IMP3 can predict aggressive behaviour of lung adenocarcinoma

Diagnostic Pathology (Impact Factor: 2.6). 11/2012; 7(1):165. DOI: 10.1186/1746-1596-7-165
Source: PubMed


BACKGROUND: Lung cancer most often presents as an inoperable tumour and the diagnosis is usually performed on a small biopsy/cytology specimen. In the group of non small cell lung cancer - not otherwise specified, adenocarcinoma phenotype can be determined immunohistochemically using TTF-1 and Napsin A. Expression of oncofetal protein IMP3 in human cancer is associated with poor differentiation and aggressive behaviour. In the present study expression of IMP3 was correlated with expression of TTF-1 and Napsin A, histological subtype and clinical stage of lung adenocarcinoma. We were interested whether distant metastases are associated with IMP3 overexpression, regardless of the histologic subtype of adenocarcinoma. METHODS: In retrospective study, consecutive series of 105 patients with advanced lung adenocarcinoma diagnosed from 2006 to 2009 in Clinical Hospital Center Split, Croatia, were analysed. Clinical data were collected from the Pulmology Department and time of death from the Mortality Registry. Paraffin blocks of bronchoscopic biopsies were collected from the Institute of Pathology and 15 cases excluded from the analysis due to insufficient material. Expression of IMP3, Napsin A and TTF-1 were analysed by indirect enzyme immunohistochemistry. Statistical analysis was performed and P values less than 0.05 considered significant. RESULTS: Of 90 patients, 71 (78%) were males and 19 (22%) females. Median age for males was 61.5 years (min-max 43-83) and for females 61 years (min-max 44-86). Pleural effusion was found in 15 (16.6%) and distant metastases in 45 (50%) cases. According to histological subtypes, there were 34 acinar, 2 lepidic, 2 papillary and 52 solid subtypes. IMP3 overexpression was found in 63 cases (70%) and was correlated with solid subtype (P = 0.002) and negative/weak Napsin A expression (P = 0.004). Strong Napsin A expression correlated with TTF-1 expression (P = 0.003) and lower histological grades (P = 0.031). Patients with IMP3 overexpression more often had distant metastases than patients with negative IMP3, 55.5% versus 33.3% (P = 0.033). Non solid subtypes with IMP3 overexpression developed distant metastasis more common than non solid subtypes with negative IMP3, 72% versus 35% (P = 0.028). CONCLUSIONS: Expression of IMP3 correlates with solid subtype and with distant metastases regardless of histological subtype of lung adenocarcinoma. Virtual slides

