. Due to the oncogenic role NF-κB signaling, its activation enhances metastasis of tumor cells via EMT induction. This has been confirmed in various cancers including brain, breast, lung and gastric cancers, among others. The ZEB1/2, transforming growth factor-ß, and Slug as inducers of EMT undergo upregulation by NF-κB to promote metastasis of tumor cells. After EMT induction driven by NF-κB, a significant decrease occurs in E-cadherin levels, while N-cadherin and vimentin levels undergo an increase. The noncoding RNAs can potentially also function as upstream mediators and modulate NF-κB/EMT axis in cancers. Moreover, NF-κB/EMT axis is involved in mediating drug resistance in tumor cells. Thus, suppressing NF-κB/EMT axis can also promote the sensitivity of cancer cells to chemotherapeutic agents.

Micronutrients in Support to The Carbon Cycle Activate Antioxidant Defences and Reduce Sperm DNA Damage in Infertile Men Attending Assisted Reproductive Technology Programs: Clinical Trial Study.

BACKGROUND: Micronutrients in support to the carbon cycle were shown to reduce sperm DNA damage both in animal models and infertile men. Besides supporting DNA methylation, their positive effect may be mediated by an improved performance of the endogenous antioxidant system but this has not yet been proven in clinical settings. The present study aimed at evaluating the effects of micronutrient supplementation in infertile male partners of assisted reproductive technology (ART) resistant couples. MATERIALS AND METHODS: In this experimental clinical trial study, infertile male partners of couples resistant to at least one ART cycle, with a sperm fragmentation rate >20% (TUNEL), underwent a 4-month oral supplementation with micronutrients in support to the carbon cycle including folates, B vitamins, zinc and cysteines. Semen, sperm DNA fragmentation (TUNEL), nuclear maturation (CMA3 and blue aniline staining) and lipid peroxidation (BODIPY) were assessed before and after treatment. The couples were followed-up to record clinical outcomes. RESULTS: Forty-three patients completed the program but full data of pre- and post-treatment were available only for 25 patients. The treatment did not modify sperm concentration or motility but improved morphology. Nuclear maturation, DNA fragmentation and lipid peroxidation significantly improved after the treatment. Overall, 10 clinical pregnancies (23.3%) and 4 live births (9.3%) were recorded during the follow-up following expectant management (25 couples) or a new intracytoplasmic sperm injection (ICSI) cycle (18 couples). CONCLUSION: The micronutrients appeared to induce both DNA methylation, resulting in improved sperm nuclear maturation, and antioxidant defences, resulting in less DNA fragmentation and lipid peroxidation. The clinical outcomes were aligned with a possible positive effect on reproductive function. Micronutrients could be regarded as an alternative to antioxidants in correcting oxidative damage in infertile men; however, to confirm such findings, further clinical investigations are warranted (Registration number: IRCT201510207223N6).

Relationship between Sperm Parameters with Sperm Function Tests in Infertile Men with at Least One Failed Cycle after Intracytoplasmic Sperm Injection Cycle.

BACKGROUND: Imbalance between production of reactive oxygen species (ROS) and total antioxidant capacity in testis, epididymis, and seminal fluid can eventually lead to infertility. Abnormal sperm chromatin packaging, and DNA fragmentation is considered as the main underlying causes of infertility. Therefore, we aimed to assess relationship between sperm parameters with DNA damage, protamine deficiency, persistent histones, and lipid peroxidation in infertile men with at least one failed cycle after intracytoplasmic sperm injection (ICSI). MATERIALS AND METHODS: In this experimental study, semen samples were collected from infertile men with at least one failed cycle after ICSI (n=20). Sperm parameters, DNA damage, protamine deficiency, persistent histones, and lipid peroxidation were assessed using computer-assisted sperm analysis (CASA) system, sperm chromatin structure assay (SCSA) and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, chromomycin A3, aniline blue, and BODIPY C11 staining, respectively. RESULTS: A negative significant correlation was observed between sperm concentration with percentage of sperm persistent histone (r=-0.56, P=0.02), while positive significant correlations were found between percentage of sperm persistent histones with abnormal sperm morphology (r=0.54, P=0.02), CMA3-positive spermatozoa (r=0.6, P=0.008) and intensity of lipid peroxidation (r=0.6, P=0.01). In addition, a significant correlation was observed between sperm DNA damage with intensity and percentage of lipid peroxidation (r=0.62, P=0.009, r=0.77, P=0.007). Correlation between CMA3-positive spermatozoa and intensity of lipid peroxidation (r=0.5, P=0.03) were also significant. CONCLUSION: Observed significant correlations between sperm functional tests in infertile men with at least one failed cycle after ICSI, indicated that the reduction of oxidative stress by antioxidant supplementation may be considered as one therapy approach for improvement of sperm function and increase the chance of successful clinical outcomes in next assisted reproductive cycle.

Correlation between Different Patterns of Hypo-Osmotic Swelling and Sperm Functional Tests.

BACKGROUND: Sperm membrane integrity is not only important as a barrier between intra- and extra-cellular spaces, but also it can be considered as a sign of DNA integrity. Hypoosmotic swelling test reflects membrane integrity and has been used to evaluate sperm quality. Intracytoplasmic sperm injection (ICSI) in adjunct with hypo-osmotic swelling test (HOST) has been used for treatment of males with asthenozoospermia. Therefore, this study aims to evaluate correlation of different pattern of HOST with sperm parameters, protamine deficiency and apoptosis. MATERIALS AND METHODS: In this case-control study, sixteen semen samples were randomly collected from infertile normozospermic men. Semen samples were divided into two portions as follows: one portion was assessed for sperm parameters according toWorld Health Organization (WHO)-2010, while the other portion, after applying HOST procedure, was used for assessment of sperm morphology, protamine deficiency and late or early apoptosis. Statistical analysis was carried out using the Statistical Package for the Social Studies (SPSS 11.5). RESULTS: Our results showed that, the lowest odds ratio (OR) of abnormal sperm head morphology and abnormal acrosome was in d-sperm as compared to a-pattern or nonviable spermatozoa (p=0.00, p=0.01). In addition, a significant correlation was observed between d-sperm with sperm concentration and percentage of DNA damage (p=0.03 and p=0.04, respectively). A significant correlation was observed between percentage of sperm motility and DNA fragmentation (r=-0.56; p=0.01). Furthermore, significant correlations were observed between percentages of early apoptotic sperm with protamine deficiency and sperm concentration (p=0.009 and p=0.01, respectively). CONCLUSION: Significant correlations exist between d-pattern and sperm DNA integrity. Semen samples with low sperm concentration have low percentage of d-sperm which are mature and intact sperms.