NPC1L1 knockout protects against colitis-associated tumorigenesis in mice

Abstract

BackgroundColorectal cancer is strongly associated with lipid metabolism. NPC1L1, a sterol transporter, plays a key role in modulating lipid homeostasis in vivo. Its inhibitor, ezetimibe, began to be used clinically to lower cholesterol and this caused the great debate on its role in causing carcinogenesis. Here we explored the role of NPC1L1 in colorectal tumorigenesis.MethodsWild-type mice and NPC1L1−/− (NPC1L1 knockout) mice were treated with azoxymethane (AOM)-dextran sodium sulfate (DSS) to induce colitis-associated colorectal tumorigenesis. Mice were sacrificed 10, 15, 18 or 20 weeks after AOM treatment, respectively. Colorectal tumors were counted and analyzed. Plasma lipid concentrations were measured using enzymatic reagent kit. Protein expression level was assayed by western blot.ResultsNPC1L1−/− mice significantly had fewer tumors than wild-type. The ratio of malignant/tumor in NPC1L1−/− mice was significantly lower than in wild-type 20 weeks after AOM-DSS treatment. NPC1L1 was highly expressed in the small intestine of wild-type mice but its expression was undetectable in colorectal mucous membranes or tumors in either group. NPC1L1 knockout decreased plasma total cholesterol and phospholipid. NPC1L1−/− mice had significant lower intestinal inflammation scores and expressed inflammatory markers p-c-Jun, p-ERK and Caspase-1 p20 lower than wild-type. NPC1L1 knockout also reduced lymphadenectasis what may be caused by inflammation. NPC1L1 knockout in mice decreased β-catenin in tumors and regulated TGF-β and p-gp in adjacent colons or tumors. There was not detectable change of p53 by NPC1L1 knockout.ConclusionsOur results provide the first evidence that NPC1L1 knockout protects against colitis-associated tumorigenesis. NPC1L1 knockout decreasing plasma lipid, especially cholesterol, to reduce inflammation and decreasing β-catenin, p-c-Jun and p-ERK may be involved in the mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1230-0) contains supplementary material, which is available to authorized users.

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

“…Studies in mice have shown that knocking out the cell surface cholesterol-sensing receptor gene NPC1L1, which plays a critical role in the absorption of intestinal cholesterol, reduces CRC risk. 31 However, the biological mechanism by which cholesterol may affect CRC risk remains to be established. Cholesterol is thought to have multiple carcinogenic/ cancer promoting effects at the cellular level and several mechanisms have been variously suggested, including the cholesterol-mediated activation of the NLRP3 inflammasome.…”

Integrin�β4 reduces DNA damage‑induced p53 activation in colorectal cancer

“…1D). These structures mimicked colorectal tumors at an avascular stage or avascular regions of colorectal tumors in vivo (2,7). The ultrastructure of 3D cultures was observed using a transmission electron microscope.…”

“…Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males, and the second most common in females worldwide (1). The highest incidence rates are mainly in developed countries and the incidence is increasing in developing countries, which is partly attributable to lipid metabolism (1)(2)(3). Despite an enormous amount of effort spent in the development of therapies to treat CRC, the 5-year survival rate has increased slowly in the USA, from 60% during the 1980s to 66% during 2005 to 2011 (4).…”

An Optimized Protocol of Azoxymethane-Dextran Sodium Sulfate Induced Colorectal Tumor Model in Mice

“…1 The incidence is increasing in most of developing countries, partly attributing to lipid metabolism. [1][2][3] According to its inci-dence, CRC is categorized in three forms: family, hereditary, and sporadic (about 80% of CRC). 4,5 Many in vitro models and in vivo models have been developed and used in understanding CRC.…”

“…4,5 Many in vitro models and in vivo models have been developed and used in understanding CRC. 2,6 In vivo models include inoculated CRC models and tumors induced by "diet" (high fat, low calcium, etc), by chemical, by gene mutation or genetic modification (APC lines, Kras, Msh2, P53, Rb, and so on). 7-9 Subcutaneous inoculation models are widely used to study responses of CRC to chemotherapy, radiotherapy and other types of therapy 10,11 .…”