Effect of AR antagonist combined with PARP1 inhibitor on sporadic triple-negative breast cancer bearing AR expression and methylation-mediated BRCA1 dysfunction.

Triple-negative breast cancer (TNBC) patients usually present worse clinical outcomes due to their high heterogeneity. The purpose of our study is to investigate the prognostic role of AR and BRCA1 expression in sporadic TNBC patients, and effect of AR blockade and PARP1 inhibitor for TNBC patients who characterized by positive-AR expression and BRCA1 inactivation or dysfunction. In our present study, we found that AR is expressed in 43.6% and 34.0% of TNBC tissues, when 1% or 10% staining was used as the threshold for AR positivity, respectively. When 1% staining was used as the threshold, AR expression indicates a poor disease-free survival (DFS) of TNBC patients. TNBC patients with negative BRCA1 show a poor DFS, and BRCA1 suppression is associated with the methylation status of its promoter. Interestingly, BRCA1-/AR + TNBC patients have shorter DFS than other TNBC patients regardless of the threshold for AR positivity. AR antagonists MDV3100 enhances the PARP1 inhibitor Olaparib-mediated decrease of cell viability in AR-positive/BRCA1-inactivated cells in vitro and in vivo. Our results suggested that combination of AR blockade and PARP1 inhibitor may be a potential strategy for sporadic TNBC patients who characterized by positive-AR expression and BRCA1 inactivation or dysfunction.

Tumor suppressive miR-6775-3p inhibits ESCC progression through forming a positive feedback loop with p53 via MAGE-A family proteins.

Accumulating evidences indicate that microRNAs (miRNAs) play vital roles in multiple diseases, including cancer. In the present study, we showed that miR-6775-3p plays a tumor suppressive role in esophageal squamous cell carcinoma (ESCC). High expression miR-6775-3p is associated with good clinical outcomes of ESCC patients. Over-expression of miR-6775-3p inhibited tumor growth and liver metastasis of ESCC xenograft tumors. Enforced expression of miR-6775-3p inhibited ESCC cell proliferation, migration, and invasion. KEGG pathway analysis revealed that miR-6775-3p was associated with the genes on "pathway in cancer". Mechanically, miR-6775-3p inhibited the expression of tumor antigens MAGE-A family through direct binding the 3'UTR region of MAGE-A mRNAs, and attenuated MAGE-A-inhibited transcriptional activity of tumor suppressor p53. In addition, miR-6775-3p also directly inhibits its host gene SLC7A5 which has been reported to play oncogenic roles in cancer progression. Interestingly, miR-6775-3p and its host gene SLC7A5 were directly transcriptionally induced by p53. Thus, for the first time, our study proposed a novel positive feedback regulation between miR-6775-3p and p53 via MAGE-A family, which plays crucial role in ESCC progression.

Epigenetic regulation of MAGE family in human cancer progression-DNA methylation, histone modification, and non-coding RNAs.

The melanoma antigen gene (MAGE) proteins are a group of highly conserved family members that contain a common MAGE homology domain. Type I MAGEs are relevant cancer-testis antigens (CTAs), and originally considered as attractive targets for cancer immunotherapy due to their typically high expression in tumor tissues but restricted expression in normal adult tissues. Here, we reviewed the recent discoveries and ideas that illustrate the biological functions of MAGE family in cancer progression. Furthermore, we also highlighted the current understanding of the epigenetic mechanism of MAGE family expression in human cancers.

Circular RNA ciRS-7 Maintains Metastatic Phenotypes as a ceRNA of miR-1299 to Target MMPs.

