3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

Abstract

Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3’-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69–5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a “risk genotype” of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC.

Fatty acid activation in carcinogenesis and cancer development: Essential roles of long‑chain acyl‑CoA synthetases (Review)

“…A recent bioinformatics study (37) utilizing online databases Oncomine (https://www.oncomine.org/resource/login .html) and PrognoScan (http://www.abren.net/PrognoScan/) stated certain novel associations between ACSL expression and cancer survival outcomes. On the one hand, which was in line with previous findings (12,18,27), the study showed that the overexpression of either ACSL1 or ACSL4 was associated with a poorer prognosis in patients with colon cancer, and that ACSL5 downregulation was associated with poor survival in breast cancer patients. On the other hand, the study suggested certain novel links.…”

“…Upregulation of ACSL1 was found in multiple types of cancer, including colon (11,12), breast (13) and liver (14,15) cancer, and myeloma (16), while downregulation was found in lung squamous cell carcinoma (17). More importantly, ACSL1 overexpression was associated with a poor clinical outcome in colon cancer patients (18). Like those of ACSL1, the majority of studies of ACLS4 favor an oncogenic role.…”

“…It was suggested that the genotype difference in 3'UTR may affect the binding affinity of microRNA and the resultant ACSL1 mRNA stability. More importantly, those patients with the T/T genotype and colon cancer had a poor disease-free survival outcome (18). Note that, in liver cancer, HBx repressed miR-205 expression and consequently increased ACSL4 mRNA stability (41).…”

The function of SNHG7/miR‐449a/ACSL1 axis in thyroid cancer

“…20 Acyl-CoA synthetase long-chain family member 1 (ACSL1) is one of the distinct members of ACSLs family and has been regarded as an oncogene in some cancers. 10,11,21 In this study, ACSL1 was overexpressed in TC cells. When SNHG7 was downregulated, the expression of ACSL1 was inhibited.…”

Precision Nutrition for Targeting Lipid Metabolism in Colorectal Cancer

“…Regarding CRC, key enzymes involved in lipid-metabolic pathways have been found differentially expressed in normal and tumoral tissues. Some of them were associated with cancer survival and were individually proposed as prognosis markers [ 6 , 10 , 11 ]. Furthermore, one of the transcriptomic consensus molecular subtypes (CMS) of CRC described by Guinney and colleagues [ 12 ], the “metabolic subtype 3” (CMS3), exhibits a clear enrichment for multiple metabolism signatures along with KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog)-activating mutations that have been described as inducing metabolic reprogramming [ 12 ].…”