Meixiang Sang

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.

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.

The downregulation of miR-200c/141 promotes ZEB1/2 expression and gastric cancer progression.

AbstractGastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (miR-200) family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR-141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-β signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR-200c/141 induced by TGF-β in SGC-7901 cells. Our study revealed that miR-200c/141 was downregulated by CpG island methylation and TGF-β signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment.

Advances in viral-vector systemic cytokine gene therapy against cancer

Current strategies for cancer gene therapy consist mainly of direct inhibition of tumor cell growth and activation of systemic host defense mechanisms. Cytokine gene-transduced tumor cells have been used as vaccines in clinical trials, which have shown good safety profiles and some local responses but substantial lack of systemic efficacy. Cytokines should be directed at the level of gene selection and delivery, in order to identify the optimal cytokine and achieve efficient and durable cytokine expression at the level of improving immune stimulation. In this review, we will summarize the current achievements of cytokine gene therapy, especially viral-vector, and their applications in cancer treatment. Additionally, we will also discuss and propose future perspectives about cancer gene therapy.

Multiple MAGE-A genes as surveillance marker for the detection of circulating tumor cells in patients with ovarian cancer

Abstract Ovarian cancer is a leading cause of death among gynecologic malignancies. In this study, we reported the expression of melanoma-associated antigens A (MAGE-A) genes in peripheral blood from 80 patients with ovarian cancer and 30 healthy donors. MAGE-As expression was associated with the factors indicating poor prognosis. The expressions of MAGE-As and each individual MAGE-A genes were also associated with low overall survival of patients with ovarian cancer. Our results suggested MAGE-A genes may have the potential to be surveillance markers for the detection of circulating tumor cells and represent a poor prognosis for patients with ovarian cancer.

Potential biomarkers for esophageal carcinoma detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

Abstract Background: Currently, no satisfactory biomarkers are available to screen for esophageal squamous cell carcinoma (ESCC). The goal of this study was to find biomarkers and establish a serum protein fingerprint model for early diagnosis of ESCC using the ClinProt protocol of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Methods: Serum samples were collected from 62 patients with ESCC, nine patients with esophageal adenocarcinoma (EA) and 38 healthy individuals. Proteomic spectra of mass to charge ratio (m/z) were generated following the application of plasma to weak cationic-exchanger magnetic beads (WCX-MB). The spectral data were analyzed using a support vector machine, and potential biomarkers were chosen for system training and used to construct diagnostic models. Results: Three differential patterns were established using MALDI-TOF MS. Pattern 1, consisting of 11 protein peaks, separated ESCC patients from the healthy individuals with a sensitivity of 90.0% and a specificity of 88.4%. Pattern 2, consisting of eight protein peaks, separated ESCC in stage I and stage II from stage III and stage IV with a sensitivity of 92.9% and a specificity of 82.3%. Pattern 3, consisting of seven protein peaks, separated ESCC from EA with a sensitivity of 91.3% and a specificity of 80.0%. Conclusions: These results suggested that MALDI-TOF MS combined with MB separation yields significantly higher sensitivity and specificity for the detection of serum protein in patients with ESCC. Clin Chem Lab Med 2010;48:855–61.

The flavonoid Baohuoside-I inhibits cell growth and downregulates survivin and cyclin D1 expression in esophageal carcinoma via β-catenin-dependent signaling.

Esophageal cancer is one of the most common malignancies and is associated with a dismal prognosis. Although treatment options have increased for some patients, overall progress has been modest. Thus, there is a great need to develop new treatments. We found that Baohuoside-I, a flavonoid extracted from a Chinese medicinal plant, exhibits anticancer activity. Here, we demonstrated that Baohuoside-I significantly inhibited Eca109 human esophageal squamous carcinoma cell proliferation and induced Eca109 cell apoptosis in vitro and in vivo. The growth inhibitory effect of Baohuoside-I on the Eca109 tumor cell line was examined by MTT assay; the induction of apoptosis was analyzed by flow cytometry. Eca109-luc cells were injected into the subcutaneous tissue of nude mice to establish xenograft tumors. Our results revealed that Baohuoside-I caused a dose- and time-dependent inhibition of cell growth and an induction of apoptosis. Furthermore, Baohuoside-I-treated cells were characterized by decreased expression of the β-catenin gene and protein in the total cell lysates. Thus, the gene and protein expression of the downstream elements survivin and cyclin D1 was downregulated. To determine the precise inhibitory mechanisms involved, further in-depth in vivo studies of Baohuoside-I are warranted. Our study provides the first evidence that Baohuoside-I inhibits tumor growth and induces apoptosis by inhibiting β-catenin-dependent signaling pathways. Thus, Baohuoside-I is a potential candidate in ESCC disease therapy.

LIM-domain-only proteins: multifunctional nuclear transcription coregulators that interacts with diverse proteins.

The LIM-only subclass of LIM proteins is a family of nuclear transcription co-regulators that are characterized by the exclusive presence of two tandem LIM domains and no other functional domains. To date, four LIM-domain-only (LMO) proteins (LMO1-LMO4) have been identified. They regulate gene transcription by functioning as “linker” or “scaffolding” proteins with a remarkable potential to mediate protein–protein interactions. These proteins play important roles in cell fate determination, cell growth and differentiation, tissues patterning, and organ development. In this review, we briefly described the functions of LMO proteins in the organ development and diseases. We also summarized the interaction proteins of each LMO family member, which may contribute to elucidating the functions of these mysterious and important linker proteins.

The expression and clinical significance of melanoma-associated antigen-A1, -A3 and -A11 in glioma

Melanoma-associated antigens (MAGEs) were initially identified in melanoma and have since been widely studied. Melanoma-associated antigen-As (MAGE-As), a subfamily of MAGEs, are expressed in germ cells and various types of cancer, and are considered to be ideal targets for cancer immunotherapy. Glial cells and melanocytes originate from the neural ectoderm, so tumors derived from these two types of cells, i.e. gliomas and melanomas, may have common biological characteristics. However, studies on the expression of the MAGE-A family in gliomas are limited and conflicting. In the present study, the expression levels of MAGE-A1, -A3 and -A11 were detected by immunohistochemistry, and the association of their expression levels with the clinicopathological parameters, overall survival (OS) and ki-67 labeling indices of glioma patients were analyzed. The results showed that i) the expression levels of MAGE-A1, -A3 and -A11 proteins in the glioma tissues were 64.1, 51.3 and 57.7%, respectively and that no MAGE-A1, -A3 or -A11 expression was detected in the normal brain specimens; ii) the expression levels of MAGE-A1 and -A11 increased with ascending pathological grades and were positively correlated with the ki-67 labeling index; and iii) the OS of the patients in the groups with high MAGE-A1 (P=0.005) and -A11 (P=0.019) expression was statistically lower compared with the groups with low expression and no significant differences in OS were detected between the patients in the groups with high and low MAGE-A3 expression (P=0.304). Based on these results, we conclude that MAGE-A1, -A3 and -A11 may be used as ideal targets for glioma immunotherapy, and that MAGE-A1 and -A11 expression may be involved in tumor cell proliferation. These proteins may be potential indicators of a poor prognosis in glioma patients.