scholarly journals Role of miR-506 in ulcerative colitis associated with primary sclerosing cholangitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Agnieszka Kempinska-Podhorodecka ◽  
Monika Adamowicz ◽  
Ewa Ostrycharz ◽  
Mateusz Chmielarz ◽  
Maciej Wójcicki ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Target Genes ◽  
Colon Tissue ◽  
Tissue Samples ◽  
Expression Of Genes ◽  
Vitro Analysis ◽  
S1p Lyase

AbstractPrimary sclerosing cholangitis (PSC) is commonly accompanied by ulcerative colitis (UC). MicroRNA-506 modulates expression of genes which are essential for sphingosine-mediated signaling pathway and intestinal mucosa protection. We investigated whether miR-506 and its target genes are involved in phenotypic presentations of colonic inflammation and/or neoplasia. We analyzed serum and colon tissue samples collected from patients with PSC, PSC with concurrent UC (PSC + UC), UC alone, and healthy controls (n = 10 each). MiR-506 was substantially upregulated in ascending colons of PSC and PSC + UC patients, in contrast to sigmoid colons of PSC and UC patients. Upregulation of miR-506 was associated with inhibition of SPHK1, AE2, InsP3R3, and p53. Colonic suppression of miR-506 presented in UC was accompanied by substantially increased DNMT1, SPHK1, and S1P lyase expressions. A functional in vitro analysis in Caco-2 cells showed that the induction of miR-506 activity by miR-506 mimic or GDCDA bile acid suppressed, whereas inhibition of miR-506 by miR-506 inhibitor or lipopolysaccharide (LPS) upregulated the expression of the examined target genes. A different phenotypic presentation of colitis may be related to miR-506 expression. In ascending colons with PSC + UC, upregulation of miR-506 may result in failure of bicarbonate secretion and inhibition of p53, which predisposes to pro-tumorigenic transformation. In contrast, downregulation of miR-506 enhances S1P production, leading to pro-inflammatory signaling.

scholarly journals The Bisindole Alkaloid Caulerpin, from Seaweeds of the Genus Caulerpa, Attenuated Colon Damage in Murine Colitis Model

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 318 ◽  
Author(s):  
Alessandra Lucena ◽  
Cássio Souza ◽  
Jéssica Jales ◽  
Paulo Guedes ◽  
George de Miranda ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Activity Index ◽  
Disease Activity Index ◽  
Colon Tissue ◽  
Inflammatory Infiltration ◽  
Tissue Samples ◽  
Murine Colitis ◽  
Tnf Α ◽  
Effective Doses

Caulerpin (CLP), an alkaloid from algae of the genus Caulerpa, has shown anti-inflammatory activity. Therefore, this study aimed to analyze the effect of CLP in the murine model of peritonitis and ulcerative colitis. Firstly, the mice were submitted to peritonitis to evaluate which dose of CLP (40, 4, or 0.4 mg/kg) could decrease the inflammatory infiltration in the peritoneum. The most effective doses were 40 and 4 mg/kg. Then, C57BL/6 mice were submitted to colitis development with 3% dextran sulfate sodium (DSS) and treated with CLP at doses of 40 and 4 mg/kg. The disease development was analyzed through the disease activity index (DAI); furthermore, colonic tissue samples were submitted to histological analysis, NFκB determination, and in vitro culture for cytokines assay. Therefore, CLP at 4 mg/kg presented the best results, triggering improvement of DAI and attenuating the colon shortening and damage. This dose was able to reduce the TNF-α, IFN-γ, IL-6, IL-17, and NFκB p65 levels, and increased the levels of IL-10 in the colon tissue. Thus, CLP mice treatment at a dose of 4 mg/kg showed promising results in ameliorating the damage observed in the ulcerative colitis.

scholarly journals Oncomir  Microrna-346  is Upregulated  in Ascending but Not Sigmoid Colon in Patients with Primary Sclerosing Cholangitis with Concurrent Ulcerative Colitis.

