miR-181 regulation of BAX controls cisplatin sensitivity of prostate cancer cells.

Prostate cancer is one of the most common male malignancies and remains the second leading cause for cancer-specific mortalities in men. Cisplatin is commonly used as a chemotherapeutic agent against advanced cancers, and is now used in metastatic prostate cancers. Cisplatin exerts its cytotoxic effects by cross-linking genomic DNA (gDNA) which induces DNA damage on rapidly dividing cancer cells. However, cisplatin leads to systemic side effects and some patients never respond. Our previous report demonstrated an oncogenic role of miR-181a in human prostate cancer. In this study, we investigate the mechanistic potential of miR-181a in regulating cisplatin sensitivity in this context. We report that cisplatin treatment significantly enhanced miR-181a expression and that exogenous overexpression of miR-181a decreased sensitivity of prostate cancer cells to cisplatin. Additionally, we observed that cisplatin-resistant prostate cancer cells harbored high levels of miR-181a expression. Mechanistically, we demonstrate the pro-apoptotic protein, BAX, is typically enhanced by cisplatin treatment but its suppression promoted resistance. Here we demonstrate miR-181a regulation of BAX was mediated through a complimentary interaction with the 3'UTR of the BAX transcript. We subsequently show that BAX expression restored cisplatin sensitivity in miR-181a overexpressing prostate cancer cells. In parallel, we demonstrate inhibition of miR-181a restored BAX expression as well as cisplatin sensitivity in resistant cells. This study suggests that miR-181a is a potential therapeutic target for prostate cancers that are resistant to cisplatin.

Farnesoid X receptor inhibits LNcaP cell proliferation via the upregulation of PTEN.

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. In the present study, the activation of the farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, was demonstrated to inhibit cell proliferation in LNcaP cells. Using clinical samples, mRNA and protein levels of FXR were found to be significantly decreased by quantitative PCR and western blot analysis in prostate cancer tissues. In vitro studies identified further that activation or overexpression of FXR suppressed prostate cancer cell proliferation as measured by BrdU incorporation assays. At the molecular level, the results further revealed that the expression of the tumor suppressor gene, PTEN, was upregulated by FXR activation. Therefore, the observations indicated that FXR functions as a tumor suppressor in prostate cancer, which may provide a novel method for molecular targeting cancer treatment.

microRNA-181 promotes prostate cancer cell proliferation by regulating DAX-1 expression.

microRNAs (miRNAs) are a class of short noncoding RNA molecules that have a critical role in the initiation and progression of types of human cancer, including prostate cancer. In the present study, the expression of miR-181 in prostate cancer tissues was evaluated and was demonstrated to be significantly upregulated in prostate cancer tissues compared with that in adjacent normal tissues. The results of in vitro MTT and BrdU incorporation assays, as well as cell-cycle analysis, indicated that miR-181 overexpression markedly promoted the proliferation of LNCaP cells. Furthermore, miR-181 overexpression was found to promote the progression of LNCaP tumor growth in nude mice. Mechanistic studies demonstrated that dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1), a negative regulator of androgen receptor in prostate cancer, was inhibited by miR-181 overexpression. Therefore, the results from the present study suggest that miR-181 functions as a growth-suppressive miRNA during prostate cancer development.

Serum major-histocompatibility-complex class I-related chain A antibody detection for the evaluation of graft dysfunction in renal allograft recipients.

BACKGROUND: In addition to the well-known antibodies against human leukocyte antigens (HLA)-induced kidney-graft rejection, polymorphic major-histocompatibility-complex (MHC) class I-related chain A (MICA) antigens can elicit antibodies and have been suggested to play a role in the antibody-mediated allograft rejection (AMR). We carried out a prospective study of MICA antibodies in post-renal transplant patients to determine the association between MICA antibodies, C4d staining, histological features, and graft outcome. METHODS: We tested 52 patients who had biopsy results due to graft dysfunction. The MICA antibodies in concurrent sera were determined by Luminex. All patients were followed up for one year after renal biopsy. The influence of antibody production on the function of graft was analyzed. RESULTS: Antibodies against MICA were positive in 15 out of the 52 patients (28.9%). The presence of MICA antibodies was associated with renal-allograft deterioration. During one-year follow-up, the estimated glomerular filtration rate (eGFR) decreased (24.0 ± 3.4)% among recipients with anti-MICA antibodies. However, among recipients without anti-MICA antibodies, the eGFR has declined only (8.4 ± 3.0)% (P = 0.017). The association between C4d staining, histological features and MICA antibody production was found no significant difference. CONCLUSION: Besides anti-HLA antibodies, the presence of post-transplant MICA antibody is associated with poor graft outcome and increases the risk of graft failure.