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Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Emerging evidence has revealed the vital functions of microRNAs (miRNAs) in cancer malignant progressions. miR-375 has been verified to serve as an antioncogene in tumorigenesis and a potential therapeutic target in various types of cancer. In this study, we aimed to determine the role of miR-375 in the regulation of chemoresistance and metastasis of HCC. Differentially expressed miR-375 and NCAPG2 were externally validated using expression data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-375 in HCC tissues and cell lines. miR-375 mimics and NCAPG2-overexpression were transfected into HepG2 and Huh7 cells to establish miR-375 overexpression models. Cell Counting Kit-8, Transwell, and flow cytometry experiments were conducted to monitor cell proliferation, migration, and apoptosis. The targeting relationship between miR-375 and non-SMC condensin II complex subunit G 2 (NCAPG2) was determined by qRT-PCR, western blot, and luciferase reporter gene assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using Gene Set Enrichment Analysis (GSEA). The pathway enrichment analysis was used to predict the potential pathways for further study. miR-375 was significantly downregulated in HCC tissues and cells compared to adjacent tissue and normal hepatocyte cell line respectively while NCAPG2 was upregulated. The targeting relationship was verified by luciferase reporting assay, and miR-375 could target the 3'UTR of NCAPG2 mRNA and effectively suppress NCAPG2 protein expression. Replenishing of miR-375 significantly repressed HCC cell proliferation and migration, and induced cell apoptosis. Overexpression of NCAPG2 recovered those biological abilities in miR-375 overexpressed cells. Collective data suggested that miR-375 served as a tumor suppressor via regulating NCAPG2. Replenishing of miR-375 or knockout of NCAPG2 could be therapeutically exploited for HCC.

BACKGROUND: Liver function is a key determinant for the survival of hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE). However, establishing robust prognostic indicators for liver insufficiencies and patient survival remains an unmet demand. This retrospective study evaluated the prognostic value of splenic volume (SV) in HCC patients undergoing TACE. METHODS: A total of 67 HCC patients who underwent at least two consecutive TACE procedures were retrospectively included in this study. Comprehensive clinical information and follow-up data were collected, and the SV was measured based on dynamic contrast enhanced images. Risk factors of SV enlargement were assessed. The prognostic value of SV on survival was analyzed and compared with Child-Pugh (CP) classification and albumin-bilirubin (ALBI) grade. RESULTS: The baseline SV was 299.74±143.63 cm(3), and showed a moderate and statistically significant correlation with CP classification (R=0.31, P

Nasopharyngeal carcinoma (NPC) is the most common primary malignancy that originates from the nasopharynx. Some regulatory networks involved in nasopharyngeal carcinoma have been reported, but the relevant genes have not been fully identified. We have used mRNA microarray to identify differential expression genes between NPC tissues and adjacent normal tissues. Then high-content shRNA screening was carried out to screen the genes that may control proliferation in nasopharyngeal carcinoma. Cell proliferation was monitored by MTT assays and Celigo image cytometry in vitro and subcutaneous transplantation model in vivo. Flow cytometric analysis was carried out to detect the distribution of cell cycle stages and apoptosis. Transwell assay was performed to measure the migratory and invasive capacities of NPC cells. We identified 20 genes that potentially play an important role in the proliferation of nasopharyngeal carcinoma by mRNA microarray and functional analysis. The result of high-content shRNA screening indicated that STIL had the greatest effect on reducing the proliferation rate of NPC cells. The analysis of The Cancer Genome Atlas (TCGA) data showed that STIL was upregulated in several human cancer tissues, and higher STIL expression level was correlated with shorter survival time. STIL knockdown also inhibited NPC cell migration and invasion, promoted G1/S phase transition and apoptosis. Three genes including ITGA2, SMAD2, JAK1, associated with molecular mechanisms of cancer were influenced by downregulating STIL. Our study confirmed STIL as a key regulator that promotes the proliferation of NPC, providing insight into the molecular mechanisms of nasopharyngeal carcinoma and suggesting a novel therapeutic strategy.

