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Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia.

ABSTRACT: Although a protective role for mesalamine against colon cancer in ulcerative colitis has been shown epidemiologically, its molecular mechanism is unknown. We cloned and sequenced a novel human tropomyosin (hTM) isoform, TC22, which is an alternatively spliced variant of normal epithelial hTM isoform 5 (hTM5), identical apart from 25 C-terminal amino acids. TC22 is expressed in 100% of colorectal carcinoma but is not expressed in normal colon epithelial cells. To explore a molecular mechanism of chemoprevention, we examined the effect of mesalamine on TC22 expression using LS180 colon cancer cells. Expression of hTM5 and TC22 was investigated at the protein and gene levels by fluorescence-activated cell sorting and real-time reverse transcription-polymerase chain reaction. Small interference RNA (siRNA) against the TC22 variant were transfected into LS180 colon cancer cells, reducing protein and transcript levels by 45 to 50%. Mesalamine or sulfasalazine (2 mM), but not sulfapyridine, significantly (p < 0.02-0.006) reduced the expression of the TC22 transcript and significantly (p < 0.05 to <0.0002) reduced the expression of TC22 protein in a dose-dependent and reversible manner. Rosiglitazone, a specific peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, similarly and significantly (p < 0.002) reduced TC22 protein expression. A polymerase chain reaction array of 84 cancer-related genes performed on TC22 siRNA-transfected cells demonstrated a significant (more than two times) change in targets involved in apoptosis, adhesion, angiogenesis, and tissue remodeling. We conclude that mesalamine, sulfasalazine, and rosiglitazone significantly reduced the cellular expression of TC22, implicating PPARgamma in this modulation. Similar suppression of TC22 by siRNA produced gene level changes on several critical carcinogenic pathways. These findings suggest a novel antineoplastic molecular effect of mesalamine.

SUBMITTER: Das KK

PROVIDER: S-EPMC2701462 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia.

Das Koushik K KK Bajpai Manisha M Kong Yingxin Y Liu Jianying J Geng Xin X Das Kiron M KM

Molecular pharmacology 20090415 1

Although a protective role for mesalamine against colon cancer in ulcerative colitis has been shown epidemiologically, its molecular mechanism is unknown. We cloned and sequenced a novel human tropomyosin (hTM) isoform, TC22, which is an alternatively spliced variant of normal epithelial hTM isoform 5 (hTM5), identical apart from 25 C-terminal amino acids. TC22 is expressed in 100% of colorectal carcinoma but is not expressed in normal colon epithelial cells. To explore a molecular mechanism of ...[more]

PMID: 19369484

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Project description:We have performed the first extensive profiling of Epstein-Barr virus (EBV) miRNAs on in vivo derived normal and neoplastic infected tissues. We describe a unique pattern of viral miRNA expression by normal infected cells in vivo expressing restricted viral latency programs (germinal center: Latency II and memory B: Latency I/0). This includes the complete absence of 15 of the 34 miRNAs profiled. These consist of 12 BART miRNAs (including approximately half of Cluster 2) and 3 of the 4 BHRF1 miRNAs. All but 2 of these absent miRNAs become expressed during EBV driven growth (Latency III). Furthermore, EBV driven growth is accompanied by a 5-10 fold down regulation in the level of the BART miRNAs expressed in germinal center and memory B cells. Therefore, Latency III also expresses a unique pattern of viral miRNAs. We refer to the miRNAs that are specifically expressed in EBV driven growth as the Latency III associated miRNAs. In EBV associated tumors that employ Latency I or II (Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric carcinoma), the Latency III associated BART but not BHRF1 miRNAs are up regulated. Thus BART miRNA expression is deregulated in the EBV associated tumors. This is the first demonstration that Latency III specific genes (the Latency III associated BARTs) can be expressed in these tumors. The EBV associated tumors demonstrate very similar patterns of miRNA expression yet were readily distinguished when the expression data were analyzed either by heat-map/clustering or principal component analysis. Systematic analysis revealed that the information distinguishing the tumor types was redundant and distributed across all the miRNAs. This resembles "secret sharing" algorithms where information can be distributed among a large number of recipients in such a way that any combination of a small number of recipients is able to understand the message. Biologically, this may be a consequence of functional redundancy between the miRNAs.

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Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia.

Publications

Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia.

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