Transgenic overexpression of the oncofetal RNA binding protein KOC leads to remodeling of the exocrine pancreas

Wagner, Martin; Kunsch, Steffen; Duerschmied, Daniel; Beil, Michael; Adler, Guido; Mueller, Friederike; Gress, Thomas M.

doi:10.1016/s0016-5085(03)00402-5

Cited by 50 publications

(47 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…28 Although the precise mechanism and causal relationship are unknown, substitution of acinar parenchyma by tubular complexes in association with increased acinar proliferation is similarly observed in transgenic mice overexpressing KH domain containing protein overexpressed in cancer or the dominant-negative TGF beta type II receptor. 29,30 In our study, the transient feature of this response in both control and ElasCCK2 pancreas appears to represent a reaction to acinar cell trauma resulting from 1 single carcinogen exposure. 31 Second, our results provide evidence for a relationship between expression of the CCK2 receptor and the susceptibility to azaserine.…”

Section: Discussionmentioning

confidence: 52%

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Mathieu

Clerc

Portolan

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: G protein coupled receptors; CCK2 receptor; precancerous conditions; gastrin; transdifferentiation; experimental animal model; developmental gene Peptides of the cholecystokinin (CCK)/gastrin family are present in the gastrointestinal tract where they are known to physiologically regulate gallbladder and bowel motility, pancreatic and gastric secretion as well as growth and trophicity of gastrointestinal epithelial mucosa. 1 Two receptors that mediate the actions of cholecystokinin and gastrin have been pharmacologically classified as CCK1 and CCK2 receptors on the basis of their binding affinity for their natural ligands. While the CCK1 receptor is highly selective towards cholecystokinin vs. gastrin, the CCK2 receptor binds the 2 agonists with similar high affinities. 2 Both are G-protein coupled receptors with extrinsic tyrosine kinase activity. They activate many intracellular mediators classically described in the regulation of mitogenesis by growth factors. 3 Mitogen-activated protein kinases, ERK1/2, Jun kinase and p38MAPK, as well as the phosphatidylinositol 3-kinase (PI3K) and early responsive genes (c-fos, c-myc and c-jun), are known targets of gastrin. 4-7 Several groups including ours, have documented the contribution of Src and focal adhesion kinase (Fak) families' tyrosine kinases upstream the activation of these pathways. 4,8 The role of gastrin and CCK2 receptors as positive regulators of proliferation of normal...

show abstract

Section: Discussionmentioning

confidence: 52%

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Mathieu

Clerc

Portolan

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…6 AA vs. GG (non-obese controls), p = 0.03 (Mann-Whitney U-test). 7 AA vs. GG (non-obese T2D patients), p = 0.081 (Mann-Whitney U-test). 8 AA vs. GG (non-obese controls), p = 0.03 (Mann-Whitney U-test).…”

Section: Igf2bp2 Isoformmentioning

confidence: 97%

“…Their expression declines with development towards birth, and is low or undetectable in most adult animals [1]. Transgenic overexpression of IGF2BP3 causes subtle morphological alterations in the pancreas [7]. Loss-of-function analysis in Xenopus embryos indicated that the IGF2BP3 orthologue Vg1-RBP is required for establishment of the pancreatic fate within the endoderm [8].…”

mentioning

confidence: 99%

The rs11705701 G>A Polymorphism of IGF2BP2 is Associated With IGF2BP2 mRNA and Protein Levels in the Visceral Adipose Tissue - A Link to Type 2 Diabetes Susceptibility

