The aberrant expression of transforming growth factor (TGF)-␤1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell motility and invasiveness. How EMT affects motility and invasion is not well understood. Here we report that HDAC6 is a novel modulator of TGF-␤1-induced EMT. HDAC6 is a microtubule-associated deacetylase that predominantly deacetylates nonhistone proteins, including ␣-tubulin, and regulates cell motility. We showed that TGF-␤1-induced EMT is accompanied by HDAC6-dependent deacetylation of ␣-tubulin. Importantly, inhibition of HDAC6 by small interfering RNA or the small molecule inhibitor tubacin attenuated the TGF-␤1-induced EMT markers, such as the aberrant expression of epithelial and mesenchymal peptides, as well as the formation of stress fibers. Reduced expression of HDAC6 also impaired the activation of SMAD3 in response to TGF-␤1. Conversely, inhibition of SMAD3 activation substantially impaired HDAC6-dependent deacetylation of ␣-tubulin as well as the expression of EMT markers. These findings reveal a novel function of HDAC6 in EMT by intercepting the TGF-␤-SMAD3 signaling cascade. Our results identify HDAC6 as a critical regulator of EMT and a potential therapeutic target against pathological EMT, a key event for tumor progression and fibrogenesis. Epithelial-mesenchymal transition (EMT)2 is defined as a series of events through which epithelial cells lose many of their epithelial characteristics and acquire properties that are typical of mesenchymal cells (1). Aberrant EMT has been well documented in chronic fibrosis in multiple organs and carcinoma progression. During progression to metastatic competence, carcinoma cells acquire mesenchymal gene expression patterns and properties through EMT, which results in coordinated alterations in adhesive properties, activation of proteolysis and motility, and competence to metastasize and establish secondary tumors at distant sites (1). Fibrosis is characterized by an increased number of myofibroblasts that deposit interstitial extracellular matrix. Mounting evidence indicates that a significant fraction of these myofibroblasts arise from the resident epithelial cells via EMT during renal and lung fibrogenesis (2-6).Family members of transforming growth factor (TGF)-␤ are among the most potent inducers of EMT in a variety of physiological and pathological contexts (7). The aberrant expression of TGF-␤1 is well documented in the tumor microenvironment and fibrotic lesions where TGF-␤1 is widely believed to promote tumor progression and tissue fibrosis (7). Several recent studies have elegantly demonstrated EMT of lung alveolar epithelial cells in biopsies from patients with idiopathic pulmonary fibrosis and in experimental pulmonary fibrosis (4,5,8). A host of evidence indicates an essential role for SMAD3 in the expression of a panel of EMT-related genes upon translocation into the nucleus (9). The molecular me...

The lethality of small-intestinal adenocarcinoma appears to be related to a delay in diagnosis and treatment. When a definitive surgical procedure is performed before lymph node metastases appear, the patient's chance for long-term survival is greatly improved.

For colitis-associated colorectal cancers, as for noncolitic cancers, histologic stage is the most important variable determining postoperative survival. The distribution of stages in our series and the survival rates within each stage did not differ appreciably from the distributions and survival rates reported for noncolitic colorectal cancers.

Curative gastric resection was achieved in 66% of patients and resulted in a significant prolongation of survival as compared with patients who had a palliative procedure. Wedge resection of tumor or partial gastric resection appears to be an acceptable surgical approach to these tumors as long as negative margins can be obtained. Chemotherapy, radiation therapy and debulking surgery did not result in significant prolongation of survival in the face of advanced disease. None of the staging systems for gastric sarcoma currently in use is completely satisfactory. Tumor grade and extent of disease seem to be the most important factors when determining prognosis or considering adjuvant therapy.

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