BACKGROUND The authors suggested that the loss of collagen IV and laminin‐containing basement membrane and the loss of Disabled‐2 (Dab2) expression were two critical events associated with morphologic dysplastic changes of the ovarian surface epithelium as a step in tumorigenicity. Both the basement membrane and Dab2, a candidate tumor suppressor of ovarian carcinoma, were involved in epithelial cell surface positioning and organization. The authors speculated that the purging of the basement membrane may be similar to the proteolysis during gonadotropin‐stimulated ovulation, a cyclooxygenase 2 (Cox‐2)‐mediated process. METHODS Prophylactic oophorectomy is used to prevent breast and ovarian carcinoma in high‐risk populations. These ovarian tissue specimens often contain an increased presence of morphologically abnormal lesions that are believed to be preneoplastic. The authors evaluated archived prophylactic oophorectomy specimens to verify whether the loss of Dab2 expression and the removal of the basement membrane that occur at the ovarian surface and inclusion cyst epithelia are molecular markers of preneoplastic lesions. Of the 36 samples containing identifiable ovarian surface epithelial components on slides, immunostaining was employed to evaluate the intactness of the basement membrane (periodic acid–Schiff [PAS], collagen IV, and laminin) and the expression of Dab2 and Cox‐2. Expression of Cox‐1 and Cox‐2 also were evaluated in cultured ovarian surface epithelial cells prepared from ovarian tissue specimens removed from patients who underwent prophylactic surgery. RESULTS The morphologically normal ovarian surface epithelium typically contained a collagen IV‐ and laminin‐positive basement membrane, which also was detected by PAS staining. Many morphologically altered areas, such as papillomatosis, invaginations, inclusion cysts, stratification, adenomas, and microscopic adenocarcinomas, were found in these specimens. Both the morphologically altered and adjacent morphologically normal epithelia consistently exhibited loss of basement membrane and/or Dab2 expression and an increase in Cox‐2 staining. Frequently, an increase in Cox‐2 staining was correlated with the loss of epithelial basement membrane in morphologically normal areas. CONCLUSIONS The loss of Dab2 and basement membrane and the overexpression of Cox‐2 were observed in presumptive neoplastic precursor areas of oophorectomy specimens obtained from a population at high risk for ovarian carcinoma. Transient loss of collagen IV and laminin in the basement membrane of the preneoplastic epithelium and the loss of Dab2 expression are common early events associated with morphologic alteration and tumorigenicity of the ovarian surface epithelium. The authors concluded that Cox‐2 overexpression may play a role in the purging of basement membrane of the ovarian surface epithelium, mimicking the process of ovulation. Further experiments may be able to test the hypothetical model derived from these histologic observations. Cancer 2003;98:2607–23. ...
The M(3) muscarinic cholinergic receptor has important physiological functions on normal colonic cells. It is frequently expressed on human colon cancer cells and is biologically active. Although it is mitogenic in certain cell models, the importance of this receptor on colon carcinogenesis is unknown. In the present study we have determined expression of the M(3) receptor on human colon cancer tissue compared with matched normal tissue and examined the downstream effect of receptor activation in the HT-29 human colon carcinoma cell line. Using reverse transcription-PCR, M(3) receptor RNA expression was detected in all matched colon carcinoma and normal specimens from eight patients. Five of the eight (62%) patients showed an up to 8-fold greater level of M(3) receptor expression in cancer compared with the matched normal tissue. Exposure of HT-29 cells to carbachol, a stable receptor agonist, results in a 10-fold increase in cyclooxygenase-2 (COX-2) protein. This induction of COX-2 protein was dose dependent and was inhibited by the cholinergic receptor antagonist N-methylscopolamine (NMS). Carbachol caused a dose-dependent increase in prostaglandin E(2) (PGE(2)), the main product of cyclooxygenase activity. The maximum stimulatory effect (40-fold increase) was noted with 1mM carbachol. The increase in PGE(2) was completely abolished by NMS and by the COX-2 selective inhibitor NS398. This suggests that the M(3) receptor mediates PGE(2) production by a mechanism involving COX-2. As COX-2 and PGE(2) are known promoters of gastrointestinal cancer, these data suggest that M(3) receptor activation may facilitate progression of colon carcinoma, in part by a COX-2-mediated cellular mechanism.
Induction of many primary-response genes by a variety of stimuli occurs in a transient manner. The precise mechanism responsible for these transient kinetics is not completely understood. We report here that the orphan nuclear receptor, TIS1, which is a potent sequence-specific transcription factor, was transiently induced by the adrenergic agonist isoprenaline in the C2C12 skeletal-muscle cell line. Moreover, we showed that the rapid decline in mRNA level after peak induction was due in part to a specific desensitization of the isoprenaline-mediated induction pathway. Desensitization of the induction response presumably occurred at the level of the receptor, as agents that either bypass the adrenergic receptor or activate alternative signalling pathways were able to induce TIS1 expression in the desensitized cells. However, stimulation by agents that directly activate intracellular enzymes also resulted in the signal-transduction-pathway-specific desensitization of TIS1 inducibility. Our results suggest that the pathway-specific nature of the desensitization process may be important for directing an integrated response to multiple physiological stimuli.
Paraquat has been implicated as an environmental toxin which may induce the syndrome of Parkinson's disease after exposure to this agent. However, the biochemical mechanism by which paraquat causes cell death and neurodegeneration has not been extensively studied. Paraquat was rapidly taken up by nerve terminals isolated from mouse cerebral cortices. It induced lipid peroxidation in a concentration dependent manner in the presence of NADPH and ferrous ion. The maximal stimulation effect was obtained at a paraquat concentration around 100 microM and the Km value for paraquat was 46.7 microM. The lipid peroxidation required microsomal enzymes. Antioxidants, such as superoxide dismutase, catalase and promethazine significantly inhibited paraquat-induced lipid peroxidation. Due to its structural similarity to the pyridinium compound MPP+ (N-methyl-4-phenyl pyridium ion), it may be taken up by dopamine neurons and cause lipid peroxidation and cell death resulting in the manifestation of Parkinsonian syndrome.
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