Cholesterol Enhances Colorectal Cancer Progression via ROS Elevation and MAPK Signaling Pathway Activation

Abstract

Background/Aims: Elevated serum cholesterol levels were linked to a higher risk of colorectal adenoma and colorectal cancer (CRC), while the effect of cholesterol on CRC metastasis has not been widely studied. Methods: CRC patients were enrolled to evaluate the association between low-density lipoprotein cholesterol (LDL) and CRC metastases, and LDL receptor (LDLR) level of the CRC tissue was assessed by immunohistochemistry. The effects of LDL on cell proliferation, migration and stemness were assessed in CRC cells in vitro, and the effects of high fat diet (HFD) on tumor growth and intestinal tumorigenicity were investigated in vivo. ROS assays, gene expression array analysis and western blot were used to explore the mechanisms of LDL in CRC progression. Results: The level of LDL was positively correlated with liver metastases, and a higher level of LDL receptor (LDLR) expression was associated with advanced N and M stages of CRC. In vitro, LDL promoted the migration and sphere formation of CRC cells and induced upregulated expression of “stemness” genes including Sox2, Oct4, Nanog and Bmi 1. High-fat diet (HFD) significantly enhanced tumor growth in vivo, and was associated with a shorter intestinal length in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Furthermore, LDL significantly elevated reactive oxygen species (ROS) levels and Whole Human Genome Microarray found 87 differentially expressed genes between LDL-treated CRC cells and controls, which were largely clustered in the MAP kinase (MAPK) signaling pathway. Conclusions: LDL enhances intestinal inflammation and CRC progression via activation of ROS and signaling pathways including the MAPK pathway. Inflammation is strongly associated with cancer initiation, and the role of LDL in intestinal tumorigenicity should be further explored.

Combined Features Based on Preoperative Controlling Nutritional Status Score and Circulating Tumour Cell Status Predict Prognosis for Colorectal Cancer Patients Treated with Curative Resection

“…To the best of our knowledge, this is the first study to uncover that preoperative CONUT-CTC score is associated with tumour progression and can be considered an independent marker for better predicting the prognosis of patients with CRC treated with curative resection. The CONUT score is proposed as a blood-based marker for reflecting host immune-nutritional status [20,23], and growing evidence has shown that higher preoperative CONUT score indicates worse nutritional condition and pro-tumour immunity status [20,[22][23][24], which facilitates the migration, invasion and metastasis of tumour cells [31][32][33][34][35] and affects patients' prognosis with multiple solid tumours [21], including lung [36], liver [37], gastric [38] and colorectal cancer [22][23][24]. As a component of peripheral blood in patients with cancer, CTC was originally considered to be an important mediator of tumour recurrence and metastasis [6] and was also reported to be significantly associated with poor prognosis in a variety of malignancies [9,11,39].…”

The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia

“…Recent studies suggest that conditions that are commonly associated with obesity, such as high blood cholesterol levels and a high lipid diet, are likely to increase the incidence of breast cancer and metastasis to other organs (1,2). Hypercholesterolemia, which is a risk factor for breast cancer (2), is reported to increase reactive oxygen species (ROS) and to promote cancer progression; experimentally, LDL cholesterol consistently enhances colorectal cancer progression via the activation of ROS generation (3).…”

Macranthoidin B Modulates Key Metabolic Pathways to Enhance ROS Generation and Induce Cytotoxicity and Apoptosis in Colorectal Cancer

“…Among them, sphinganine may potentiate apoptosis in HCT-116 cells after MB exposure [38]. Likewise, cholestanol was reported with CRC progression via activation of ROS [39], and high level of cholestanol might be associated with apoptosis in HCT-116 cells, since it is a marker of cholesterol absorption, which was reported to cause endoplasmic reticulum stress-induced apoptosis [40]. The results here also revealed an alteration of nucleotide metabolism associated with AMP, IMP, 5’-GMP, 5’-CMP, and pseudouridine, which are necessary for a number of key cellular processes, and imbalance in their levels lead to tumor progression [41].…”