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Available from: Renata Beljan, Oct 21, 2015
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    • "RESULTS IMP3 and HMGA2 mRNA Are Coexpressed in Human Cancers High levels of RNA-binding IMP3 have been associated with poor outcome and metastasis in cancers of the lung, kidney, colorectal, breast, and ovary (Beljan Perak et al., 2012; Bellezza et al., 2009; Findeis-Hosey et al., 2010; Hoffmann et al., 2008; Jiang et al., 2008a, 2008b; Kö bel et al., 2009; Lochhead et al., 2012; Walter et al., 2009; Yuan et al., 2009). To identify putative oncogenic mechanisms connected to IMP3, we examined IMP3 mRNA expression in a series of 270 tumors from the above cancers and searched for transcripts that were correlated with the presence of IMP3. "
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    ABSTRACT: The IMP3 RNA-binding protein is associated with metastasis and poor outcome in human cancer. Using solid cancer transcriptome data, we found that IMP3 correlates with HMGA2 mRNA expression. Cytoplasmic IMP3 granules contain HMGA2, and IMP3 dose-dependently increases HMGA2 mRNA. HMGA2 is regulated by let-7, and let-7 antagomiRs make HMGA2 refractory to IMP3. Removal of let-7 target sites eliminates IMP3-dependent stabilization, and IMP3-containing bodies are depleted of Ago1-4 and miRNAs. The relationship between Hmga2 mRNA and IMPs also exists in the developing limb bud, where IMP1-deficient embryos show dose-dependent Hmga2 mRNA downregulation. Finally, IMP3 ribonucleoproteins (RNPs) contain other let-7 target mRNAs, including LIN28B, and a global gene set enrichment analysis demonstrates that miRNA-regulated transcripts in general are upregulated following IMP3 induction. We conclude that IMP3 RNPs may function as cytoplasmic safe houses and prevent miRNA-directed mRNA decay of oncogenes during tumor progression.
    Cell Reports 04/2014; 7(2). DOI:10.1016/j.celrep.2014.03.015 · 8.36 Impact Factor
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    • "Non-small cell lung cancer (NSCLC) is the most predominant type of lung cancer, and about 70-80% of lung cancer fall under the classification of NSCLC with adenocarcinoma as the most common subtype [23]. In this study, we engaged NSCLC cell A549 and H1299 to observe the effects of myricetin on combination with radiotherapy enhances tumor radiosensitivity in vitro and in vivo, in order to provided a novel insight into myricetin as a potential agent for lung cancer radiosensitizers. "
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    ABSTRACT: Myricetin, a common dietary flavonoid is widely distributed in fruits and vegetables, and is used as a health food supplement based on its immune function, anti-oxidation, anti-tumor, and anti-inflammatory properties. The aim of this study was to investigate the effects of myricetin on combination with radiotherapy enhance radiosensitivity of lung cancer A549 and H1299 cells. A549 cells and H1299 cells were exposed to X-ray with or without myricetin treatment. Colony formation assays, CCK-8 assay, flow cytometry and Caspase-3 level detection were used to evaluate the radiosensitization activity of myricetin on cell proliferation and apoptosis in vitro. Nude mouse tumor xenograft model was built to assessed radiosensitization effect of myricetin in vivo. Compared with the exposed group without myricetin treatment, the groups treated with myricetin showed significantly suppressed cell surviving fraction and proliferation, increased the cell apoptosis and increased Caspase-3 protein expression after X-ray exposure in vitro. And in vivo assay, growth speed of tumor xenografts was significantly decreased in irradiated mice treated with myricetin. The study demonstrated both in vitro and in vivo evidence that combination of myricetin with radiotherapy can enhance tumor radiosensitivity of pulmonary carcinoma A549 and H1299 cells, and myricetin could be a potential radiosensitizer for lung cancer therapy.Virtual slides:
    Diagnostic Pathology 03/2014; 9(1):68. DOI:10.1186/1746-1596-9-68 · 2.60 Impact Factor
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    • "therapeutic strategies. Nevertheless, other independent factors with a potential influence on survival that have recently been discussed could be considered, e.g. an overexpression of MTA3 gene in NSCLC as a risk factor on survival [30] or an overexpression of IMP3 as a predictor of aggressive tumor behavior [31]. Further investigations in this direction should follow. "
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    ABSTRACT: Background: Hamartin (TSC1) and tuberin (TSC2), encoded by the tuberous sclerosis complex (TSC) genes, form a tumor-suppressor heterodimer which is implicated in PI3K-Akt signaling and acts as a functional inhibitor of the mammalian target of rapamycin (mTOR). Dysregulation of mTOR has been assigned to carcinogenesis and thus may be involved in cancer development. We have addressed the role of hamartin, phospho-tuberin (p-TSC2) and phospho-mTOR (p-mTOR) in a series of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) samples.Methods: We collected 166 NSCLC and SCLC samples for immunohistochemical studies and performed western blot analyses in NSCLC and SCLC cell lines as well as comparative analyses with EGFR phosphorylation and downstream effectors.Results: In cell lines we found an inverse correlation between hamartin and p-mTOR expression. In surgical specimens cytoplasmic hamartin expression was observed in more than 50% of adenocarcinoma (AC) and squamous cell carcinoma (SCC) compared to 14% of SCLC. P-mTOR and p-TSC2 staining was found in a minority of cases.There was a significant correlation between p-EGFR Tyr-1068, p-EGFR Tyr-992 and hamartin, and also between p-mTOR and p-EGFR Tyr-1173 in AC. In SCC an inverse correlation between hamartin and p-EGFR Tyr-992 was detected. Phosphorylation of TSC2 was associated with expression of MAP-Kinase. Hamartin, p-TSC2 and p-mTOR expression was not dependant of the EGFR mutation status. Hamartin expression is associated with poorer survival in SCC and SCLC.Conclusions: Our findings confirm the inhibitory role of the tuberous sclerosis complex for mTOR activation in lung cancer cell lines. These results reveal hamartin expression in a substantial subset of NSCLC and SCLC specimens, which may be due to EGFR signaling but is not dependant on EGFR mutations. Our data provide evidence for a functional role of the tuberous sclerosis complex in lung cancer.
    Diagnostic Pathology 03/2014; 9(1):48. DOI:10.1186/1746-1596-9-48 · 2.60 Impact Factor
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