The present study demonstrated that the levels of TC, HDL-C, and LDL-C were significantly lower in lung cancer patients. Notably, significant non-linear and negative associations between TC and HDL-C and lung cancer risk were found after multivariate adjustment. Furthermore, we identified negative linear trends for the risk of abnormal tumor markers across TG and HDL-C quartiles among lung cancer patients when all four lipid indicators were considered jointly.
Several previous studies have demonstrated a relationship between lipid profiles and risk for various types of cancer, including prostate, breast, and colorectal cancers [4–8]; however, the relationship between blood lipid profiles and lung cancer remains unclear. Studies aiming to evaluate the association between TC and non-small cell lung cancer have drawn inconsistent conclusions. Lin et al.  and Lyu et al.  demonstrated that low TC levels were associated with lung cancer risk. In contrast, Chandler et al.  found that high TC levels were associated with increased incidence of lung cancer, although the significance disappeared after multivariable adjustment. In the present study, we demonstrated that hyper-TC was associated with decreased lung cancer risk after adjusting for age, sex, smoking status, alcohol consumption, and other lipid profile components, consistent with the findings of Lin et al. and Lyu et al. However, it remains to be determined whether the observed relationship is causal or due to the effect of pre-diagnosed cancer on serum cholesterol levels. There are several underlying mechanisms that could be involved in this relationship. Plasma polyunsaturated fatty acids, which can decrease TC levels, were found to be higher in lung cancer patients . As well, low cell cholesterol has been associated with increased NF-κB activity, upregulated mevalonate pathway activity, and suppressed immunity [17, 18]. Finally, due to the rapid growth and high rate of division, malignant cells require far more cholesterol, which could lead to lower levels of blood cholesterol, including TC levels. We additionally found that there was a negative non-linear relationship between TG/TC and lung cancer risk. The identification of this non-linear pattern revealed the complexity of the relationship arising from interactions between multiple risk factors and suggests that lung cancer risk cannot be reduced simply by lowering blood lipids. This was demonstrated by the U-shaped association, which indicated that adjusting TC levels as low as possible did not reduce lung cancer risk.
HDL-C plays an important role in the reverse transport process of cholesterol, which facilitates the removal of excess cholesterol from peripheral tissues, and it is widely recognized as a protective factor in cardiovascular disease . However, the role of HDL-C in the occurrence and progression of cancer, especially lung cancer, has not been determined. A meta-analysis of randomized controlled trials concluded that there was a significant inverse association between HDL-C and the risk of cancer , although this conclusion contradicts those of other studies [21, 22]. Some researchers have demonstrated that HDL-C was negatively associated with a risk of lung cancer , while Lyu et al.  found that no significant relationship existed. Our present results indicate that low HDL-C was associated with increased lung cancer risk, and there exists a significant non-linear and negative association between HDL-C and lung cancer risk after multivariate adjustment. There are numerous underlying mechanisms that may account for these findings. First, HDL-C could confer anti-inflammatory effects and organ protection through leukocyte adhesion and cytokine production; thus, the decrease in HDL-C level may lead to inflammation, which plays a role in the development of neoplasms [23, 24]. Second, lower HDL may have induced a reduction in antioxidant activity, which is associated with lung cancer . Third, a decrease in the ability of HDL-C to inhibit apoptosis, resulting from decreased HDL-C levels, may contribute to the development of cancer [26, 27].
Research to evaluate the relationship between TG and lung cancer risk has drawn inconsistent conclusions as well. Some researchers demonstrated that TG was positively associated with increased lung cancer risk [9, 28], while Siemianowicz et al.  found that TG levels were lower in lung cancer patients. In our study, there was no significant difference in TG levels between lung cancer patients and healthy controls, and hyper-TG was not associated with lung cancer risk after multivariable adjustment. LDL-C, another component of cholesterol, was found to be associated with various cancers [30–33], while the relationship between LDL-C levels and lung cancer risk has not been clarified [10, 11]. The present study indicated that LDL-C levels were lower in lung cancer patients, and that high LDL-C was associated with decreased lung cancer risk. Of note, the association disappeared after multivariable adjustment. We speculate that interactions between the confounding factors may exist, and that this relationship requires further investigation. In addition, large-scale prospective studies are needed to clarify these relationships.
The association between biomarkers and tumors has aroused much attention [34, 35]. In order to comprehensively evaluate the linear relationship between blood lipid profiles and lung cancer risk, we explored the association between abnormal tumor markers and lipid profiles among lung cancer patients. Tumor markers, including CYFRA21-1, SCC, CEA, NSE, and CA125 have been commonly used to predict lung cancer because of their excellent sensitivity [12, 36]. We found that TG was associated with a decreased risk of hyper-NSE and hyper-CYFRA21-1, and that HDL-C was associated with a decreased risk of hyper-NSE, hyper-CYFRA21-1, and hyper CA-125, after multivariable adjustment. To our best knowledge, there is no research to explore the relationship between blood lipids and tumor markers of lung cancer, and the involved mechanisms were not clarified. One possible mechanism relating TG with abnormal tumor markers was that hyper TG was associated with the production of reactive oxygen species, which could affect normal cell proliferation . However, hyper TG was not associated with lung cancer risk in aforementioned study. As to HDL-C, the involved mechanism may be related to inflammation, reduced antioxidant activity and disability to inhibit apoptosis [23–27]. In order to clarify the biological mechanism, large-scale prospective cohort studies taking tumor markers as primary target need to be performed.
Although our investigations were performed on a large sample that adjusted for multiple potential confounding factors, there were still several limitations. First, this observational study had a case-control rather than a prospective design; thus, the cause-consequence relationship cannot be evaluated. Second, although many common confounding factors were adjusted for, other potential confounding factors such as dietary habits, obesity, and physical activity were not considered. Therefore, further research is warranted to clarify the causal relationship and to enhance credibility.