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      Overexpression of TWIST2 correlates with poor prognosis in Head and Neck Squamous Cell Carcinomas

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          Abstract

          Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of tumors with variable presentation and clinical behavior. Despite improvements in surgical and radiation therapy techniques, the 5-year survival rate has not improved significantly over the past decades. Thus, there is an urgent need to identify novel markers that may allow for the development of personalized therapeutic approaches. In the present study we evaluated the prognostic role of the expression of genes related to the induction of epithelial mesenchymal transition (EMT). To this aim, a consecutive series of 69 HNSCC were analyzed for the expression of TWIST1, TWIST2, SNAI1, SNAI2, E-Cadherin, N-Cadherin and Vimentin.

          TWIST1, TWIST2, SNAI1 and SNAI2 were significantly overexpressed in HNSCC, with TWIST2, SNAI1 and SNAI2 being more markedly increased in tumors compared to normal mucosae. The expression of TWIST1 and SNAI2 was associated with upregulation of mesenchymal markers, but failed to correlate with pathological parameters or clinical behaviour. In contrast, we found that upregulation of TWIST2, which was independent of the activation of a mesenchymal differentiation program, correlated with poor differentiation grade (p=0.016) and shorter survival (p=0.025), and identifies a subset of node-positive oral cavity/pharynx cancer patients with very poor prognosis (p<0.001).

          Overall our study suggests that the assessment of TWIST2 expression might help to stratify HNSCC patients for risk of disease progression, pointing to TWIST2 as a potential prognostic marker.

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          Most cited references35

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          Epithelial-mesenchymal transitions in development and pathologies.

          The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. The molecular mechanisms of EMT were primarily studied in epithelial cell lines, leading to the discovery of transduction pathways involved in the loss of epithelial cell polarity and the acquisition of a variety of mesenchymal phenotypic traits. Similar mechanisms have also been uncovered in vivo in different species, showing that EMT is controlled by remarkably well-conserved mechanisms. Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.
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            Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence.

            Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.
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              Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer.

              Slug, Snail, and Twist are transcription factors that regulate the expression of tumor suppressors such as E-cadherin. We examined the distribution and expression of these three molecules together with the methylation of the Twist gene promoter in human breast cancer to elucidate their clinical significance. Frozen sections from breast cancer primary tumors (tumor, n = 114; background, n = 30) were immunostained with Slug, Snail, and Twist antibodies. RNA was reverse-transcribed, quantified, and analyzed by quantitative polymerase chain reaction (Q-PCR). Results were expressed as copy number of transcript per 50 ng of RNA (standardized against beta-actin). Immunohistochemistry revealed that all three molecules were stained in mammary tissues, with an increase in Twist within tumor tissues; this was supported by Q-PCR analysis. Q-PCR analysis showed that Slug was elevated with increasing tumor grade and prognostic indices. Twist was elevated with increasing nodal involvement (tumor-node-metastasis status). Conversely, Snail was reduced in expression corresponding with prognostic indices and tumor grade. Increased levels of Slug were associated with tumors from patients with metastatic disease or disease recurrence, and increased expression of Twist was associated with tumors from patients who had died from breast cancer. It is interesting to note that Snail expression was significantly reduced in patients with a poor outcome and those who had node-positive tumors. In addition, tumors exhibited methylation of the Twist promoter. These data demonstrate that all three transcription factors have inappropriate expression in breast cancer and that this may play a part in the progression of human breast tumors.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                December 2011
                22 December 2011
                : 2
                : 12
                : 1165-1175
                Affiliations
                1 Unit of Experimental Oncology 1, CRO National Cancer Institute, Aviano, Italy
                2 Unit of Epidemiology and Biostatistics, CRO National Cancer Institute, Aviano, Italy
                3 Unit of Pathology, Pordenone City Hospital, Pordenone, Italy
                4 Unit of Otorhinolaryngology, Pordenone City Hospital, Pordenone, Italy
                5 Unit of Pathology, San Raffaele Institute, Milano, Italy
                Author notes
                Correspondence to: Roberta Maestro, maestro@ 123456cro.it
                Article
                3282075
                22201613
                c6eed04c-952f-4bfd-bda2-2c822ec145ea
                Copyright: © 2011 Gasparotto et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 19 December 2011
                : 20 December 2011
                Categories
                Research Papers

                Oncology & Radiotherapy
                twist2,snai1,emt,hnscc,twist1,snai2
                Oncology & Radiotherapy
                twist2, snai1, emt, hnscc, twist1, snai2

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