Except for the well-known immunoglobulin G (IgG) producing cell types, ie, mature B lymphocytes and plasma cells, various non-lymphoid cell types, including human cancer cells, neurons, and some specified epithelial cells, have been found to express IgG. In this study, we detected the expression of the heavy chain of IgG (IgGc) and kappa light chain (Igj) in papillary thyroid cancer cells. Using in situ hybridization, we detected the constant region of human IgG1 (IGHG1) in papillary thyroid cancer cells. With laser capture microdissection followed by RT-PCR, mRNA transcripts of IGHG1, Igj, recombination activating gene 1 (RAG1), RAG2, and activation-induced cytidine deaminase genes were successfully amplified from isolated papillary thyroid cancer cells. We further confirmed IgG protein expression with immunohistochemistry and found that none of the IgG receptors was expressed in papillary thyroid cancer. Differences in the level of IgGc expression between tumor size, between papillary thyroid cancer and normal thyroid tissue, as well as between papillary thyroid cancer with and without lymph node metastasis were significant. Taken together, these results indicate that IgG is produced by papillary thyroid cancer cells and that it might be positively related to the growth and metastasis of papillary thyroid cancer cells. Furthermore, it was demonstrated that IgGc colocalized with complement proteins in the same cancer cells, which could indicate that immune complexes were formed. Such immune complexes might consist of IgG synthesized by the host against tumor surface antigens and locally produced anti-idiotypic IgG with specificity for the variable region of these 'primary' antibodies. The cancer cells might thus escape the host tumor-antigen-specific immune responses, hence promoting tumor progression.
CF is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) which is an anion selective transmembrane ion channel that mainly regulates chloride transport, expressed in the epithelia of various organs. Recently, we have demonstrated CFTR expression in the brain, the spinal cord and the sympathetic ganglia. This study aims to investigate the expression and distribution of CFTR in the ganglia of the human gastrointestinal tract. Fresh tissue and formalin-fixed paraffin-embedded normal gastrointestinal tract samples were collected from eleven surgical patients and five autopsy cases. Immunohistochemistry, in situ hybridization, laser-assisted microdissection and nested reverse transcriptase polymerase chain reaction were performed. Expression of CFTR protein and mRNA was detected in neurons of the ganglia of all segments of the human gastrointestinal tract examined, including the stomach, duodenum, jejunum, ileum, cecum, appendix, colon and rectum. The extensive expression of CFTR in the enteric ganglia suggests that CFTR may play a role in the physiology of the innervation of the gastro-intestinal tract. The presence of dysfunctional CFTRs in enteric ganglia could, to a certain extent, explain the gastrointestinal symptoms frequently experienced by CF patients.
It has long been accepted that immunoglobulins (Igs) were produced by B lymphoid cells only. Recently Igs have been found to be expressed in various human cancer cells and promote tumor growth. Recombination activating gene 1 (RAG1) and RAG2, which are essential enzymes for initiating variable-diversity-joining segment recombination, have also been found to be expressed in cancer cells. However, the mechanism of RAG activation in these cancer cells has not been elucidated. Here, we investigated the regulatory mechanism of RAG expression in four human cancer cell lines by analyzing transcription factors that induce RAG activation in B cells. By RT-PCR, Western blot and immunofluorescence, we found that transcription factors E2A, FOXO1 and FOXP1 were expressed and localized to the nuclei of these cancer cells. Over-expression of E2A, FOXO1 or Foxp1 increased RAG expression, while RNA interference of E2A, FOXO1 or FOXP1 decreased RAG expression in the cancer cells. Chromatin immunoprecipitation experiments showed acetylation of RAG enhancer (Erag) and E2A, FOXO1 or FOXP1 were bound to Erag in vivo. These results indicate that in these cancer cells the transcription factors E2A, FOXO1 and FOXP1 regulate RAG expression, which initiates Ig gene rearrangement much in the way similar to B lymphocytes.
Recently immunoglobulin G (IgG) was found to be produced by neoplasms and promote tumor growth in cancer cell lines and animal models. To investigate the pathophysiological significance of cancer-produced IgG in breast cancer, we examined the expressions of IgG in 68 breast cancers including 40 primary cancers without metastasis and 28 cancers with axillary lymph node metastases. IgG gene expression was detected in all these samples. We found that IgG-expressing cancer cells were predominantly located in the periphery of the primary cancer nest and that these cells showed more cellular atypia and nuclear pleomorphism. We also found that the abundance of IgG-expressing cancer cells was higher and the cells were more evenly distributed in the metastatic cancer cells than that in the primary lesion. These findings suggest that IgG-expressing breast cancer cells have a more aggressive biological behavior than the IgG negative cancer cells and it could be an indicator for progression and metastasis of the disease. Co-localization of IgG and C1q complement was detected in both primary and metastatic lesions implying that immune complexes might be formed in situ. We speculate that such immune complexes might facilitate immune escape of cancer cells. Our findings suggest that locally produced IgG plays important roles in breast cancer, and may serve as a potential therapeutic target.
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