Circular RNA ciRS-7 has been reported to act as a competing endogenous RNA (ceRNA) of the miRNA miR-7, resulting in reduced miR-7 activity and increased miR-7-targeted transcripts. However, it is unknown if ciRS-7 harbors other miRNAs with regulatory roles in triple-negative breast cancer (TNBC). The present study determined that the expression of ciRS-7 in TNBC clinical specimens and representative cells is significantly higher than other breast cancer subtypes. Functionally, downregulation of ciRS-7 inhibited cell migration and invasion of TNBC cells. Knockdown of ciRS-7 expression also inhibited the liver and lung metastasis of TNBC cells in vivo Mechanistic studies revealed that ciRS-7 contains 20 miR-1299-binding sites and functions as a ceRNA of miR-1299 in TNBC cells. High expression of ciRS-7 maintains the high migration and invasion properties of TNBC cells by acting as a ceRNA of miR-1299 to enhance the expression of matrix metalloproteinases family members (MMP).Implications: Circular RNA ciRS-7 is highly expressed in TNBC tumor specimens and cells, and its downregulation inhibits cell migration and invasion of TNBC cells in vitro and in vivo In addition, ciRS-7 functions as a ceRNA of miR-1299 to enhance the expression of MMPs, which maintains the high migration and invasion properties of TNBC cells. Mol Cancer Res; 16(11); 1665-75. ©2018 AACR.

Circular RNA ciRS-7 accelerates ESCC progression through acting as a miR-876-5p sponge to enhance MAGE-A family expression.

As the most well-known circular RNA, ciRS-7 (also termed CDR1as) has been reported to act as a miR-7 sponge, resulting in reduced miR-7 activity and increased miR-7-targeted transcripts. Here, we showed that ciRS-7 is up-regulated in esophageal squamous cell carcinoma (ESCC), and is associated with the poor clinicopathological parameters of ESCC patients. Moreover, over-expression of ciRS-7 increased the proliferation, migration and invasion of ESCC cells. Mechanistic studies revealed that ciRS-7 contains nineteen miR-876-5p binding sites and acts as a miR-876-5p sponge. Over-expression of ciRS-7 resulted in the reduced tumor-repressive function of miR-876-5p on its downstream target MAGE-A family. In animal experiments, enforced ciRS-7 increased ESCC tumor growth and metastasis through targeting miR-876-5p/MAGE-A family axis. Collectively, our study provided novel evidence that ciRS-7 accelerates ESCC progression by acting as a miR-876-5p sponge to enhance MAGE-A family expression.

MAGE-A family is involved in gastric cancer progression and indicates poor prognosis of gastric cancer patients.

BACKGROUND: As the best characterized CTA family members, melanoma-associated antigens (MAGE) have been reported to express in various malignant tumors. However, the expression pattern of MAGE-A family in gastric cancer (GC) specimens and their prognostic and therapeutic significance for GC patients is still unclear. MATERIALS AND METHODS: Tissue microarray - based immunohistochemistry analysis was used to examine the expression of MAGE-A family members (including MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12) in 86 cases of GC specimens, 20 cases of the corresponding adjacent normal gastric specimens, and 9 cases of intraepithelial neoplasia specimens. The association between MAGE-A expression and the clinicopathological parameters as well as the 5-year overall survival of GC patients was analyzed. RESULTS: 54.7% of GC specimens showed positive MAGE-A expression. In the adjacent normal gastric specimens, MAGE-A was not expressed in the normal surface mucous cells, but expressed in some normal fundic glands. In addition, MAGE-A expression was also detected in intraepithelial neoplasia specimens. In GC specimens, MAGE-A expression was associated with lymph node metastasis, poor differentiation, and high clinical TNM stage. MAGE-A expression was also correlated with the poor 5-year overall survival of GC patients. However, MAGE-A expression is not an independent prognostic factor for GC patients. CONCLUSIONS: MAGE-A family may be involved in the gastric cancer progression, and their expression could be considered to improve the prognostic evaluation for GC patients.

MAGE-A family serves as poor prognostic markers and potential therapeutic targets for epithelial ovarian cancer patients: a retrospective clinical study.

OBJECTIVE: The aim of our study is to investigate the expression pattern and prognostic significance of melanoma-associated antigens-A (MAGE-A) family in primary epithelial ovarian cancer (EOC) patients. STUDY DESIGN: The expression of MAGE-A family members, including MAGE-A1, -A2, -A3, -A4, -A6, -A10 and -A12 was immunohistochemically detected in 82 cases of primary EOC and 10 cases of pericarcinoma ovarian tissues. The association between MAGE-A family expression and the clinicopathological parameters as well as the prognosis of primary EOC patients was analyzed. RESULTS: MAGE-A family expressed in 48.8% of primary EOC tissues, but not expressed in pericarcinoma ovarian tissues. MAGE-A expression was associated with the pathological types, FIGO stage, and pre-operative serum CA125 level. Overall survival of EOC patients with positive MAGE-A family expression was significantly shorter than those patients with negative MAGE-A expression. Multivariate analysis showed that although MAGE-A family expression can affect the overall survival, it was not an independent prognostic marker for EOC patients. CONCLUSIONS: Molecular assessment of MAGE-A family members could be helpful to improve the prognostic evaluation and to provide a new potential therapeutic target for primary EOC patients.

