Role of epithelial to mesenchymal transition in hepatocellular carcinoma

The MAGE protein family and cancer.

Non-small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies consisting essentially of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although the diagnosis and treatment of ADC and SCC have been greatly improved in recent decades, there is still an urgent need to identify accurate transcriptome profile associated with the histological subtypes of NSCLC. The present study aims to identify the key dysregulated pathways and genes involved in the development of lung ADC and SCC and to relate them with the clinical traits. The transcriptional changes between tumour and normal lung tissues were investigated by RNA-seq. Gene ontology (GO), canonical pathways analysis with the prediction of upstream regulators, and weighted gene co-expression network analysis (WGCNA) to identify co-expressed modules and hub genes were used to explore the biological functions of the identified dysregulated genes. It was indicated that specific gene signatures differed significantly between ADC and SCC related to the distinct pathways. Of identified modules, four and two modules were the most related to clinical features in ADC and SCC, respectively. CTLA4, MZB1, NIP7, and BUB1B in ADC, as well as GNG11 and CCNB2 in SCC, are novel top hub genes in modules associated with tumour size, SUVmax, and recurrence-free survival. Our research provides a more effective understanding of the importance of biological pathways and the relationships between major genes in NSCLC in the perspective of searching for new molecular targets.

Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA)

// Fei Fei 1, 2 , Jie Qu 1, 2 , Mingqing Zhang 3 , Yuwei Li 3 and Shiwu Zhang 2 1 Nankai University School of Medicine, Nankai University, Tianjin, 300071, PRChina 2 Department of Pathology, Tianjin Union Medical Center, Tianjin, 300121, PR China 3 Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, PR China Correspondence to: Shiwu Zhang, email: zhangshiwu666@aliyuncom Keywords: S100A4, metastasis, malignant tumor, epithelial-mesenchymal transition Received: April 11, 2017      Accepted: May 08, 2017      Published: May 19, 2017 ABSTRACT Metastasis is the leading cause of cancer-related death and directly associates with cancer progression, resistance to anticancer therapy, and poor patient survival Current efforts focusing on the underlying molecular mechanisms of cancer metastasis attract a special attention to cancer researchers The epithelial-mesenchymal transition is a complex of molecular program during embryogenesis, inflammation, tissue fibrosis, and cancer progression and metastasis S100A4, an important member of S100 family proteins, functions to increase the tumor progression and metastasis The molecular mechanisms of S100A4 involving in the progression and metastasis are diverse in various malignant tumors Detection of S100A4 expression becomes a promising candidate biomarker in cancer early diagnosis and prediction of cancer metastasis and therefore, S100A4 may be a therapeutic target This review summarized up to date advancement on the role of S100A4 in human cancer development, progression, and metastasis and the underlying molecular events and then strategies to target S100A4 expression experimentally

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S100A4 in cancer progression and metastasis: A systematic review.

Neuroblastoma is the most common extracranial solid tumour in children and is histologically classified by its Schwannian stromal cells. Although having fewer Schwannian stromal cells is generally associated with more aggressive phenotypes, the exact roles of other stromal cells (mainly macrophages and fibroblasts) are unclear. Here, we examined 41 cases of neuroblastoma using immunohistochemistry for the tumour-associated macrophage (TAM) markers CD68, CD163, and CD204, and a cancer-associated fibroblast (CAF) marker, alpha smooth muscle actin (αSMA). Each case was assigned to low/high groups on the basis of the number of TAMs or three groups on the basis of the αSMA-staining area for CAFs. Both the number of TAMs and the area of CAFs were significantly correlated with clinical stage, MYCN amplification, bone marrow metastasis, histological classification, histological type, and risk classification. Furthermore, TAM settled in the vicinity of the CAF area, suggesting their close interaction within the tumour microenvironment. We next determined the effects of conditioned medium of a neuroblastoma cell line (NBCM) on bone marrow-derived mesenchymal stem cells (BM-MSCs) and peripheral blood mononuclear cell (PBMC)-derived macrophages in vitro. The TAM markers CD163 and CD204 were significantly up-regulated in PBMC-derived macrophages treated with NBCM. The expression of αSMA by BM-MSCs was increased in NBCM-treated cells. Co-culturing with CAF-like BM-MSCs did not enhance the invasive ability but supported the proliferation of tumour cells, whereas tumour cells co-cultured with TAM-like macrophages had the opposite effect. Intriguingly, TAM-like macrophages enhanced not only the invasive abilities of tumour cells and BM-MSCs but also the proliferation of BM-MSCs. CXCL2 secreted from TAM-like macrophages plays an important role in tumour invasiveness. Taken together, these results indicate that PBMC-derived macrophages and BM-MSCs are recruited to a tumour site and activated into TAMs and CAFs, respectively, followed by the formation of favourable environments for neuroblastoma progression. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.4769

Collaboration of cancer-associated fibroblasts and tumour-associated macrophages for neuroblastoma development

