Altered Expression and Localization of Creatine Kinase B, Heterogeneous Nuclear Ribonucleoprotein F, and High Mobility Group Box 1 Protein in the Nuclear Matrix Associated with Colon Cancer

Abstract

Identification of biomarkers could lead to the development of effective screening tests for colorectal cancer. A previous study from our laboratory showed specific alterations of nuclear structure in colon cancer. In an effort to characterize these biomarkers, protein spots were selected from separations made by two-dimensional gel electrophoresis, which were analyzed by mass spectrometry. The sequences obtained from the isolated spots revealed that they have close similarity to creatine kinase B (CKB) isoforms, heterogeneous nuclear ribonucleoprotein F (hnRNP F) and high mobility group box 1 protein (HMGB1) isoforms. To determine the expression of these proteins in colon cancer, expression was studied in 9 tumor and matched adjacent normal pairs, 5 donor colons, 16 polyps, 4 metastatic liver lesions and matched adjacent normal pairs, and 3 liver donors. CKB and hnRNP F were expressed in 78% and 89% of colon tumors, respectively. hnRNP F had a higher frequency of expression than CKB in premalignant polyps. With the establishment of differential expression of the proteins in colon cancer, their subcellular localization was analyzed. The subcellular fractions studied both showed high protein levels of hnRNP F in colon tumors compared with normal colon tissues. Surprisingly, subcellular levels of CKB were decreased in colon tumors, suggesting that the observed high CKB levels in nuclear matrix extracts are caused by the enhanced localization of CKB to the nuclear matrix during colon tumorigenesis. These results suggest an involvement of hnRNP F and CKB in colorectal cancer. Additionally, they suggest that hnRNP F is a potential marker for colorectal cancer progression. (Cancer Res 2006; 66(2): 763-9)

Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis

“…Second, chronic inflammation associated with IBD is a major risk factor for colitis-associated cancer. A number of studies have now identified reduced levels of CKB in colonic tumors (35,36), whereas studies using dominant negative CKB mutants have defined a correlation with molecular markers of epithelial-to-mesenchymal transition in colon cancer cells (37). Taken together, these observations provide a compelling argument for Cr supplementation as an adjuvant therapy to promote epithelial restitution and ameliorate mucosal inflammation via enhanced cellular energetics.…”

Comparative Proteomic Expression Profile in All-trans Retinoic Acid Differentiated Neuroblastoma Cell Line

“…This suggests hnRNP F as a potential marker for colorectal cancer progression. 62 Furthermore, the DDX1, eIF4A1, eIF4A2, eEF1-gamma, and LDH genes are detected in several NB cDNA libraries. Moreover, eIF4A1 mRNA has been shown to be consistently overexpressed in human melanoma cells in vitro, 63 in hepatocellular carcinoma 64,65 and in early stage non-smallcell lung cancer.…”

Human Mesenchymal Stem Cells Migrate toward Colon Cancer Partially Regulated by HMGB1

“…Indeed, several reports described the feasibility of using these cells as anti-cancer delivery vehicles since they secrete different anti-cancer molecules such as Tissue Necrosis Factor (TNF), TNF Related Apoptosis Inducing Ligand (TRAIL) or interferon (IFN)−β by gene modulation. These studies showed sufficient effect in suppressing tumor progression [10,23,41]. However, Karnoub et al suggested that MSCs have a supportive effect on tumor progression showing that co-injection of MSCs with breast cancer cell-line led to a higher degree of metastasis, but this effect was not significant in local tumor growth [20].…”

“…It was reported that the migration capacity of MSC toward tumors is partly regulated by HMGB1 mediated signaling [41]. We first measured secreted HMGB1 from 7 different human colon cancer cell lines (WiDr, LoVo, SW480, SW867, HT15, HCT29, and HCT115) as well as HUVEC and neonatal NHDF as controls by ELISA (Chondrex, WA, USA).…”