NPC1L1 is a known target of ezetimibe, which is used to treat dyslipidemia. However, its prognostic relevance in cancers has been poorly characterized. This study showed, for the first time, that NPC1L1 is upregulated in CRC and is associated with N and pathological stages. Moreover, the present study showed that high NPC1L1 expression in CRC is associated with poorer survival, suggesting that NPC1L1 is an independent prognostic marker in CRC.
Chen et al. showed that NPC1L1 was expressed at lower levels in hepatocellular carcinoma (HCC) compared to that in liver tissues adjacent to HCC tissues . However, in the present study, NPC1L1 expression was increased in CRC compared to that in normal tissues (Fig. 2). Thus, the results suggest that NPC1L1 may be involved in the development of cancer and that NPC1L1 expression in cancer is type-specific.
A previous study showed that NPC1L1 expression was inversely correlated with the pathological stage, tumor differentiation, and vascular invasion in HCC . In contrast, in the present study, NPC1L1 expression was positively associated with the N and pathological stages (Table 2). Many studies have shown that the roles of a specific gene in cancer development and progression differ based on the cancer type. For example, increased Notch levels were correlated with tumor grade and metastasis in CRC , whereas in glioblastoma, Notch signaling has tumor-suppressive effects . Even in the same tumor cells, a gene may modulate cancer progression and suppression in an environment- or time-dependent manner [17, 18]. Although He et al. showed that NPC1L1-knockout mice had fewer tumors in colitis-associated tumorigenesis , the association between NPC1L1 expression and pathological features in cancers has been poorly characterized. This may be because the expression of NPC1L1, a membrane protein, is low in organs other than the liver and small intestine, making it difficult to study. To determine why the roles of NPC1L1 in pathological features differ depending on the cancer type, it is necessary to study the proliferation, migration, and invasion of various cancer cells.
Abnormal lipid metabolism is pathologically associated with vascular disorders, hyperlipidemia, lipid storage-associated diseases, and obesity. Recent studies have shown that changes in lipid metabolism play an important role in the development and progression of cancer [19–21]. Lipids are used for energy supply, as structural materials for the cell membrane and signaling molecules, and for the post-transcriptional modification of cancer cells to promote cell proliferation and alter cell characteristics . Studies have confirmed changes in the contents and compositions of fatty acids, oxylipins, and triacylglycerols in the serum, tumor tissues, and adipose tissue in patients with CRC , and shown that the molecules involved in altered lipid metabolism are potential biomarkers of CRC development, progression, and prognosis . Among them, NPC1L1 is known to be an important molecule for cholesterol absorption and is associated with prognosis in patients with HCC . Among patients with CRC in the TCGA cohort, the high NPC1L1 expression group showed poorer OS than the low NPC1L1 expression group (Fig. 3A). Consistent with the results of the first analysis, results of the analysis of the second cohort (GSE17536) also showed that high expression of NPC1L1 was associated with poor survival in patients with CRC (Fig. 3B). In the univariate and multivariate analyses of prognostic factors, NPC1L1 expression, along with age and disease stage, was significantly linked to OS in patients with CRC (Table 3). To confirm whether NPC1L1 represents an independent prognostic marker of CRC, the prognostic significance of NPC1L1, along with other CRC prognostic markers, such as VEGF-A, MACC1, and TGF-β1, was determined by multivariate regression analysis (Table 4). According to previous studies, the OS of CRC patients showing high expression of VEGF-A or MACC1 was significantly worse than that of CRC patients with low expression of VEGF-A or MACC1 [22, 23]. Based on a meta-analysis, Chen et al. showed that TGF-β may be used as a prognostic factor for patients with CRC . In this study, we showed that NPC1L1 expression, along with VEGF-A expression, was significantly associated with the prognosis of CRC. Thus, our results suggest that NPC1L1, along with other known prognostic markers, may be an independent prognostic marker of CRC.
Drugs used to treat a disease can have several side effects, including cancer development. Statins, which are used to lower lipid levels, block the 3-hydroxy-3-methylglutaryl CoA reductase needed for cholesterol synthesis. According to previous studies, statins inhibit cell growth and induce apoptosis in CRC, thereby lowering the risk of gastrointestinal cancers, including CRC . Ezetimibe, on the other hand, increased cancer incidence in the SEAS study (n = 1872), despite lowering the levels of lipids, similar to the effects of statins . Consequently, the use of statin-ezetimibe combination therapy has been restricted in many guidelines. However, large-scale studies, such as SHARP (n = 9270) and IMPROVE-IT (n = 18144), showed that ezetimibe was not associated with cancer incidence [27, 28]. Thus, ezetimibe is currently used to treat uncontrolled dyslipidemia. These results suggest that it is necessary (for evidence-based medicine) to investigate the molecular mechanism underlying the action of NPC1L1 as the target of ezetimibe and to examine the association between NPC1L1 and the carcinogenesis and prognosis of cancers.
A limitation of this study is that we did not provide experimental evidence for the development and progression of CRC resulting from NPC1L1 overexpression; further, this study did not investigate the effects of ezetimibe, an inhibitor of NPC1L1, on the growth, invasion, and migration of CRC cells. Although our study does not provide any experimental evidence per se, it provides a framework for future studies to experimentally investigate the role of NPC1L1 at the molecular and cellular levels.