This report describes a Phase II, multicenter, contraceptive efficacy clinical trial using monthly injections of testosterone undecanoate (TU) alone at a dose of 500 mg in healthy Chinese men. Three hundred eight healthy men were recruited in six centers distributed throughout China. Volunteers underwent a control period with no treatment, then a 12-month treatment period including a 6-month suppression phase followed by a 6-month efficacy phase and a 12-month recovery period. During the suppression phase, an initial loading dose of 1000 mg TU, followed by 500 TU at monthly intervals were given until azoospermia or severe oligozoospermia was achieved, up to a maximum of six injections. During the efficacy phase, 500 mg TU were administered at monthly intervals for 6 months. Nine of 308 men did not achieve azoospermia or severe oligozoospermia (3 x 10(6)/ml) within the 6-month suppression phase. This gave a methodological failure rate of 2.9/100 couple years (95% confidence interval of 1.0-4.8/100 couple years). Two hundred ninety-six men entered the efficacy phase. The continuation rate during the efficacy phase was 95/100 couple years. There were no pregnancies caused by men who achieved azoospermia or severe oligozoospermia. Reappearance of sperm occurred in six men during the efficacy phase, and one pregnancy was attributed to sperm rebound. This gave a secondary failure rate of 2.3/100 couple years (95% confidence interval of 0.5-4.2/100 couple years). Thus, the total failure rate was 5.2%, and total efficacy was 94.8%. Spermatogenesis in all subjects returned to the normal reference range within the recovery period. The mean serum testosterone concentration increased 131%, and the mean serum LH and FSH concentrations decreased 72% and 70%, respectively, after TU injections during the treatment period. The mean level of serum high density lipoprotein cholesterol decreased (14%), and the mean hematocrit increased 6% compared with baseline. No serious adverse events and no significant changes in serum chemistry occurred during the study. The results showed that monthly TU injection at a dose of 500 mg after an initial loading dose of 1000 mg can effectively, safely, and reversibly suppress spermatogenesis in healthy Chinese men without serious adverse effects.

This is a pilot dose-finding study of spermatogenic suppression using testosterone undecanoate (TU) injections alone in normal Chinese men. Thirty-two healthy men were recruited. Volunteers underwent pretreatment evaluation, then a treatment period in which group I (n = 13) received 500 mg TU, group II (n = 12) received 1000 mg TU, and group III (n = 7) received placebo, respectively, at monthly intervals during the treatment period (or until azoospermia was achieved). Thereafter, they underwent a recovery period until all parameters returned to pretreatment levels. Eleven of 12 volunteers in the 500-mg TU group, and all volunteers in the 1000-mg TU group became azoospermic. Faster suppression of spermatogenesis was achieved in the 1000-mg TU group. Serum testosterone increased significantly in the higher dose group at weeks 8 and 12, but remained within the normal range. Mean serum LH and FSH were profoundly suppressed by both doses to undetectable levels at week 16. TU injections did not cause a significant change in high density lipoprotein cholesterol levels. No serious side-effects were found. We conclude that both dosages of TU can effectively, safely, and reversibly suppress spermatogenesis in normal Chinese men.

To analyze the changes of seminal parameters in Chinese fertile men during the past 25 years.We collected semen samples from 5,834 fertile men in 14 different provinces (including Beijing) between 1980 and 2005 and retrospectively studied their seminal parameters, abstinence durations and total testis volumes by meta-analysis.Compared with the first 15 years, a significant decrease was observed in both sperm density and total number of sperm per ejaculate in the semen samples collected between 1996-2000 (P0.0001 and P0.05), but not obvious in those between 1996-2000 and after 2005 (P0.05). As for sperm motility, no time-related changes were noted (P0.05) except a reduction with the increase of age.There was a decline in sperm density and total number of sperm per ejaculate in Chinese fertile men over the past 25 years, although not significant in the latter 10 years since 1996, but with no time-related changes in sperm motility.

