Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells

Birkenkamp‐Demtröder, Karin; Maghnouj, Abdelouahid; Mansilla, Francisco; Thorsen, Kasper; Andersen, Claus Lindbjerg; Øster, Bodil; Hahn, Stephan A.; Ørntoft, Torben F.

doi:10.1038/bjc.2011.268

Cited by 97 publications

(119 citation statements)

References 29 publications

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“…However, the protein has two GG domains, consisting of two well-conserved Gly residues, one G8 domain that contains eight conserved Gly residues in five β-strand pairs (24,25), four PbH1 domains (26), and seven predicted N-glycosylation sites (26). In the present study, we have shown that mutations of the ARG 187 residue (R187C and R187H) located in the GG domain eliminate HA-degrading activity.…”

Section: Discussionmentioning

confidence: 60%

“…Although further studies are needed to obtain direct evidence, it is tempting to speculate that enhanced degradation and release of HA from the skin by fibroblasts overexpressing KIAA1199 may contribute to the clinical characteristic of Werners syndrome. Previous studies have shown that KIAA1199 is up-regulated in gastric and colorectal cancers and immortalized renal cell carcinomas, and a splice variant is detected in primary colon adenocarcinomas, although the functional significance of these findings is not clear (21,26,38). In addition, enhanced expression and activity of HYAL1 and HYAL2/CD44 are reportedly related to growth and malignancy of tumor cells (11,39).…”

Section: Discussionmentioning

confidence: 93%

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KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization

Yoshida¹,

Nagaoka²,

Kusaka-Kikushima³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

216

305

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Hyaluronan (HA) has an extraordinarily high turnover in physiological tissues, and HA degradation is accelerated in inflammatory and neoplastic diseases. CD44 (a cell surface receptor) and two hyaluronidases (HYAL1 and HYAL2) are thought to be responsible for HA binding and degradation; however, the role of these molecules in HA catabolism remains controversial. Here we show that KIAA1199, a deafness gene of unknown function, plays a central role in HA binding and depolymerization that is independent of CD44 and HYAL enzymes. The specific binding of KIAA1199 to HA was demonstrated in glycosaminoglycan-binding assays. We found that knockdown of KIAA1199 abolished HA degradation by human skin fibroblasts and that transfection of KIAA1199 cDNA into cells conferred the ability to catabolize HA in an endo-β-N-acetylglucosaminidase-dependent manner via the clathrin-coated pit pathway. Enhanced degradation of HA in synovial fibroblasts from patients with osteoarthritis or rheumatoid arthritis was correlated with increased levels of KIAA1199 expression and was abrogated by knockdown of KIAA1199. The level of KIAA1199 expression in uninflamed synovium was less than in osteoarthritic or rheumatoid synovium. These data suggest that KIAA1199 is a unique hyaladherin with a key role in HA catabolism in the dermis of the skin and arthritic synovium. HA is ubiquitously present as a major constituent of the extracellular matrix (ECM) in vertebrate tissues, providing structural and functional integrity to cells and organs. Although many organs maintain high concentrations of HA, skin contains approximately half the total body HA (1). HA is rapidly depolymerized within tissues, from extralarge native molecules of 1,000-10,000 kDa, to intermediate-size fragments of 10-100 kDa present in the extracellular milieu (2). Approximately one-third of total body HA is replaced daily, and the skin is a major determinant organ for HA turnover, with a metabolic half-life of 1-1.5 d (2). HA degradation is enhanced under certain pathological conditions and its lower molecular weight products are commonly detected in diseases, such as arthritis and cancers (3-5). The reduced average molecular weight of HA (as low as 200 kDa) in synovial fluids from patients with osteoarthritis (OA) or rheumatoid arthritis (RA) leads to decreased synovial viscosity and is associated with synovial inflammation (6). In addition, much lower molecular weight HA fragments (∼20 kDa) are known to stimulate neovascularization and facilitate tumor cell motility and invasion (5,7,8).There are six human hyaluronidase-related genes clustered on two chromosomal loci, 3p21.3 (HYAL1, HYAL2, and HYAL3) and 7q31.3 (HYAL4, HYALP1, and SPAM1) (9). However, because HYALP1 is a pseudogene (9), and HYAL4 and SPAM1 have restricted expression patterns, HYALP1, HYAL4, and SPAM1 are unlikely to have major roles in constitutive HA degradation in vivo. HYAL3 has a restricted expression pattern (9) and its ability to degrade HA is questionable (10). Therefore, HYAL1 and HYAL2 are most likely ...

