Article

Anterior Gradient 2 Overexpression in Lung Adenocarcinoma

Department of Medical Diagnostic Sciences & Special Therapies, University of Padova, Padova, Italy.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry (Impact Factor: 2.06). 07/2011; 20(1):31-6. DOI: 10.1097/PAI.0b013e3182233f9f
Source: PubMed

ABSTRACT The histologic subtyping of the 2 major histotypes of nonsmall-cell lung cancer, that is, adenocarcinoma (AdC) and squamous cell carcinoma (SCC), is crucial to therapeutic decision making, but making this distinction can be a challenge. Querying the Oncomine database pinpointed anterior gradient 2 (AGR2) as being upregulated in lung AdC. On applying both quantitative real-time polymerase chain reaction and immunohistochemistry, this study tested the reliability of AGR2 status as a histotype-specific marker of lung AdC. AGR2 immunohistochemistry expression was semiquantitatively assessed in 120 cases of lung cancer (60 AdCs, 60 SCCs); 35 additional tissue samples from non-neoplastic lungs were considered as normal controls. To further support our findings, the expression of AGR2 mRNA was tested by quantitative real-time polymerase chain reaction in 30 of the considered cases (10 AdCs, 10 SCCs, and 10 normal lungs). AGR2 was consistently expressed in normal bronchial/bronchiolar columnar cells. Cases of AdC always expressed the protein (staining moderately in 30% and strongly in 70%), whereas none of the SCC cases strongly expressed AGR2 (staining was negative in 55%, weak in 33%, and moderate in 12%). AGR2 mRNA was significantly overexpressed in AdCs by comparison with SCCs (P=0.003) or normal lung tissue (P=0.002). AGR2 is upregulated in lung AdC (by comparison with either SCC or normal bronchial/bronchiolar columnar cells). AGR2 protein expression may support the histologic subtyping of nonsmall-cell lung cancer and be of clinical value in differentiating lung AdC from SCC.

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    • "Our recent work indicates that DNP induces NPC metastasis, following high expression of anterior gradient 2 (AGR2), cathepsin B (CTSB), and cathepsin D (CTSD) [27]. AGR2 is upregulated in multiple cancers, including breast [28], lung adenocarcinoma [29], [30], ovarian [31], and prostate cancers [32]. Its high expression is associated with tumor metastasis and poor prognosis [33], while silencing AGR2 inhibits cell growth and cell cycle progression, and induces cell death [34]. "
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) has a high metastatic character in the clinic, but its mechanism is not clear. As a carcinogen with organ specificity for the nasopharyngeal epithelium, N,N'-Dinitrosopiperazine (DNP) is involved in NPC metastasis. Herein, our data revealed that anterior gradient 2 (AGR2) was overexpressed in human NPC tissues, particularly in cervical lymph node metastatic NPC (LMNPC). High AGR2 expression was associated with NPC metastasis. Importantly, DNP induced AGR2 expression, and increased cell motility and invasion in the NPC cell line 6-10B. However, DNP-mediated cell motility and invasion was dramatically decreased when transfected with siRNA-AGR2. Further, AGR2 directly regulated cathepsin (CTS) B and D by binding them in vitro. These results indicate that DNP induces AGR2 expression, regulates CTSB and CTSD, increases cell motility and invasion, and promotes NPC tumor metastasis. Therefore, DNP-mediated AGR2 expression may be an important factor in prolific NPC metastasis.
    PLoS ONE 05/2014; 9(4):e92081. DOI:10.1371/journal.pone.0092081 · 3.23 Impact Factor
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    • "Mice lacking AGR-2 are prone to develop colitis [7]. AGR-2 has drawn considerable attention in recent years for its putative role in neoplastic progression and metastasis [8]–[15]. AGR-2 has been found to be over-expressed in various adenocarcinomas and has been linked to poor survival of patients with breast and prostate cancers [16], [17]. "
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    ABSTRACT: Anterior Gradient Protein (AGR-2) is reported to be over-expressed in many epithelial cancers and promotes metastasis. A clear-cut mechanism for its observed function(s) has not been previously identified. We found significant upregulation of AGR-2 expression in a bone metastatic prostate cancer cell line, PC3, following culturing in bone marrow-conditioned medium. Substantial AGR-2 expression was also confirmed in prostate cancer tissue specimens in patients with bone lesions. By developing stable clones of PC3 cells with varying levels of AGR-2 expression, we identified that abrogation of AGR-2 significantly reduced cellular attachment to fibronectin, collagen I, collagen IV, laminin I and fibrinogen. Loss of cellular adhesion was associated with sharp decrease in the expression of α4, α5, αV, β3 and β4 integrins. Failure to undergo apoptosis following detachment is a hallmark of epithelial cancer metastasis. The AGR-2-silenced PC3 cells showed higher resistance to Tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) induced apoptosis in vitro. This observation was also supported by significantly reduced Caspase-3 expression in AGR-2-silenced PC3 cells, which is a key effector of both extrinsic and intrinsic death signaling pathways. These data suggest that AGR-2 influence prostate cancer metastasis by regulation of cellular adhesion and apoptosis.
    PLoS ONE 02/2014; 9(2):e89940. DOI:10.1371/journal.pone.0089940 · 3.23 Impact Factor
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    • "Also of interest are AGR2, KRT8, and SFN. AGR2 is a known proto-oncogene recently confirmed to be overexpressed in lung adenocarcinoma (Pizzi et al. 2012), and has been shown to promote cell proliferation and migration in several different cancers (Ramachandran et al. 2008; Vanderlaag et al. 2010; Park et al. 2011). KRT8, encoding keratin 8, was previously reported to be up-regulated in lung adenocarcinoma (Wikman et al. 2002); and SFN, encoding stratifin, has been reported to be overexpressed in early invasive lung adenocarcinoma (Shiba-Ishii et al. 2011). "
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    ABSTRACT: Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell-cell and cell-matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.
    Genome Research 05/2012; 22(7):1197-211. DOI:10.1101/gr.132662.111 · 13.85 Impact Factor
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