MAGE-A family expression is correlated with poor survival of patients with lung adenocarcinoma: a retrospective clinical study based on tissue microarray.

OBJECTIVES: As the best characterised cancer/testis antigen family members, melanoma-associated antigens (MAGE) have been reported to be expressed in various malignant tumours. However, the expression pattern of MAGE-A family in lung adenocarcinoma (LAC) specimens and their prognostic and therapeutic significance for patients with LAC is still unclear. MATERIALS AND METHODS: Tissue microarray-based immunohistochemistry analysis was used to examine the expression of MAGE-A family members (including MAGE-A1, A2, A3, A4, A6, A10, A11 and A12) in 105 paired LAC specimens and the corresponding pericarcinoma specimens. The association between MAGE-A expression and the clinicopathological parameters, and the 10-year overall survival of patients with LAC were analysed. In addition, the association between MAGE-A expression and the epithelial growth factor receptor (EGFR) amplification and ALK-EML4 rearrangements of patients with LAC were also analysed. RESULTS: The immunohistochemical evaluation revealed that MAGE-A family was expressed in 46.66% of LAC specimens, but not in the corresponding pericarcinoma specimens. MAGE-A expression was not associated with the clinicopathological factors but with worse 10-year survival, and was a poor prognostic marker for patients with LAC. MAGE-A expression was not correlated with EGFR amplification and ALK rearrangements. Interestingly, MAGE-A expression can affect the overall survival of patients with LAC without EGFR amplification or ALK rearrangements, but not affect the overall survival of patients with LAC and EGFR amplification or ALK rearrangements. CONCLUSIONS: Molecular assessment of MAGE-A family members could be considered to improve the prognostic evaluation and to provide a new potential therapeutic strategy for patients with LAC.

Prognostic Significance of MAGE-A11 in Esophageal Squamous Cell Carcinoma and Identification of Related Genes Based on DNA Microarray.

BACKGROUND AND AIMS: This study aims to investigate the expression pattern of melanoma-associated antigen-A11 (MAGE-A11) in esophageal squamous cell carcinoma (ESCC) specimens and analyze its prognostic significance for ESCC patients. In addition, the purpose of our study was also to explore the biological function of MAGE-A11 in ESCC cells based on DNA microarray. METHODS: Immunohistochemistry was used to detect the expression of MAGE-A11 in ESCC specimens, and its prognostic significance was analyzed by statistical analysis. DNA microarray and quantitative RT-PCR were used to explore the different expression of MAGE-A11 downstream genes in ESCC cells. Cell invasion assay and MTT assay were used to detect the effect of MAGE-A11 cDNA on the invasion and proliferation of ESCC cells. RESULTS: Of the ESCC specimens, 59.3% showed positive MAGE-A11 expression. MAGE-A11 expression in ESCC specimens was positively associated with distant lymph node metastasis. Overall survival of ESCC patients with positive MAGE-A11 expression was shorter than in patients with negative MAGE-A11 expression. Multivariate Cox regression analysis showed MAGE-A11 expression is an independent poor prognostic factor for ESCC patients. Overexpression of MAGE-A11 changed a variety of gene expressions, which was associated with various cell functions such as protein ubiquitination, cell proliferation and apoptosis, tumor invasion and metastasis. Overexpression of MAGE-A11 directly increased the invasion and proliferation of ESCC cells. CONCLUSIONS: MAGE-A11 is an independent poor prognostic marker for ESCC patients. MAGE-A11 regulates various cell functions and directly increases the invasion and proliferation of ESCC cells.

Expressions of MAGE-A10 and MAGE-A11 in breast cancers and their prognostic significance: a retrospective clinical study.

