Cytoplasmic expression of laminin γ2 chain correlates with postoperative hepatic metastasis and poor prognosis in patients with pancreatic ductal adenocarcinoma

Takahashi, Shinichiro; Hasebe, Takahiro; Oda, Tatsuya; Sasaki, Satoshi; Kinoshita, Taira; Konishi, Masaru; Ochiai, Takenori; Ochiai, Atsushi

doi:10.1002/cncr.10395

Cited by 71 publications

(58 citation statements)

References 26 publications

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“…The present study demonstrated that MMP-7, cytoplasmic laminin c2 and EGFR at the invasive front of GC play a pivotal role in tumor progression and regional lymph node metastasis, whereas all these molecules except cytoplasmic laminin c2 at the control regions were not associated with any clinicopathologic parameters. In particular, cytoplasmic expression of laminin c2 in GCs might be a potent predictive factor for tumor aggressiveness as previously reported in pancreatic ductal adenocarcinomas [52]. Laminin 5 reportedly plays an important role in EMT through down-regulation of E-cadherin and translocation of b-catenin into the nuclei [53].…”

Section: (21 %) 580supporting

confidence: 55%

Clinicopathological significance of MMP-7, laminin γ2 and EGFR expression at the invasive front of gastric carcinoma

et al. 2013

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Background For several types of cancer, including gastric cancer (GC), tumor cells at the invasive front are considered to have a more aggressive behavior compared with those in the more central region. The aim of the present study was to analyze the expression of MMP-7, laminin c2 and EGFR in a large number of GCs and to investigate how these expression patterns correlate with clinicopathologic parameters, infiltrative patterns, histology or mucin phenotype. Methods We immunohistochemically examined the expression of MMP-7, laminin c2 and EGFR using a tissue microarray analysis of 790 GCs, and evaluated their clinicopathological significance. Results MMP-7, cytoplasmic laminin c2, extracellular laminin c2 and EGFR expression were observed in 25, 25, 8 and 21 % of the 790 GC cases, respectively. Expression of MMP-7, cytoplasmic laminin c2 and EGFR was associated with advanced T grade, N grade and tumor stage. Extracellular laminin c2 expression was not associated with any clinicopathologic parameters, infiltrative patterns, histology or mucin phenotype. Furthermore, we investigated the correlations of MMP-7, laminin c2 and EGFR expression. MMP-7 expression was significantly more frequent in positive expression of cytoplasmic laminin c2 than negative cases, and EGFR expression was significantly more frequent in positive expression of cytoplasmic laminin c2 and MMP-7.

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Section: (21 %) 580supporting

confidence: 55%

Clinicopathological significance of MMP-7, laminin γ2 and EGFR expression at the invasive front of gastric carcinoma

et al. 2013

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“…In concordance with the CGH findings, cDNA microarray analysis demonstrated that a higher proportion of these genes were dysregulated in TCV. 48,49), and TNC (cervical carcinoma, glioma, and non-small cell lung cancer; Refs. 50 -52).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Profiling of Papillary Thyroid Cancer Identifies MUC1 as an Independent Prognostic Marker

Wreesmann¹,

Sieczka²,

Socci

et al. 2004

Cancer Research

136

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Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological cPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P ‫؍‬ 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34 -36, 1q21, 6p21-22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21-31, 4, 5p14-q21, 6q11-22, 8q11-22, 9q11-32, and 13q21-31 were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P ‫؍‬ 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P ‫؍‬ 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1-5.5; P ‫؍‬ 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.

