NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling

Abstract

The activity of the Wnt pathway undergoes complex regulation to ensure proper functioning of this principal signaling mechanism during development of adult tissues. The regulation may occur at several levels and includes both positive and negative feedback loops. In the present study we employed one of such negative feedback regulators, naked cuticle homolog 1 (Nkd1), to follow the Wnt pathway activity in the intestine and liver and in neoplasia originated in these organs. Using lineage tracing in transgenic mice we localized Nkd1 mRNA to the bottom parts of the small intestinal crypts and hepatocytes surrounding the central vein of the hepatic lobule. Furthermore, in two mouse models of intestinal tumorigenesis, Nkd1 expression levels were elevated in tumors when compared to healthy tissue. We utilized a collection of human intestinal polyps and carcinomas to confirm that NKD1 represents a robust marker of neoplastic growth. In addition, expression analysis of NKD1 in liver cancer showed that high expression levels of the gene distinguish a subclass of hepatocellular carcinomas related to aberrant Wnt signaling. Finally, our results were confirmed by bioinformatic analysis of large publicly available datasets that included gene expression profiling and high-throughput sequencing data of human colon and liver cancer specimens.

Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events

“…4b). For example, two out of three genic lncRNAs associated here with mutations in CTNNB1 (β-catenin) co-localize with NKD1 , an established transcriptional target of β-catenin complexes51 and a marker of aberrant Wnt/β-catenin signalling52 (Fig. 4c shows RP11-401P9.6 , antisense intronic to NKD1 ).…”

Sensitivity analysis based ranking reveals unknown biological hypotheses for down regulated genes in time buffer during administration of PORCN-WNT inhibitor ETC-1922159 in CRC†

“…The implication of these low rankings indicate or confirm the effectiveness of the pipeline in assigning appropriate biologically induced priority to the ETC-1922159 influenced down regulation of these genes. Surprisingly, BMP7 [100] and NKD1 [101] are known to be highly expressed in colorectal cancer case and were down regulated after the drug treatment. But these were assigned high rank with RNF43.…”

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

“…In agreement with the fluorescent microscopy images, we observed temporal downregulation in mRNA levels of genes specifically expressed in cells located at the bottom of the crypt. The genes included Paneth cell markers ephrin receptor B3 ( EphB3 ) and lysozyme 1 ( Lyz1 ) (van Es et al ., 2005) or genes with broader expression in various crypt cells such as division cycle associated 7 ( Cdca7 ), ephrin receptor B2 ( EphB2 ), naked cuticle homolog 1 ( Nkd1 ), and SRY (sex determining region Y)‐box 9 ( Sox9 ) (Batlle et al ., 2002; Schuijers et al ., 2015; Stancikova et al ., 2015). Remarkably, the most robust downregulation was recorded for three genes that encode Wnt signaling‐activated markers of ISCs achaete‐scute complex homolog 2 ( Ascl2 ), Lgr5 , and Troy (Fafilek et al ., 2013; van der Flier et al ., 2009).…”