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Background: The KIAA1199 transcript is upregulated in colon adenomas and downregulated upon β-catenin knockdown., Methods: Transcript profiling was performed on >500 colon biopsies, methylation profiling data were compared with transcript data. Immunohistochemistry assessed KIAA1199 protein expression in 270 stage II/III tumours (>3 years follow-up). The effects of stable KIAA1199 knockdown in SW480 cells (three different constructs) were studied using transcriptional profiling, proliferation and protein analysis., Results: The KIAA1199 transcript was strongly upregulated in 95% of adenocarcinomas. Absent expression in normal mucosa correlated with KIAA1199 promotor methylation. Nuclear and cytoplasmic KIAA1199 protein expression was identified in colon adenocarcinomas and other types of cancers. A subpopulation of patients with tumours strongly expressing KIAA1199 in the nucleus showed a better outcome with regard to recurrence as lung or liver metastases. The KIAA1199 knockdown affected the cell cycle and the Wnt-signalling pathway. Reduced cellular proliferation and decreased KI67, phosphorylated retinoblastoma, β-catenin and ASCL2 protein expression supported these findings. Eighteen Wnt-signalling genes differentially expressed upon KIAA1199 knockdown correlated with the KIAA1199 expression profile in clinical specimens., Conclusion: The KIAA1199 knockdown attenuates the effects of the Wnt/β-catenin signalling and it may thus be regarded as a regulatory part of this pathway.

The alteration of the choline metabolite profile is a well-established characteristic of cancer cells. In colorectal cancer (CRC), phosphatidylcholine is the most prominent phospholipid. In the present study, we report that lysophosphatidylcholine acyltransferase 1 (LPCAT1; NM&#95;024830.3), the enzyme that converts lysophosphatidylcholine into phosphatidylcholine, was highly overexpressed in colorectal adenocarcinomas when compared to normal mucosas. Our microarray transcription profiling study showed a significant (p < 10(-8)) transcript overexpression in 168 colorectal adenocarcinomas when compared to ten normal mucosas. Immunohistochemical analysis of colon tumors with a polyclonal antibody to LPCAT1 confirmed the upregulation of the LPCAT1 protein. Overexpression of LPCAT1 in COS7 cells localized the protein to the endoplasmic reticulum and the mitochondria and increased LPCAT1 specific activity 38-fold. In cultured cells, overexpressed LPCAT1 enhanced the incorporation of [(14)C]palmitate into phosphatidylcholine. COS7 cells transfected with LPCAT1 showed no growth rate alteration, in contrast to the colon cancer cell line SW480, which significantly (p < 10(-5)) increased its growth rate by 17%. We conclude that LPCAT1 may contribute to total choline metabolite accumulation via phosphatidylcholine remodeling, thereby altering the CRC lipid profile, a characteristic of malignancy.

Background: The identification of new prognostic markers in prostate cancer (PC) is essential to improve patient treatment and management. Data suggest that SMARCC1 protein, a part of the intranuclear SWI/SNF complex which enhances the transactivation of the androgen receptor, is upregulated in PC and therefore a possible candidate marker for PC progression., Materials: Expression of SMARCC1 immunostaining was analysed on a tissue microarray containing specimens from 327 patients with prostate cancer and clinical follow-up information. Furthermore, 30 specimens from patients with benign prostate hyperplasia were included as controls as well as 30 specimens of benign prostate tissue from PC patients. Also, 18 specimens from lymph node metastases were analysed., Results: All benign specimens showed no or minimal staining for SMARCC1. In contrast, 20% of the specimens from patients with non-metastatic and non-recurrent disease showed moderate to marked staining. In 31% of the patients with recurrent disease and in 31% of the patients with metastatic disease we found moderate to strong SMARCC1 immunostaining. In total, 23% of lymph node metastases expressed SMARCC1. SMARCC1 expression was also positively correlated to Gleason score (p<0.05), clinical T stage (p<0.01) and time to recurrence (p<0.001). In a logistic regression analysis, patients with a marked SMARCC1 immunostaining had a significantly elevated odds ratio (OR) of 16 for recurrent cancer and an OR of 4.5 for metastatic disease. Conclusions. Our present results demonstrate an increased expression of SMARCC1 protein in prostate cancer and reveal a positive correlation with tumour dedifferentiation, progression, metastasis and time to recurrence.

Transcript profiling of 27 normal colon mucosas and 258 adenocarcinomas showed Keratin23 to be increased in 78% microsatellite-stable tumors, while microsatellite-instable tumors showed low transcript levels, comparable to normal mucosas. Immunohistochemical analyses demonstrated that 88% of microsatellite-instable tumors were negative for Keratin23 protein, while 70% of MSS tumors and metastases derived from MSS-tumors showed high Keratin23 levels. Immunofluorescence analysis localized Keratin23 in the Golgi-apparatus. Golgi accumulation was unique for gastrointestinal adenocarcinomas. Immunoprecipitation and 2D-blot analysis revealed Keratin23 to be a 46.8 kDa phosphoprotein. Keratin23 impaired the proliferation of human colon cancer cells significantly, leading to cell death in microsatellite-instable but not microsatellite-stable cell lines, while COS7 cells experienced multiple nuclei and apoptosis. Keratin23 expression correlated significantly with transcription factor CEBPB. In conclusion, Keratin23 expression is a novel and important difference between microsatellite-stable and microsatellite-instable colon cancers.