Original ArticlesCholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide [1]. The rapid progression, especially the high frequency of postoperative recurrence or metastasis, is the most important reason for the extremely poor prognosis of HCC patients [2]; however, the mechanism underlying this process has not been fully elucidated. Thus, a greater understanding of the key molecules or cellular regulators during invasion and metastases of HCC is required.
Recently, several epidemiologic surveys have suggested an inverse association between the serum cholesterol level and liver cancer incidence. Four independent studies illustrated that a low serum cholesterol level predicted poor postoperative outcomes for HCC patients, possibly because of worse preoperative liver functional reserve [[3], [4], [5], [6]]. However, the possibility of a high cholesterol level having a protective effect against liver cancer progression and the underlying molecular mechanism remain unclear.
Cholesterol plays a major role in determining the structure of bilayers and the function of eukaryotes, as a precursor of biosynthetic pathways [7,8]. In combination with sphingolipids, cholesterol forms lipid rafts in specific regions of the membrane and regulates signaling molecule assembly, membrane fluidity, protein trafficking in cell transformation and cancer progression [[9], [10], [11]]. As sites of membrane trafficking, lipid rafts provide a stable platform for various receptors, glycosyl phosphatidyl inositol (GPI) anchored proteins, and adhesion molecules, such as TNFR, E-cadherin, CD44, Muc-1 and integrins, to contribute to cell migration and invasion [[12], [13], [14], [15], [16]].
CD44, a widely expressed multifunctional cell-surface glycoprotein, controls malignant transformation and cancer metastasis, despite its role in lymphocyte activation and normal hematopoiesis [[17], [18], [19]]. It mainly acts as a receptor for hyaluronic acid and interacts with other ligands, such as osteopontin, collagens, and matrix metalloproteinases. CD44 mediates cell adhesion and migration through binding with actin-binding partners, among which the Ezrin protein is the major molecule [20]. As a member of the ezrin-moesin-radixin (ERM) family, Ezrin forms a bridge between CD44 and the actin cytoskeleton, and this complex contributes to cell morphology changes [21]. It has been reported that promoting CD44 retention inside lipid rafts abolishes CD44-Ezrin interactions to decrease cell migration [14,22]. To date, it is unknown whether cholesterol influences HCC invasion and metastasis through regulating the membrane localization and function of CD44.
In the present study, univariate and multivariate analyses of a large HCC cohort revealed the prognostic importance of serum cholesterol. Cholesterol restrained the invasive potential of HCC cells via promoting CD44 translocation into lipid rafts and blocking CD44-Ezrin interaction outside rafts. More importantly, downregulation of CD44 or promoting its retention inside lipid rafts could be a new strategy for HCC treatment.
Section snippets
Patients
We retrospectively collected 969 patients who underwent hepatectomy at the Eastern Hepatobiliary Surgery Hospital, Shanghai (EHBH), between 2008 and 2010. The study was approved by the Institutional Ethics Committee of the EHBH. Informed consent was obtained from all patients before surgery for using their data in the research. The inclusion criteria were 1) histopathologically proven HCC; 2) without distant metastasis; and 3) without gross portal/hepatic vein invasion such as portal vein tumor
Serum total cholesterol level is a predicting factor for recurrence and survival in patients with HCC
We first investigated the relationship between TSC level and clinicopathologic characteristics in a large HCC cohort. The included patients were divided into two groups, namely, the high-cho group (TSC>3.96 mmol/L, n = 477) and low-cho group (TSC≤3.96 mmol/L, n = 492) based on the cutoff value. As shown in Table 1, no significant difference in liver function was observed between the two groups, as evidenced by the comparable serum level of glutamic pyruvic transaminase (ALT), glutamic
Discussion
Although an inverse correlation has been reported between the TSC level and HCC incidence/prognosis [[3], [4], [5], [6]], the causality of this correlation requires consideration. Given that the liver acts as the main organ for cholesterol synthesis, some researchers argued that preclinical cancer accompanied by impaired liver function may lower the cholesterol level and thus exaggerate the correlation [[3], [4], [5]]. Nevertheless, the association between TSC and HCC incidence continued to
Conflicts of interest statement
There is no conflict of interest to disclose.
Acknowledgements
This work was funded by the National Natural Science Foundation of China (81472768, 81522035, 81670568, 81521091 and 91529306), the State Key Project for Infectious Diseases (2015ZX09J15107, 2012ZX10002016) and the Shanghai Committee of Science and Technology (16QA1404900, 15431901600 and 14XD1400100).
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2023, Hepatobiliary and Pancreatic Diseases InternationalCitation Excerpt :Similar to previous findings in patients with hepatectomy for HCC [12,15-17], we revealed that early post-LT increased serum cholesterol, but not triglyceride, had a favorable influence on HCC prognosis. As regards relevant biological mechanism, some experimental studies have partly disclosed that cholesterol can suppress the invasive potential of HCC cells through translocating CD44 into lipid rafts [17], enhance the anti-tumor functions of nature killer cells [32], or inhibit de novo lipogenesis of HCC [33]. Of note, our analysis indicated that there was a disparity in prognostic value between B-EPHC and S-EPHC, suggesting that the role of cholesterol played in LT was complicated and might vary by serum cholesterol concentration.
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These authors contributed equally to this work.