Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

Femia, Angelo Pietro; Luceri, Cristina; Toti, Simona; Giannini, A. James; Dolara, Piero; Caderni, Giovanna

doi:10.1186/1471-2407-10-194

Cited by 47 publications

(51 citation statements)

References 52 publications

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“…NO reinforces angiogenesis by stimulating of cyclooxygenase which promotes the production of proangiogenic factors and prostaglandins. Femia et al [22] reported that DMH-induced colorectal cancer has high pro-inflammatory enzyme inducible nitric oxide synthase (iNOS) expression. Many researches report high iNOS activity in colon cancer [23-24] and support our findings.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats

El‐Khadragy

Nabil

Hassan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Stem cell based therapies are being under focus due to their possible role in treatment of various tumors. Bone marrow stem cells believed to have anticancer potential and are preferred for their activities by stimulating the immune system, migration to the site of tumor and ability for inducting apoptosis in cancer cells. The current study was aimed to investigate the tumor suppressive effects of bone marrow cells (BMCs) in 1,2-dimethylhydrazine (DMH)-induced colon cancer in rats. Methods: The rats were randomly allocated into four groups: control, BMCs alone, DMH alone and BMCs with DMH. BMCs were injected intrarectally while DMH was injected subcutaneously at 20 mg/kg body weight once a week for 15 weeks. Histopathological examination and gene expression of survivin, β-catenin and multidrug resistance-1 (MDR-1) by real-time reverse transcription-polymerase chain reaction (RT-PCR) in rat colon tissues. This is in addition to oxidative stress markers in colon were performed across all groups. Results: The presence of aberrant crypt foci was reordered once histopathological examination of colon tissue from rats which received DMH alone. Administration of BMCs into rats starting from zero-day of DMH injection improved the histopathological picture which showed a clear improvement in mucosal layer, few inflammatory cells infiltration periglandular and in the lamina propria. Gene expression in rat colon tissue demonstrated that BMCs down-regulated survivin, β-catenin, MDR-1 and cytokeratin 20 genes expression in colon tissues after colon cancer induction. Amelioration of the colon status after administration of MSCs has been evidenced by a major reduction of lipid peroxidation, nitric oxide, and increasing of glutathione content and superoxide dismutase along with catalase activities. Conclusion: Our findings demonstrated that BMCs have tumor suppressive effects in DMH-induced colon cancer as evidenced by down-regulation of survivin, β-catenin, and MDR-1 genes and enhancing the antioxidant activity.

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Section: Discussionmentioning

confidence: 99%

Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats

El‐Khadragy

Nabil

Hassan

et al. 2018

Cell Physiol Biochem

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“…4,9 PIRC (n 5 8) and wt (n 5 4) rats aged one month were analyzed with procedures previously described. 18 What's new? The majority of human colorectal cancers (CRCs) are associated with mutations in APC, which encodes the tumor suppressing APC protein.…”

Section: Semi-quantitative Rt-pcrmentioning

confidence: 99%

Multiple mucin depleted foci, high proliferation and low apoptotic response in the onset of colon carcinogenesis of the PIRC rat, mutated in Apc

