ABSTRACT
VIMAS1, a cancerspecific long noncoding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIMAS1 in the proliferation and resistance to antiandrogen therapy of LNCaP and C42 prostate cancer cells remains to be determined. In the current study, gainandloss experiments were used to investigate the effects of VIMAS on the proliferation and antiandrogen therapy of LNCaP and C42 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIMAS1 driving prostate progression. It was demonstrated that VIMAS1 was upregulated in C42 cells, an established castrationresistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormonesensitive prostate cancer cell line. The present study further demonstrated that VIMAS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIMAS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIMAS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C42 cells in vitro and in vivo. Mechanistically, 3hydroxy3methylglutarylCoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIMAS1, and VIMAS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIMAS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNAprotein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIMAS1 overexpression. Overall, the present study determined the roles and mechanism of the VIMAS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIMAS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.
Subject(s)
Drug Resistance, Neoplasm , Prostatic Neoplasms, Castration-Resistant , RNA, Long Noncoding , Humans , Male , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm/genetics , Hydroxymethylglutaryl-CoA Synthase/metabolism , Nitriles/pharmacology , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction , RNA, Long Noncoding/genetics , RNA StabilityABSTRACT
OBJECTIVE: To evaluate the therapeutic effects of Xuanju compound capsule combined with urofollitropin (uFSH) in the treatment of idiopathic oligoasthenozoospermia. METHODS: From June 2022 to June 2023, patients with idiopathic oligoastheospermia were enrolled in this study, and divided into trail group (Xuanju compound capsule combined with urofollitropin tablets, n=53) and control group (urofollitropin tablets, n=61) according to the difference in treatment. Treatment methods: Xuanju compound capsule, 3 pills, three times a day; Urofollitropin, 75IU, one times three day. The curses of treatments for control group and trail group is 12 weeks. In order to evaluate the therapeutic effects of control group and trial group, semen volume, sperm concentration, progressive sperm ratio (PR), peripheral serum sex hormone, liver functions were analyzed before and after treatment for two times. RESULTS: Compared with the baseline, the semen volume and liver function were not significantly changed after the treatment in control group and trial group. However, sperm concentration, PR, testosterone (T) levels, follicle stimulating hormone (FSH) levels, and luteinizing hormone (LH) levels were significantly unregulated after the treatment in control group and trial group. More importantly, compared to control group, sperm concentration, PR, T leves, FSH levels, LH levels, and T/E2 ratio of trial group were further enhanced after the treatment, which were statistically significant (P < 0.05). CONCLUSIONS: Xuanju compound capsule combined with urofollitropin tablets could significantly improve the semen quality, up-regulate the testosterone levels and T/E2 ratio in patients with idiopathic oligoasthenozoospermia.
Subject(s)
Urofollitropin , Humans , Male , Follicle Stimulating Hormone , Semen , Semen Analysis , Sperm Count , Testosterone , Treatment Outcome , Urofollitropin/therapeutic useABSTRACT
Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro. Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo. Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antigens, Surface/immunology , Carrier Proteins/antagonists & inhibitors , Glutamate Carboxypeptidase II/immunology , Molecular Targeted Therapy/methods , Prostatic Neoplasms, Castration-Resistant/drug therapy , RNA, Small Interfering/administration & dosage , Animals , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Male , Mice, Nude , Models, Theoretical , Therapeutic Uses , Tumor Stem Cell Assay , Xenograft Model Antitumor AssaysABSTRACT
It is widely acknowledged that interleukin 17-producing T helper (Th17) cells are critically participant in the pathogenesis of multiple sclerosis. In the current study, we identified that the expression of CD4+T cells specific co-inhibitory molecule B7-homologue 1(B7-H1) in spleenocytes and mononuclear cells isolated from brains and spinal cord were positive correlated with Th1 and Th17 cells generation and disease severity in experimental autoimmune encephalomyelitis (EAE). Furthermore, B7-H1 transgenic mice developed milder EAE symptoms and fewer Th17 cells than B7-H1 wild type mice. We also found the proliferation of naïve CD4+CD62+T cells isolated from B7-H1 transgenic mice was inhibited. And naïve T cells isolated from B7-H1 transgenic mice produced fewer Th17 cells than WT mice in Th17-polarizing conditions, but the Th1, Th2, and inducible Treg differentiation were the similar in naïve T cells isolated from B7-H1 transgenic mice and WT mice. In conclusion, our study show CD4+T cells specific B7-H1 is a slective inhibitor in proliferation of naïve T cells, Th17 differentiation and pathogenesis of multiple sclerosis.
ABSTRACT
In order to determine the diagnostic and prognostic value of miR-26a in Cholangiocarcinoma (CCA), we compared miR-26a levels in serum from 66 CCA patients and 66 healthy controls, which was followed by serum analysis between the pre-operative serum and post-operative serum of these CCA patients. We found the concentration levels of miR-26a in serum of CCA patients were significantly higher than that from healthy controls (P < 0.01). Furthermore, the concentration levels of miR-26a in the post-operative serum were significantly reduced when compared to the pre-operative serum (P < 0.001). High miR-26a in serum was correlated significantly with clinical stage, distant metastasis, differentiation status, and poor survival of CCA patients. More importantly, serum miR-26a was an independent prognostic marker for CCA. In conclusion, our results suggested that miR-26a in serum might be a potential and useful noninvasive biomarker for the early detection of CCA.