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 93%

KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization

Yoshida¹,

Nagaoka²,

Kusaka-Kikushima³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

216

305

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“…For example, KIAA1199 was significantly downregulated by B-Raf or MEK inhibition. KIAA1199 emerges as a marker of poor prognosis in several tumor entities, including colorectal carcinoma, but has never been linked to BRAF mutations before (39,40,55). Its activity as a promoter of cell migration in noncolorectal carcinoma cell lines (55) fits well to the strong reduction of invasive behavior of Colo-205 cells with inhibition or knockdown of B-Raf V600E .…”

Section: V600ementioning

confidence: 76%

B-Raf Inhibitors Induce Epithelial Differentiation in BRAF-Mutant Colorectal Cancer Cells

et al. 2015

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BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf V600E oncoprotein. Doxycyclin-inducible knockdown of endogenous B-Raf V600E decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell-cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-Raf V600E in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells.

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“…24 The KIAA1199 transcript functions in Wnt pathway signaling and is upregulated in colorectal cancer with respect to normal mucosa. [25][26][27] Lymphocyte antigen 6 complex is overexpressed in non-small cell lung cancer and esophageal squamous cell carcinoma, and its inhibition has been shown to suppress tumor growth. 28 In conclusion, classifiers derived from transcriptomic profiles distinguish malignant and normal rectal epithelium with near certainty.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiles Differentiate Normal Rectal Epithelium and Adenocarcinoma

Hogan

DeJulius

Liu

et al. 2015

International Surgery

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Adenocarcinoma is a histologic diagnosis based on subjective findings. Transcriptional profiles have been used to differentiate normal tissue from disease and could provide a means of identifying malignancy. The goal of this study was to generate and test transcriptomic profiles that differentiate normal from adenocarcinomatous rectum. Comparisons were made between cDNA microarrays derived from normal epithelium and rectal adenocarcinoma. Results were filtered according to standard deviation to retain only highly dysregulated genes. Genes differentially expressed between cancer and normal tissue on two-groups t test (P , 0.05, Bonferroni P value adjustment) were further analyzed. Genes were rank ordered in terms of descending fold change. For each comparison (tumor versus normal epithelium), those 5 genes with the greatest positive fold change were grouped in a classifier. Five separate tests were applied to evaluate the discriminatory capacity of each classifier. Genetic classifiers derived comparing normal epithelium with malignant rectal epithelium from pooled stages had a mean sensitivity and specificity of 99.6% and 98.2%, respectively. The classifiers derived from comparing normal and stage I cancer had comparable mean sensitivities and specificities (97% and 98%, respectively). Areas under the summary receiver-operator characteristic curves for each classifier were 0.981 and 0.972, respectively. One gene was common to both classifiers. Classifiers were tested in an independent Gene Expression Omnibus-derived dataset. Both classifiers retained their predictive properties. Transcriptomic profiles comprising as few as 5 genes are highly accurate in differentiating normal from adenocarcinomatous rectal epithelium, including early-stage disease.

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Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells

Cited by 97 publications

References 29 publications

KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization

KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization

B-Raf Inhibitors Induce Epithelial Differentiation in BRAF-Mutant Colorectal Cancer Cells

Transcriptomic Profiles Differentiate Normal Rectal Epithelium and Adenocarcinoma

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