To observe the change of erythropoietin (EPO) in patients of hypogonadism who received androgen replacement treatment and explore the mechanism of androgen-induced increase of red blood cells and haemoglobin.Eight patients with Klinefelter's syndrome, divided into two groups, received TU intramuscular injections of 500 mg or 1000 mg dose, respectively. After three months, seven patients received the second injection of crossover dose. Testosterone levels in serum were measured with RIA before and after the injections treatment. RBC count, impacted volume of blood cells and haemoglobin concentration were measured before treatment and 4, 8 weeks after treatment. At the same interval, EPO levels were measured with ELISA method.Development of the secondary sex characters was improved in all patients after the TU injection. Serum testosterone levels raised significantly and reached the peak one week after the injections. Effective level of testosterone lasted for over 6 weeks. RBC count, impacted volume of blood cells and haemoglobin increased at different degrees after TU injections, but these changes were not significant in statistic(P0.05). The increased levels remained for 8 weeks. EPO levels were elevated significantly (P0.01 or 0.05) after the TU injection(Pbat0.05). The second injection could still make the EPO level go up.Androgen replacement treatment can increase the EPO levels in patients of hypogonadism, which is one of the mechanism of RBC production increase.

Two types of plasminogen activators (PA), tissue type (tPA) and urokinase type (uPA), were identified in the seminal plasma of both the human and the rhesus monkey. We studied the possible relationship between PA activities in the seminal plasma and the sperm counts and motility and demonstrated that: (i) PA activity in human seminal plasma from infertile patients was associated with immotile spermatozoa; (ii) the treatment of fertile men with testosterone enanthate (TE) to induce azoospermia was accompanied by an increase in seminal PA activity; (iii) when monomer T4 (isolated from multiglycosides of Tripterygium wilforddi) was administered to fertile male rhesus monkeys to induce azoospermia, PA activities in seminal plasma increased considerably; and (iv) immunocytochemistry studies showed that both uPA and PAI-1 antigens were localized on the surface of human spermatozoa, indicating that human spermatozoa were capable of binding uPA and PAI-1 through their receptors or forming a complex. These data demonstrate that seminal PA activity may be related to azoospermia, and possibly, to the fertilizing capability of spermatozoa in primates.

Clinically apparent prostate cancer occurs more commonly among Caucasians living in Western countries than in Chinese in the Far East. Prior studies demonstrated diminished facial and body hair and lower levels of plasma 3 alpha-androstanediol glucuronide and androsterone glucuronide in Chinese than in Caucasian men. Based upon these findings, investigators postulated that Chinese men could have diminished 5 alpha-reductase activity with a resultant decrease in prostate tissue dihydrotestosterone levels and clinically apparent prostate cancer. An alternative hypothesis suggests that decreased 3 alpha-androstanediol glucuronide and androsterone glucuronide levels might reflect reduced production of androgenic ketosteroid precursors as a result of genetic or environmental factors. The present study examined 5 alpha-reductase activity, androgenic ketosteroid precursors, and the influence of genetic and environmental/dietary factors in groups of Chinese and Caucasian men. We found no significant differences in the ratios of 5 beta-:5 alpha-reduced urinary steroids (a marker of 5 alpha-reductase activity) between Chinese subjects living in Beijing, China, and Caucasians living in Pennsylvania. To enhance the sensitivity of detection, we used an isotopic kinetic method to directly measure 5 alpha-reductase activity and found no difference in testosterone to dihydrotestosterone conversion ratios between groups. Then, addressing the alternative hypothesis, we found that the Caucasian subjects excreted significantly higher levels of individual and total androgenic ketosteroids than did their Chinese counterparts. To distinguish genetic from environmental/dietary factors as a cause of these differences, we compared Chinese men living in Pennsylvania and a similar group living in Beijing, China. We detected a reduction in testosterone production rates and total plasma testosterone and sex hormone-binding levels, but not in testosterone MCRs in Beijing Chinese as a opposed to those living in Pennsylvania. Comparing Pennsylvania Chinese with their Caucasian counterparts, we detected no significant differences in total testosterone, free and weakly bound testosterone, sex hormone-binding globulin levels, and testosterone production rates. Taken together, these studies suggest that environmental/dietary, but not genetic, factors influence androgen production and explain the differences between Caucasian and Chinese men.