Subject(s)
Bile Duct Neoplasms/genetics , Biomarkers, Tumor/genetics , Cholangiocarcinoma/genetics , MicroRNAs/genetics , Bile Duct Neoplasms/blood , Bile Duct Neoplasms/diagnosis , Biomarkers, Tumor/blood , Case-Control Studies , Cell Line, Tumor , Cholangiocarcinoma/blood , Cholangiocarcinoma/diagnosis , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Humans , Male , MicroRNAs/blood , Middle Aged , Multivariate Analysis , Neoplasm Metastasis , Neoplasm Staging , Postoperative Period , Preoperative Period , Prognosis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Trastuzumab resistance is leading cause of mortality in HER2-positive breast cancers, and the role of TGF-ß-induced epithelial-mesenchymal transition (EMT) in trastuzumab resistance is well established, but the involvement of lncRNAs in trastuzumab resistance is still unknown. Here, we generated trastuzumab-resistant breast cancer cells with increased invasiveness compared with parental cells, and observed robust epithelial-mesenchymal transition (EMT) and consistently elevated TGF-ß signaling in these cells. We identified long noncoding RNA activated by TGF-ß (lnc-ATB) was the most remarkably upregulated lncRNA in TR SKBR-3 cells and the tissues of TR breast cancer patients. We found that lnc-ATB could promote trastuzumab resistance and invasion-metastasis cascade in breast cancer by competitively biding miR-200c, up-regulating ZEB1 and ZNF-217, and then inducing EMT. In addition, we also found that the high level of lnc-ATB was correlated with trastuzumab resistance of breast cancer patients. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-ß signaling, could predispose breast cancer patients to EMT and trastuzumab resistance.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Movement/drug effects , Drug Resistance, Neoplasm , RNA, Long Noncoding/metabolism , Trastuzumab/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Epithelial-Mesenchymal Transition/drug effects , Female , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Invasiveness , Phenotype , RNA Interference , RNA, Long Noncoding/genetics , Signal Transduction , Time Factors , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection , Transforming Growth Factor beta/metabolism , Up-Regulation , Zinc Finger E-box-Binding Homeobox 1ABSTRACT
HLA-G and HLA-E are non-classical HLA Ib molecules. Recently, increasingly more reports have shown that HLA-G is highly expressed in different malignancies. In this article, we detected the expression levels of HLA-G and HLA-E in primary colorectal cancer patients. Our results showed that 70.6% and 65.7% of the colorectal cancer tissues had positive HLA-G or HLA-E expression, respectively, and that 46.1% positively expressed both molecules. We also analyzed the correlations between the expression levels of HLA-G, HLA-E or both combined and the clinical outcomes of the patients. Kaplan-Meier analysis results showed that the expression levels of HLA-G or HLA-E alone and the combined expression of both molecules were all statistically correlated with the overall survival of colorectal cancer patients. Cox multivariate analysis showed that only HLA-G expression can serve as independent factor for OS. Our results also showed that the expression of HLA-E was significantly correlated with tumor metastasis.
Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , HLA-G Antigens/genetics , Histocompatibility Antigens Class I/genetics , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Biomarkers, Tumor/immunology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Gene Expression , HLA-G Antigens/immunology , Histocompatibility Antigens Class I/immunology , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Predictive Value of Tests , Prognosis , Survival Analysis , HLA-E AntigensABSTRACT
BACKGROUND AND OBJECTIVE: The investigation concerning the B7-H1 expression in colorectal cancer cells is at an early stage. It is unclear whether B7-H1 expression may have diagnostic or prognostic value in colorectal carcinoma. Additionally, how B7-H1 is associated with the clinical features of colorectal carcinoma is not known. In order to investigate the relationship between B7-H1 and colorectal cancer, we analyzed B7-H1 expression and its effect in clinical specimens and HCT116 cells. METHODS: Paraffin-embedded specimens from 143 eligible patients were used to investigate the expression of CD274 by immunohistochemistry. We also examined whether B7-H1 itself may be related to cell proliferation, apoptosis, migration and invasion in colon cancer HCT116 cells. RESULTS: Our results show that B7-H1 was highly expressed in colorectal carcinoma and was significantly associated with cell differentiation status and TNM (Tumor Node Metastasis) stage. Patients with positive B7-H1 expression showed a trend of shorter survival time. Using multivariate analysis, we demonstrate that positive B7-H1 expression is an independent predictor of colorectal carcinoma prognosis. Our results indicate that B7-H1 silencing with siRNA inhibits cell proliferation, migration and invasion. Furthermore, cell apoptosis was also increased by B7-H1 inhibition. CONCLUSIONS: Positive B7-H1 expression is an independent predictor for colorectal carcinoma prognosis. Moreover, knockdown of B7-H1 can inhibit cell proliferation, migration and invasion.