2018 ◽  
Author(s):  
Agnieszka Kempinska-Podhorodecka ◽  
Malgorzata Blatkiewicz ◽  
Ewa Wunsch ◽  
Lukasz Krupa ◽  
Krzysztof Gutkowski ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Sigmoid Colon ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Target Genes ◽  
Colorectal Neoplasia ◽  
Liver Disorder ◽  
Protein Product ◽  
Micro Rna ◽  
High Concentration

Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder frequently associated with ulcerative colitis (UC). Patients with PSC and UC have higher risk of colorectal neoplasia than patients with UC without PSC. Oncogenic properties of micro RNA 346 (miR-346) have been recently reported. In this study we investigated expressions of miR-346 and its two target genes i.e. the receptor of vitamin D (VDR) and the tumor necrosis factor α (TNF-α), which are known to modulate carcinogenesis. Biopsies from ascending and sigmoid colon were obtained from patients with PSC with and without UC, patients with UC and healthy controls. MiR-346 expression was increased in ascending but not sigmoid colon of patients with PSC and UC when compared to other analyzed groups (p<0.001 for all). In patients with UC an exceptionally low colonic expression of miRNA-346 was accompanied by the increase in VDR expression, and the extensive upregulation of TNF-α gene which protein product is known to be cytotoxic to tumor cells at high concentration. In summary, a substantial upregulation of miRNA-346 in ascending colon of patients with PSC and UC may be responsible for the inhibition of VDR and TNF-α signaling -pathway which may result in an inadequate suppression of neoplasia.

scholarly journals Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2560
Author(s):  
Luis G. Guijarro ◽  
Patricia Sanmartin-Salinas ◽  
Eva Pérez-Cuevas ◽  
M. Val Toledo-Lobo ◽  
Jorge Monserrat ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Hepg2 Cells ◽  
Cellular Polarity ◽  
Ki 67 ◽  
Tissue Samples ◽  
Vitro Analysis ◽  
Tumoral Cells

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry to examine IRS-4 expression in biopsies of tumoral tissue from a cohort of 31 patient suffering of hepatocellular carcinoma (HCC). We simultaneously analyzed the expression of the cancer biomarkers PCNA, Ki-67, and pH3 in the same tissue samples. The in vitro analysis was conducted by studying the behavior of HepG2 cells following IRS-4 overexpression/silencing. IRS-4 was expressed mainly in the nuclei of tumoral cells from HCC patients. In contrast, in healthy cells involved in portal triads, canaliculi, and parenchymal tissue, IRS-4 was observed in the cytosol and the membrane. Nuclear IRS-4 in the tumoral region was found in 69.9 ± 3.2%, whereas in the surrounding healthy hepatocytes, nuclear IRS-4 was rarely observed. The percentage of tumoral cells that exhibited nuclear PCNA and Ki-67 were 52.1 ± 7%, 6.1 ± 1.1% and 1.3 ± 0.2%, respectively. Furthermore, we observed a significant positive linear correlation between nuclear IRS-4 and PCNA (r = 0.989; p < 0.001). However, when we correlated the nuclear expression of IRS-4 and Ki-67, we observed a significant positive curvilinear correlation (r = 0.758; p < 0.010). This allowed us to define two populations, (IRS-4 + Ki-67 ≤ 69%) and (IRS-4 + Ki-67 > 70%). The population with lower levels of IRS-4 and Ki-67 had a higher risk of suffering from multifocal liver cancer (OR = 16.66; CI = 1.68–164.8 (95%); p < 0.05). Immunoblot analyses showed that IRS-4 in normal human liver biopsies was lower than in HepG2, Huh7, and Chang cells. Treatment of HepG2 with IGF-1 and EGF induced IRS-4 translocation to the nucleus. Regulation of IRS-4 levels via HepG2 transfection experiments revealed the protein’s role in proliferation, cell migration, and cell-collagen adhesion. Nuclear IRS-4 is increased in the tumoral region of HCC. IRS-4 and Ki-67 levels are significantly correlated with the presence of multifocal HCC. Moreover, upregulation of IRS-4 in HepG2 cells induced proliferation by a β-catenin/Rb/cyclin D mechanism, whereas downregulation of IRS-4 caused a loss in cellular polarity and in its adherence to collagen as well as a gain in migratory and invasive capacities, probably via an integrin α2 and focal adhesion cascade (FAK) mechanism.

Colorectal Dysplasia and Cancer in Pediatric-Onset Ulcerative Colitis Associated With Primary Sclerosing Cholangitis

2020 ◽  
Author(s):  
Wael El-Matary ◽  
Stephen L. Guthery ◽  
Achiya Z. Amir ◽  
Matthew DiGuglielmo ◽  
Laura G. Draijer ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Pediatric Onset
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