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“…8 Besides, LAMC2 monomer expression has been frequently found in the invasive front of epithelial tumors such as ADCs of the stomach, colon, pancreas, and lung, SCCs of the esophagus, head and neck, skin and lung, and transitional cell carcinoma of the bladder. 5,[9][10][11][12][13][14] Epithelialmesenchymal transition (EMT) has a critical role in the early stages of dissemination of malignant epithelial tumors leading to metastatic spread. 15 There is growing evidence that LAMC2 expression increases in the carcinoma cells undergoing EMT, [16][17][18] and that level of LAMC2 expression is regulated directly by the EMT master regulator ZEB1 and activated β-catenin in invasive colorectal carcinoma cells.…”

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confidence: 99%

LAMC2 enhances the metastatic potential of lung adenocarcinoma

et al. 2015

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Lung cancer is the number one cancer killer, and metastasis is the main cause of high mortality in lung cancer patients. However, mechanisms underlying the development of lung cancer metastasis remain unknown. Using genome-wide transcriptional analysis in an experimental metastasis model, we identified laminin γ2 (LAMC2), an epithelial basement membrane protein, to be significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 increased traction force, migration, and invasion of lung adenocarcinoma cells accompanied by the induction of epithelial-mesenchymal transition (EMT). LAMC2 knockdown decreased traction force, migration, and invasion accompanied by EMT reduction in vitro, and attenuated metastasis in mice. LAMC2 promoted migration and invasion via EMT that was integrin β1-and ZEB1-dependent. High LAMC2 was significantly correlated with the mesenchymal marker vimentin expression in lung adenocarcinomas, and with higher risk of recurrence or death in patients with lung adenocarcinoma. We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via EMT and may be a potential therapeutic target. Cell Death and Differentiation (2015) 22, 1341-1352; doi:10.1038/cdd.2014.228; published online 16 January 2015Lung cancer is the leading cause of cancer-related death. 1 Non-small-cell lung cancer (NSCLC) accounts for~80-85% of lung cancers. 2 Only 20-30% of NSCLC are radically resectable and the majority of lung cancer patients succumb to the disease. The high mortality of NSCLC is largely attributable to late diagnosis, when metastases are present. 2 The molecular mechanisms governing metastasis of NSCLC remain poorly understood.Metastasis is a complex, multistep process, involving migration and invasion of malignant cells from the primary tumor to blood vessels, intravasation, and survival in the circulation, and ultimately extravasation, colonization, and formation of secondary tumor at distant target organs. 3 Each of these events is classically driven by the acquisition of genetic and/or epigenetic traits in tumor cells and the cooperation of nonneoplastic stromal cells. Increased or decreased expression of several genes in tumors has been found to be correlated with metastasis. 3 However, specific gene alterations that drive NSCLC metastasis remain largely elusive.Laminin γ2 (LAMC2) is a subunit of the heterotrimeric glycoprotein laminin-332 (LAM-332, formerly laminin-5), consisting of the α3, β3, and γ2 chains. Although LAMC2 is an important structural component of the epithelial basement membrane (BM) in various normal tissues, 4 there is an emerging evidence for a pathological role of LAMC2 monomer in cancer. It has been demonstrated that LAMC2 protein expression correlates with clinical outcome of stage I lung adenocarcinoma (ADC) patients. 5,6 In addition, noncontinuous expression pattern of LAMC2 predicts the prognosis of esophageal squamous cell carcinoma (SCC), 7 and secreted LAMC2 in the serum is associated with the aggressiveness of pancreatic cancer. 8 Besides, LAMC2 monom...

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Cytoplasmic expression of laminin γ2 chain correlates with postoperative hepatic metastasis and poor prognosis in patients with pancreatic ductal adenocarcinoma

Abstract: BACKGROUND.The laminin ␥2 chain is involved in tumor invasion and metastasis,

Cited by 71 publications

References 26 publications

Clinicopathological significance of MMP-7, laminin γ2 and EGFR expression at the invasive front of gastric carcinoma

Clinicopathological significance of MMP-7, laminin γ2 and EGFR expression at the invasive front of gastric carcinoma

Genome-Wide Profiling of Papillary Thyroid Cancer Identifies MUC1 as an Independent Prognostic Marker

LAMC2 enhances the metastatic potential of lung adenocarcinoma

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