Chistiakov

Nikitin²,

Сметанина³

et al. 2012

Rev Diabet Stud

View full text Add to dashboard Cite

■ AbstractBACKGROUND: Insulin-like growth factor 2 mRNAbinding protein 2 (IGF2BP2) regulates translation of IGF2, a growth factor that plays a key role in controlling fetal growth and organogenesis including adipogenesis and pancreatic development. In Caucasians, the rs4402960 G>T polymorphism of IGF2BP2 has been shown to predispose to type 2 diabetes (T2D) in multiple populations. In this study, we tested whether rs4402960 G>T and rs11705701 G>A contribute to the development of T2D in a Russian population. METHODS: Both markers were genotyped in Russian diabetic (n = 1,470) and non-diabetic patients (n = 1,447) using a Taqman allele discrimination assay. The odds ratio (OR) for the risk of developing T2D was calculated using logistic regression assuming an additive genetic model adjusted for age, sex, HbA1c, hypertension, obesity, and body mass index (BMI). Multivariate linear regression analyses were used to test genotype-phenotype correlations, and adjusted for age, sex, hypertension, obesity, and BMI. Expression of IGF2BP2 in the visceral adipose tissue was quantified using real-time PCR. The content of IGF2BP2 protein and both its isoforms (p58 and p66) in the adipose tissue was measured using Western blot analysis. RESULTS: There was no significant association between rs4402960 and T2D. Whereas, allele A of rs11705701 was associated with higher T2D risk (OR = 1.19, p < 0.001). Diabetic and non-diabetic carriers of genotype TT (rs4402960) had significantly increased HOMA-IR (p = 0.033 and p = 0.031, respectively). Nondiabetic patients homozygous for AA (rs11705701) had higher HOMA-IR (p = 0.04), lower HOMA-β (p = 0.012), and reduced 2-h insulin levels (p = 0.016). Non-obese individuals (diabetic and non-diabetic) homozygous for either AA (rs11705701) or TT (rs4402960) had higher levels of IGF2BP2 mRNA in the adipose tissue than other IGF2BP2 variants. Also, allele A of rs11705701 was associated with reduced amounts of the short isoform (p58) and increased levels of the long isoform (p66) of the IGF2BP2 protein in adipose tissue of non-obese diabetic and non-diabetic subjects. CONCLUSIONS: IGF2BP2 genetic variants contribute to insulin resistance in Russian T2D patients. The short protein isoform p58 of IGF2BP2 is likely to play an antidiabetogenic role in non-obese individuals.

show abstract

“…16 Moreover, another study showed that transgenic overexpression of IMP3 in the pancreas resulted in increased proliferation and metaplasia of acinar cells. 17 These findings might explain why IMP3 is associated with more aggressive cancers.…”

Section: Imp3 Expression In Endometrial Carcinomasmentioning

confidence: 99%

Expression of a novel oncofetal mRNA-binding protein IMP3 in endometrial carcinomas: diagnostic significance and clinicopathologic correlations

Zota

Woda

et al. 2007

Modern Pathology

View full text Add to dashboard Cite

Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is a newly identified oncofetal mRNA-binding protein that is involved in embryogenesis and carcinogenesis of some malignant neoplasms. To investigate the diagnostic and clinicopathologic significance of this protein in endometrial carcinomas, we evaluated immunohistochemical expression of IMP3 in the two most common forms of endometrial malignancies, endometrioid adenocarcinoma and serous carcinoma. We selected 167 endometrial adenocarcinoma cases including 122 cases of endometrioid adenocarcinoma and 45 cases of serous carcinoma. Twenty samples of benign endometrium obtained from 20 patients with nonmalignant uterine lesions were used as controls. Positive immunohistochemical stain for IMP3 was identified in all serous carcinoma cases, among which, 39 (86%) and 3 (7%) cases showed IMP3 immunoreactivity in 450%, and 21-50, or 6-20% of tumor cells, respectively. Immunohistochemical reaction intensity for IMP3 was identified to be strong in 38 (84%) and intermediate in 7 (16%) cases of serous carcinoma. Fifty-four (44%) cases of endometrioid adenocarcinoma were negative for IMP3. Thirty (25%), 20 (16%), 10 (8%), and 8 (7%) cases of endometrioid adenocarcinoma demonstrated positive immunoreactivity for IMP3 in 1-5, 6-20, 21-50, and 450% of the tumor cells. Strong IMP3-staining intensity was noted in 34 (28%), intermediate in 26 (21%), and weak in 8 (7%) cases of endometrioid adenocarcinoma. All 20 control cases were negative for IMP3. To compare p53 with IMP3 expressions, we found that 35 (78%) of the serous carcinoma cases showed strong p53 immunohistochemical activity in 450% of the tumor cell nuclei. In contrast, 11 of 112 (10%) endometrioid adenocarcinoma cases demonstrated strong p53 positivity in 450% of the tumor cell nuclei. In conclusion, our findings demonstrate significant expression of IMP3 in serous carcinoma as compared to endometrioid adenocarcinoma (Po0.0001). Expression of IMP3 and p53 may be helpful biomarkers in the distinction of endometrial serous carcinoma from endometrioid adenocarcinoma. In addition, expression of IMP3 in endometrioid adenocarcinoma correlates with higher nuclear and architecture grades of the tumor (P ¼ 0.0000 and P ¼ 0.0002, respectively).

show abstract

Transgenic overexpression of the oncofetal RNA binding protein KOC leads to remodeling of the exocrine pancreas

Cited by 50 publications

References 34 publications

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

The rs11705701 G>A Polymorphism of IGF2BP2 is Associated With IGF2BP2 mRNA and Protein Levels in the Visceral Adipose Tissue - A Link to Type 2 Diabetes Susceptibility

Expression of a novel oncofetal mRNA-binding protein IMP3 in endometrial carcinomas: diagnostic significance and clinicopathologic correlations

Contact Info

Product

Resources

About