PURPOSE: Melanoma-associated antigens-A (MAGE-A) family is a group of well-characterized cancer/testis antigens (CTA), because they are strictly tumor specific and are shared by many kinds of tumors. However, the expression pattern of MAGE-A10 and MAGE-A11 in breast cancer patients is still unclear. The purpose of our study is to investigate the expression pattern and prognostic significance of MAGE-A10 and MAGE-A11 in breast cancer patients. METHODS: Formalin-fixed and paraffin-embedded tissues and the clinicopathological parameters from 75 primary breast cancer patients were collected. The expressions of MAGE-A10 and MAGE-A11 proteins were immunohistochemically detected, and the association of MAGE-A10 and MAGE-A11 expressions with the clinicopathological parameters and the survival of breast cancer patients were analyzed. RESULTS: The expression rates of MAGE-A10 and MAGE-A11 in breast cancer specimens were 73.3 and 52.0%, respectively. MAGE-A11 expression was more frequent in estrogen-receptor (ER)-positive breast carcinomas compared with ER-negative breast carcinomas (P = 0.004). MAGE-A11 expression was positively associated with HER-2 expression (P = 0.003). Overall survival of patients with MAGE-A11-negative expression was significantly longer than those patients with positive MAGE-A11 expression (P = 0.030), but no difference of overall survival was found between patients with MAGE-A10-negative and -positive expression (P = 0.881). CONCLUSIONS: MAGE-A10 and MAGE-A11 are tumor-specific antigens, and MAGE-A11 expression probably is a potential poor prognostic factor for breast cancer patients.

[Effect of microRNA-mediated p65 gene silencing on the proliferation and apoptosis of human breast cancer MDA-MB-231 cells].

OBJECTIVE: To explore the effect of microRNA (miRNA)-mediated p65 gene knockdown on the proliferation and apoptosis of human breast cancer MDA-MB-231 cells. METHODS: p65-targeted miRNA plasmid was constructed and transfected into MDA-MB-231 cells via lipofectamine(TM)2000. The expression of p65 gene in the transfected cells at the mRNA and protein levels were detected by RT-PCR and Western blotting, respectively. The cell proliferation and apoptosis were measured by MTT assay and flow cytometry (FCM), respectively. The expressions of apoptosis-related proteins were detected by Western blotting in the transfected cells. RESULTS: Compared with the negative control group, the expressions of p65 mRNA and protein in p65miRNA-trasnfected cells were significantly down-regulated (P<0.05). MTT assay showed significantly lowered viability of MDA-MB-231 cells after the transfection (P<0.05). FCM showed an increased cell apoptosis rate in p65miRNA group compared with that in the negative control group (P<0.05). Caspase-3 and PARP were both cleaved into their active forms and the expression of these active forms was increased in p65miRNA group. CONCLUSION: The miRNA targeting p65 gene can inhibit the proliferation and induce apoptosis of breast cancer cells, and p65 gene might become a new target in gene therapy for human breast cancer.

MAGE-A family: attractive targets for cancer immunotherapy.

The melonoma-associated antigens family A (MAGE-A) belongs to cancer/testis antigens (CTA) that are expressed in a wide variety of malignant tumors but not in normal adult tissues except for testis. Interestingly, germ cells do not express MHC class I antigen, implying that these gene products should be ideal targets for cancer immunotherapy. The strict tumor-specific expression of MAGE-As has led to several immunotherapeutic trials targeting some of these proteins. In this review, we briefly described the expression and activation mechanism of MAGE-As in cancer. We also summarized the biological functions of MAGE-As in cell progress and the progress of the cancer immunotherapy targeting MAGE-A family.

Melanoma-associated antigen genes - an update.

To date, dozens of melanoma-associated antigens (MAGE) have been identified. Based on the differences in tissue-specific gene expression and gene structure, the MAGE family has been divided into two big subfamilies: MAGE-I and MAGE-II. MAGE-I genes were identified as a group of highly attractive targets for cancer immunotherapy because of their wide expression in a variety of malignant tumors but silent in normal adult cells except germ-line cells lacking human leukocyte antigen (HLA) expression. However, little is known regarding the functions of MAGE family members in cell activities. In this review, we briefly described the classification of MAGE family members and their expression pattern in cancer. We also summarized the mechanism of MAGE activation and the functions of MAGE family members in cell cycle progression and apoptosis. We also discussed what is known of immunotherapy targeting MAGE family.