Fibroblast growth factor 9 (FGF9) is a member of secreted polypeptide families and involved in many important biological processes, including implantation and morphogenesis during embryogenesis and adult life. Recently, Fgf9-knockout mice exhibited male-to-female sex reversal, demonstrating a novel function for FGF9 in testicular development. We hypothesized that FGF9 is involved in sex development at an early embryonic stage in humans. In this study, we systematically screened sequences of the FGF9 gene in 21 XY females and 72 XX females and XY males to examine whether sequence variants of the FGF9 gene play a pathophysiological role on human gonadal dysgenesis. No mutation was identified, but a single nucleotide variant and two microsatellites were found. The allelic distribution of polymorphic microsatellite in the 3'-UTR of FGF9 between patients and controls was slightly different with Bonferroni correction (P = 0.06). We further applied reporter gene system and quantitative RT-PCR to study the function of this microsatellite motif and results demonstrated that the (TG) n motif modulated gene expression at both preand post-transcriptional levels. The (TG) 14 allele, which showed a potential association with male-to-female sex reversal (odds ratio = 6.08, 95% confidence interval = 1.39-26.63), displayed the strongest promoter activity and longest mRNA stability. These data demonstrated that 3'-UTR microsatellite of the FGF9 is a functional polymorphism that plays dual roles in regulating FGF9 expression. Although our preliminary result suggested a possible association between FGF9 and human gonadal dysgenesis, the major limitation of small dataset in this study points out the requirement for further investigation.

Fibroblast growth factor 9 (FGF9) is an autocrine/paracrine growth factor that plays vital roles in many physiologic processes including embryonic development. Aberrant expression of FGF9 causes human diseases and thus it highlights the importance of controlling FGF9 expression; however, the mechanism responsible for regulation of FGF9 expression is largely unknown. Here, we show the crucial role of an AU-rich element (ARE) in FGF9 3′-untranslated region (UTR) on controlling FGF9 expression. Our data demonstrated that AUF1 binds to this ARE to regulate FGF9 mRNA stability. Overexpression of each isoform of AUF1 (p37, p40, p42 and p45) showed that only the p42 isoform reduced the steady-state FGF9 mRNA. Also, knockdown of p42AUF1 prolonged the half-life of FGF9 mRNA. The induction of FGF9 mRNA in prostaglandin (PG) E2-treated human endometrial stromal cells was accompanied with declined cytoplasmic AUF1. Nevertheless, ablation of AUF1 led to sustained elevation of FGF9 expression in these cells. Our study demonstrated that p42AUF1 regulates both steady-state and PGE2-induced FGF9 mRNA stability through ARE-mediated mRNA degradation. Since almost half of the FGF family members are ARE-containing genes, our findings also suggest that ARE-mediated mRNA decay is a common pathway to control FGFs expression, and it represents a novel RNA regulon to coordinate FGFs homeostasis in various physiological conditions.

Adoptive T-cell therapy involves the ex vivo expansion and subsequent transfusion of tumor-specific T lymphocytes to eliminate tumors. Using immune modulators to block immunosuppressive factors in the tumor microenvironment has emerged as a promising strategy to enhance T-cell-mediated tumor regression. Curcumin, a major component of turmeric, has been shown to possess antitumor and immunomodulatory effects by regulating a diverse range of molecular targets. Thus, we hypothesize that these beneficial effects of curcumin may improve the therapeutic efficacy of adoptive therapy. Here, we have shown that curcumin enhances cytotoxicity of CD8 þ T cells toward tumors via alteration of the tumor microenvironment when combined with adoptive therapy. We found that T-cell accumulation and function were increased in combined treatment due to the blockade of different immunosuppressors, including TGFb, indoleamine 2,3-dioxygenase, and regulatory T cells. Furthermore, bioluminescent imaging with a granzyme B promoter-conjugated optical reporter also reflected improved cytotoxicity of antigen-specific CD8 þ T cells in tumor-bearing mice during treatment. These findings suggest that combination of multitargeting drugs, such as curcumin, with adoptive therapy may have potential for clinical application. In addition, using a granzyme B-specific imaging reporter to assess T-cell function may also be applied for the development and therapeutic evaluation of new immunotherapy in preclinical studies. Cancer Prev Res; 5(3); 444-52. Ó2011 AACR.

Objectives: Women affected by rheumatoid arthritis (RA) have a higher risk of endometriosis, an estrogen-dependent, chronic inflammatory disease. Though acupuncture has long been a safe and effective therapy for treating inflammatory conditions, it is unclear whether it could prevent the onset of endometriosis. This study aims to determine the effect of acupuncture on the subsequent risk of endometriosis in female RA patients.Methods: Between 1998 and 2010, female subjects with RA were recruited from a nationwide database (5,736 patients; age ≥20 years). Enrolled patients included 2,407 acupuncture users and 2,407 nonusers randomly selected using propensity scores. The occurrence of endometriosis was recorded through the end of 2012. Cox proportional hazards regression was used to estimate the adjusted hazard ratio (HR) associated with acupuncture use.Results: During the follow-up period, 35 acupuncture users and 94 non-users developed endometriosis, with incidence rates of 2.36 and 4.91 per 1,000 person-years, respectively. Acupuncture use was associated with a 55% lower endometriosis risk (adjusted HR, 0.45; 95% confidence interval, 0.31–0.65). Those who received high intensity acupuncture (≥15 packages) had the greatest benefit.Conclusions: Findings suggest that adding acupuncture to conventional therapy may decrease the subsequent endometriosis risk in female RA patients. Prospective randomized trials are recommended to further clarify whether the association revealed in this study supports a causal link.