Gender differences in the plasma profiles of PCSK9, soluble LDLR, total cholesterol, and triglycerides in patients with colorectal cancer liver metastases: diagnostic and prognostic implications

Background. Proprotein convertase subtilisin/kexin-type 9 (PCSK9) and soluble low-density lipoprotein receptor (sLDLR) are blood proteins that down regulate LDLR-mediated uptake of plasma LDL-cholesterol into cells. In healthy subjects, the plasma level of PCSK9 and sLDLR strongly correlates with that of total cholesterol (TC) and triglycerides (TG), respectively. Since cancer is known to reprogram lipid metabolism, it may also alter the plasma levels of PCSK9 and sLDLR as well as their correlations with TC and TG. To verify this hypothesis, we measured the levels of PCSK9, sLDLR, TC, and TG in the plasma of healthy subjects and patients with colorectal cancer liver metastases (CRLM), categorized as early recurrent (ER) or non-recurrent (NR) after liver resection. Methods. The plasma levels of PCSK9 and sLDLR were determined using specific ELISA kits, those of TC and TG by enzymatic colorimetry. Results. Relative to healthy subjects, CRLM patients carried 4 to 6 higher levels of sLDLR, irrespective of category or gender ( p < 0.0001). These levels strongly correlated with those of TG ( p < 0.0001). PCSK9 correlations with sLDLR, TC, or TG varied with gender or CRLM category. Low PCSK9 levels were associated with large tumor size in CRLM_ER, particularly in women ( p < 0.01). Also in women, a TC level above the median is predictive of a poor 5-year overall survival [HR (95% CI) 1.70 (1.07 – 2.71; p = 0.0152]. Conclusions. High plasma sLDLR is a potential diagnostic biomarker of CRLM. In CRLM_ER women, low plasma PCSK9 indicates the presence of large tumors and, in CRLM women in general, high plasma TC is an unfavorable prognostic biomarker. Thus, early recurrence and gender ought to be considered when examining the clinical significance of lipid dysregulation in CRLM patients.