We determined the expression of epithelial-mesenchymal transition (EMT) indicator proteins, E-cadherin (E-cad), vimentin (VIM), mucin 1 (MUC1) and S100 calcium-binding protein A4 (S100A4) in hepatocellular carcinoma (HCC) patient tissue samples. We also investigated the relationship between the expression of these proteins and clinicopathologic factors in HCC. Finally, we assessed the potential value of these markers as prognostic indicators of survival in HCC patients. The expression of E-cad, VIM, MUC1 and S100A4 EMT indicator proteins was assessed in tissue microarray HCC tissue sections and corresponding peritumoral normal tissues by immunohistochemistry. In addition, the expression for the four EMT indicator proteins was correlated with clinicopathological features of HCC and patient outcome. Comparison of clinicopathological characteristics and immunohistochemistry by χ2 analysis revealed that downregulation of E-cad in HCC was significantly associated with later TNM cancer stage (P = 0.012), gross classification (P = 0.018), regional lymph node metastasis (P = 0.036) and liver cirrhosis (P = 0.028). Increased S100A4 expression in HCC was significantly associated with differentiation (P = 0.032), tumor with a complete fibrous capsule (P = 0.031) and portal vein invasion (P = 0.038). High VIM expression in HCC was significantly associated with high serum α-fetoprotein levels (P = 0.016). We also observed that low E-cad expression was significantly associated with overexpression of VIM (P = 0.001). Kaplan–Meier survival and Cox regression analysis revealed that low E-cad expression (HR = 0.164, 95 % CI 0.072 to 0.373, P < 0.001) and high serum α-fetoprotein levels (HR = 2.202, 95 % CI 1.054 to 4.598, P = 0.036) were independent prognostic factors in HCC. Our study demonstrates that high S100A4 and VIM expression and low E-cad expression correlate with an aggressive, malignant phenotype in HCC. These results also support a role for E-cad as a prognostic factor in HCC.

Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC

Melanoma associated antigen-A (MAGE-A) is an oncogene and correlated with tumor initiation and development. However the roles of MAGE-A9 in non-small cell lung cancer (NSCLC) are still unknown. We investigated MAGE-A9 mRNA expression in 18 tumor tissues of NSCLC by qRT-PCR and MAGE-A9 protein expression in 213 NSCLC samples of tissue arrays by immunohistochemical staining. We assessed the relationship between MAGE-A9 expression and clinical parameters. The results showed that the high expression of MAGE-A9 protein in NSCLC tumor cells were commonly present in squamous cell carcinomas (P = 0.030). It was also related to larger tumor diameter, lymph node metastasis and later stage grouping with TNM classification (all P < 0.05). Whereas the expression of MAGE-A9 in stromal cells was higher in squamous cell carcinomas as well. Cox regression univariate and multivariable analysis revealed that MAGE-A9 expression in tumor cells of NSCLC (P < 0.001) is an independent prognostic factor in five-year overall survival rate. We concluded that the molecular assessment of MAGEA9 could be considered to improve prognostic evaluation and to identify eligible patients for potential target therapy.

High expression of MAGE-A9 in tumor and stromal cells of non-small cell lung cancer was correlated with patient poor survival.

Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer.

A variety of melanoma-associated antigen-A (MAGE-A) protein are commonly detected in lung cancers. Their biological function is not well characterized but may involve cell cycle progression and the regulation of apoptosis. We hypothesized that MAGE-A9 is involved in the regulation of apoptosis. To test this hypothesis, we evaluated MAGE-A9 protein expression by immunohistochemical staining and we assessed the relationship between the expression of MAGE-A9 and clinical pathological parameters. In addition, we investigated the effect of MAGE-A9 down-regulation in lung adenocarcinoma. The results showed that a high expression level of MAGE-A9 protein in lung adenocarcinoma tumor cells was related to larger tumor diameter (P = 0.013) and poor differentiation (P = 0.029). Cox regression analysis revealed that the expression of MAGE-A9 in lung adenocarcinoma tumor cells (P < 0.001) is an independent prognostic factor in five-year survival rates. NSCLC cells with silenced MAGE-A9 had decreased cell proliferation, migration and invasion in cell culture compared to corresponding control cells. The NSCLC cells showing down-regulated MAGE-A9 induced the expression of apoptosis-associated proteins. In addition, MAGE-A9 was associated with resistance to conventional chemotherapeutic agents. Our findings provide evidence that MAGE-A9 could be a potential therapeutic target in NSCLC.

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High expression levels of MAGE-A9 are correlated with unfavorable survival in lung adenocarcinoma.

Background. Growth-related oncogene- (GRO-) β is a member of the CXC chemokine family, which may mediate various functions, such as attracting neutrophils to sites of inflammation, regulating angiogenesis, and participating in tumorigenesis and progression. However, the expression of GRO-β in ovarian cancer and its relationship to the clinical characteristics of this disease remain poorly understood. Methods. In this study, immunohistochemical analysis using tissue microarray (TMA) was employed to evaluate the expression of GRO-β in ovarian cancer and to contrast expression with normal ovarian epithelial cells and oviduct epithelial cells. Next, we observed the correlation between GRO-β expression and clinicopathological features of ovarian cancer as well as patient outcome. Results. High GRO-β cytoplasmic expression was observed in 55.15% of patients with ovarian cancer, which was related to lymph node or other metastases (P < 0.001), ascites (P = 0.027), and International Federation of Obstetricians and Gynaecologists (FIGO) stage (P = 0.032). Kaplan-Meier survival and Cox regression analysis revealed that high GRO-β expression (P = 0.002) and high CA19-9 level (P = 0.003) were independent prognostic indicators of poor outcome in ovarian cancer. Conclusions. Overall, high GRO-β expression correlates with poor prognosis and contributes to ovarian cancer tumorigenesis and metastasis.

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Xiaolu Zhai

Papers

Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC

High expression of MAGE-A9 in tumor and stromal cells of non-small cell lung cancer was correlated with patient poor survival.

Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer.

High expression levels of MAGE-A9 are correlated with unfavorable survival in lung adenocarcinoma.

Overexpression of Growth-Related Oncogene-β Is Associated with Tumorigenesis, Metastasis, and Poor Prognosis in Ovarian Cancer.