Femia

Luceri

Soares³

et al. 2014

Intl Journal of Cancer

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PIRC rats (F344/NTac-Apc am1137 ) mutated in the Apc gene spontaneously develop colon tumors thus mimicking familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC) more closely than Apc-based rodent models developing tumors mostly in the small intestine. To understand whether microscopic dysplastic lesions precede the development of macroscopic tumors, PIRC rat colon was examined for the presence of mucin depleted foci (MDF), microadenomas of the rodent and human colon. Few MDF (about 4/animal) were already present in 1-month-old rats and their number rapidly increases to about 250 in 8-month-old rats. These lesions showed Wnt signaling activation (nuclear b-catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 156 6 8 and 38 6 6 in controls and sulindac-treated rats, respectively, means 6 SE, p < 0.001). Since altered proliferation and apoptosis could underlie the early phases of carcinogenesis, we studied these processes in the apparently normal colon mucosa (NM) of 1-month-old PIRC and wt rats. Colon proliferation (PCNA expression) was significantly higher in PIRC rats. Notably, PIRC rat NM showed resistance to apoptosis since it sustained proliferation and had lower apoptosis after a cytotoxic insult with 1,2 dimethylhydrazine. Gene expression of Myc, p21, Birc5, Ogg1, Apex1 and Sod2 were significantly up-regulated in the NM of PIRC rat. The overall results put forward PIRC rat as useful model of colon carcinogenesis, either to study the process itself or to test in vivo chemopreventive agents in both short-and long-term studies.Mutations in the Apc gene, responsible for the inherited predisposition to intestinal carcinogenesis in familial adenomatous polyposis (FAP) and present in the majority of sporadic colorectal cancers (CRC), are considered early, necessary events in the development of the disease. 1 Rodent models carrying mutations in Apc have been thus developed and widely used. 2,3 However, at variance with human pathology, the majority of these strains, including Apc Min (Min) mice, develops tumors predominantly in the small intestine and not in the colon. [2][3][4] This characteristic is a considerable drawback given the inherent diversity of these two parts of the intestine in terms of anatomy, lumen environment, physiology and propensity to tumor development. [2][3][4] Few years ago, the PIRC rat (Polyposis In the Rat Colon) with a germline mutation in one allele of the Apc gene (F344/NTac-Apc am1137 ) has been described. 5 Notably, at variance with pre-existing Apcbased mouse models, PIRC rats spontaneously develop tumors in the small intestine but also in the colon, thus mimicking more closely FAP and CRC and potentially standing for as a robust model of colon cancer. 5 Here we were interested in the early phases of PIRC rat colon carcinogenesis studying (i) the presence and the biology of early-appearing precancerous lesions in the colon and (ii) the morphologically normal mucosa (NM). Small ad...

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“…It is beleived that chronic infl ammation and repeated production of NO by iNOS leads to neoplastic transformation, a key step in the process of carcinogenesis. Increased expression of iNOS in DMH-induced group was probably due to a positive regulation of the NOS2 gene, which codes iNOS [12].…”

Section: Resultsmentioning

confidence: 99%

Inulin Diet Intervention on Chemopreventive and Inflammatory Markers in Tumorigenesis of Colorectal Cancer

et al. 2014

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The aim of this experiment was to investigate the infl uence of inulin administration on chemopreventive and infl ammatory markers in dimethylhydrazine induced colorectal cancer development in rats. A group of 30 Sprague-Dawley rats was divided into a control group (CG), a group with dimethylhydrazine (DMH), and a group given dimethylhydrazine combined with the prebiotic (DMH+PRE). Dimethylhydrazine injection signifi cantly (p<0.001) elevated the immunoreactivity chemopreventive markers COX-2, NFκB, iNOS, elevated serum and jejunal mucosa levels of proinfl ammatory cytokine IL-2, and decreased serum and jejunal mucosa levels of regulatory cytokine IL-10. Inulin diet intervention signifi cantly suppressed immunoreactivity of COX-2, NFκB, iNOS positive cells in the tunica mucosae and tela submucosae of rat colon tissue, increased levels of IL-2 and decreased levels of IL-10. By determining the chemopreventive markers COX-2, iNOS and NFkB, which can be characterized as infl ammatory markers, we confi rmed the presence of infl ammation in the colon as the number of COX-2, NFkB and iNOS immunoreactive cells was signifi cantly higher after DMH application than in the control group. These fi ndings indicate that dietary intake of inulin suppressed the expression of the observed markers, which play an important role in carcinogenesis and infl ammation, which predispose the use of inulin in the prevention or treatment of human chronic diseases and its use as a nutritional supplement in veterinary medicine.

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Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

Cited by 47 publications

References 52 publications

Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats

Bone Marrow Cell Therapy on 1,2-Dimethylhydrazine (DMH)-Induced Colon Cancer in Rats

Multiple mucin depleted foci, high proliferation and low apoptotic response in the onset of colon carcinogenesis of the PIRC rat, mutated in Apc

Inulin Diet Intervention on Chemopreventive and Inflammatory Markers in Tumorigenesis of Colorectal Cancer

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