RESUMO
This review concentrates on one main aspect of cancerization in the oesophagus and stomach: principally, intestinal metaplasia. There are at least two other important pathways that lead to cancer and do not need such a morphological transformation. One is the gastric type of carcinoma on the Lauren classification, which arises directly from the stem cell zone and is the signet ring form of cancer, while the other is spasmolytic polypeptide-expressing metaplasia (SPEM)--spasmolytic polypeptide (TFF2) expressing metaplasia, where the gastric glands become filled with TFF2-expressing cells and may also lead to gastric dysplasia and cancer. The development of intestinal metaplasia is complex. Here, we examine intestinal metaplasia in molecular terms, noting the over-expression of Cdx1, Cdx2, Pdx1, Oct1, TFF3 and the downregulation of Hedgehog signalling; Runx3 is deactivated by epigenetic silencing, and pathways such as Wnt and MARK/ERK are involved. These changes start to explain the principles of the development of intestinal metaplasia and suggest that the regulation of these genes is of importance in the development of gastric cancer.
Assuntos
Neoplasias Intestinais/genética , Lesões Pré-Cancerosas/genética , Neoplasias Gástricas/genética , Animais , Fator de Transcrição CDX2 , Transformação Celular Neoplásica/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Regulação para Baixo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Marcadores Genéticos , Proteínas de Homeodomínio/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Neoplasias Intestinais/patologia , Metaplasia/genética , Transportador 1 de Cátions Orgânicos/genética , Fenótipo , Lesões Pré-Cancerosas/patologia , Proteínas Serina-Treonina Quinases/genética , Neoplasias Gástricas/patologia , Transativadores/genética , Fator Trefoil-2 , Proteína Wnt1/genéticaRESUMO
We studied the irreversible thermal denaturation of chymopapain, a papain-related cysteine proteinase. It was found that this process follows simple first-order kinetics under all conditions tested. Rate constants determined by monitoring ellipticity changes at 220 or 279 nm are essentially identical, indicating that denaturation involves global unfolding of the protein. Enthalpies (DeltaH(double dagger)) and entropies (DeltaS(double dagger)) of activation for unfolding were determined at various pH values from the temperature dependence of the rate constant. In the pH range 1.1-3.0, a large variation of both DeltaH(double dagger) and DeltaS(double dagger) was observed. For the few proteins studied so far (lysozyme, trypsin, barnase) it is known that activation parameters for unfolding vary little with pH. It is proposed that this contrasting behavior of chymopapain originates from the numerous ion pairs - especially those with low solvent accessibilities - present in its molecular structure. In contrast, fewer, more exposed ion pairs are present in the other proteins mentioned above. Our results were analyzed in terms of differences in the protonation behavior of carboxylic groups between the transition (TS) and native (N) states of the protein. For this purpose, a model of independently titrating sites was assumed, which explained reasonably well the pH dependence of activation parameters, as well as the protonation properties of native chymopapain. According to these calculations, pK values of carboxyls in TS are shifted 0.6-0.9 units upwards with respect to those in N. In addition, some groups in TS appear to be protonated with unusually large enthalpy changes.
