RELP, a Novel Human Reg-Like Protein with Up-Regulated Expression in Inflammatory and Metaplastic Gastrointestinal Mucosa

Kämäräinen, Meerit; Heiskala, Kukka; Knuutila, Sakari; Heiskala, Marja; Winqvist, Ola; Andersson, Leif C.

doi:10.1016/s0002-9440(10)63625-5

Cited by 50 publications

(57 citation statements)

References 34 publications

(19 reference statements)

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“…Total RNA (20 mg) was extracted 12 h after stimulation with cytokines or growth factors and analyzed by Northern blotting using 32 P-labeled cDNAs for REG IV and GAPDH mRNA. by Kämäräinen 17 and Oue et al, 18 and suggests functional roles for REG IV protein in normal colonic mucosa. However, in UC tissues REG IV expression is abundantly enhanced, and the distributions of positivity for REG IV and chromogranin A were apparently distinct.…”

Section: Effects Of Cytokines and Growth Factors On Reg IV Gene Exprementioning

confidence: 93%

Expression of the REG IV gene in ulcerative colitis

Nanakin

Fukui

Fujii

et al. 2007

Laboratory Investigation

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The regenerating gene (REG) IV gene was isolated from a cDNA library of ulcerative colitis (UC) tissues. However, its role in the pathophysiology of UC and subsequent development of colitic cancer is still unclear. We investigated the expression of the REG IV gene in UC and colitic cancer tissues and examined whether cytokines or growth factors are responsible for REG IV gene expression and whether REG IV gene induction affects cell growth and apoptosis in colon cancer cells. The expressions of REG IV and growth factor genes in UC tissues were analyzed by real time reverse transcription-polymerase chain reaction. The effects of cytokines and growth factors on REG IV gene expression were examined in SW403 cells by Northern blot analysis. The effects of REG IV gene induction on cell growth and H 2 O 2 -induced apoptosis were examined in DLD-1 cells by MTT and TUNEL assays, respectively. REG IV mRNA was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG IV mRNA expression was correlated with that of basic fibroblast growth factor (bFGF) as well as hepatocyte growth factor (HGF) mRNA expression in UC tissues. The REG IV gene expression in SW403 colon cancer cells was enhanced by stimulation with transforming growth factor-a, epidermal growth factor, bFGF, and HGF. REG IV gene induction promoted cell growth and conferred resistance to H 2 O 2 -induced apoptosis in DLD-1 cells. The REG IV gene is inducible by growth factors and may function as a growth promoting and/or an antiapoptotic factor in the pathophysiology of UC. The pathogenesis of ulcerative colitis (UC) is still unclear, but dysregulated immune function appears to be involved in its chronic inflammatory process, resulting in continuous damage of the colonic mucosa. [1][2][3][4][5] To regenerate the injured colonic tissues, growth factors are thought to play very important roles, and indeed, several growth factors are reported to be upregulated in the colonic tissues in UC. 3,6,7 However, few comprehensive studies have examined the expression patterns of various growth factors in UC tissues simultaneously, and the network of and the relationships among growth factors in UC tissues are not fully understood.Regenerating gene (REG) IV, the most recently discovered member of the REG gene family, was isolated from a cDNA library of UC tissues by Hartupee et al. 8 Although the biological function of REG IV protein is still unclear, REG IV protein may play a role in cell growth because other REG family proteins have been shown to act as growth factors in gastrointestinal organs. 9-14 However, it still remains unknown whether the REG IV gene is indeed involved in the pathophysiology of UC and whether REG IV protein really functions as a growth factor. Moreover, it has not been examined how REG IV gene expression is regulated. In the present study, therefore, in order to elucidate roles for REG IV in the pathophysiology of UC, we investigated the relationship between REG IV gene expression and clinicopat...

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Section: Effects Of Cytokines and Growth Factors On Reg IV Gene Exprementioning

confidence: 93%

Expression of the REG IV gene in ulcerative colitis

Nanakin

Fukui

Fujii

et al. 2007

Laboratory Investigation

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“…Cells were seeded on a 24-well plate at a density of 4x10 4 cells/well for HT-29 and 1.6x10 4 cells/ well for Caco-2/TC7. After 24 h, cells were stimulated with various concentrations (0.1-100 nM) of recombinant human REG4 (rREG4; BioVendor, Heidelberg, Germany) for 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…As reported in numerous publications, increased expression of REG proteins in various tissues is often related to injury, inflammation or carcinogenesis supporting the multifunctionality of these proteins (1,2). REG4, the most recent member of the REG gene family to be characterized, was first identified as being up-regulated in ulcerative colitis which suggests that REG4 protein may play a role in inflammatory bowel diseases (3)(4)(5). It has been shown that REG4 is also overexpressed in cancers of the stomach, colon, pancreas and prostate (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 90%

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Rafa

Dessein²,

Devisme³

et al. 2010

Int J Oncol

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Abstract. REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.

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“…1A). This gene encodes a secreted protein containing a conserved domain found in C-type lectin carbohydrate recognition domain (15). Another Reg family member, RegIIIγ, has convincingly been shown to serve an antibacterial function (16).…”

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confidence: 99%

Reg4 ⁺ deep crypt secretory cells function as epithelial niche for Lgr5 ⁺ stem cells in colon

Sasaki

Sachs

Wiebrands

et al. 2016

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

253

225

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(1,2). Although the stem cell niche varies in nature and location between different organs, in general terms it provides a unique signaling environment to maintain tissue homeostasis, inhibit stem cell loss, and control cell differentiation (1, 3, 4). The mammalian small intestine (SI) and colon represent unique models to study tissue stem cells and their niches because of their stereotypic and compact architecture combined with their exceedingly fast self-renewing kinetics (5, 6). In both SI and colon crypts, cycling stem cells are marked by leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) (7). Murine SI stem cells divide approximately every 24 h to fill a proliferative transit-amplifying compartment that occupies the remainder of the crypts. Cells exiting crypts arrest their cell cycle, differentiate, and move up the flanks of the villi. One of the differentiated cell types derived from the SI stem cell, the Paneth cell, is located at crypt bottoms and is in direct contact with Lgr5 stem cells. It produces factors that promote stem cell maintenance, including epidermal growth factor (EGF) and the related TGF-α, the Notch ligands Dll-1 and Dll-4, and Wnt3 (8-10). Whereas Paneth cells are dispensable for in vivo crypt function (as niche factors are also secreted from nonepithelial cells), Paneth cells are indispensable for the growth of epithelial miniguts in culture (9,11,12

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RELP, a Novel Human Reg-Like Protein with Up-Regulated Expression in Inflammatory and Metaplastic Gastrointestinal Mucosa

Cited by 50 publications

References 34 publications

Expression of the REG IV gene in ulcerative colitis

Expression of the REG IV gene in ulcerative colitis

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Reg4 ⁺ deep crypt secretory cells function as epithelial niche for Lgr5 ⁺ stem cells in colon

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RELP, a Novel Human Reg-Like Protein with Up-Regulated Expression in Inflammatory and Metaplastic Gastrointestinal Mucosa

Cited by 50 publications

References 34 publications

Expression of the REG IV gene in ulcerative colitis

Expression of the REG IV gene in ulcerative colitis

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Reg4 + deep crypt secretory cells function as epithelial niche for Lgr5 + stem cells in colon

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Reg4 ⁺ deep crypt secretory cells function as epithelial niche for Lgr5 ⁺ stem cells in colon