Prognostic value of LIPC in non-small cell lung carcinoma

Abstract

Non-small cell lung carcinoma (NSCLC) is the most common form of lung cancer and is associated with a high mortality rate worldwide. The majority of individuals bearing NSCLC are treated with surgery plus adjuvant cisplatin, an initially effective therapeutic regimen that, however, is unable to prevent relapse within 5 years after tumor resection in an elevated proportion of patients. The factors that predict the clinical course of NSCLC and its sensitivity to therapy remain largely obscure. One notable exception is provided by pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. PDXK has recently been shown to be required for optimal cisplatin responses in vitro and in vivo and to constitute a bona fide prognostic marker in the NSCLC setting. Together with PDXK, 84 additional factors were identified that influence the response of NSCLC cells to cisplatin, in vitro including the hepatic lipase LIPC. Here, we report that the intratumoral levels of LIPC, as assessed by immunohistochemistry in two independent cohorts of NSCLC patients, positively correlate with disease outcome. In one out of two cohorts studied, the overall survival of NSCLC patients bearing LIPChigh lesions was unaffected, if not slightly worsened, by cisplatin-based adjuvant therapy. Conversely, the overall survival of patients with LIPClow lesions was prolonged by post-operative cisplatin. Pending validation in appropriate clinical series, these results suggest that LIPClow NSCLC patients would be those who mainly benefit from adjuvant cisplatin therapy. Thus, the expression levels of LIPC appear to have an independent prognostic value (and perhaps a predictive potential) in the setting of NSCLC. If these findings were confirmed by additional studies, LIPC expression levels might allow not only for NSCLC patient stratification, but also for the implementation of personalized therapeutic approaches.

Keywords: BCL-XL; PDXP; anaplastic lymphoma kinase; apoptosis; personalized medicine; pyridoxine.

Figure 1. LIPC expression in NSCLC A549 cells and validation of a LIPC-specific immunohistochemical staining. (A and B) Immunoblotting-assisted (A) and immunohistochemical (B) detection of LIPC levels in human non-small cell lung carcinoma A549 cells that were transfected with either a control (siUNR) or with two non-overlapping LIPC-specific siRNA (siLIPC_1 and siLIPC_2). GAPDH levels were monitored to control equal lane loading.

Figure 2. LIPC constitute a prognostic marker in non-small cell lung carcinoma (NSCLC). (A) Immunohistochemical detection of LIPC levels in biopsies from NSCLC patients. Scale bars = 100 μm. (B and C) Kaplan-Meier curves for disease-free survival (DFS) and overall survival (OS) in two independent cohorts of n = 114 (B) and n = 310 (C) NSCLC patients, upon stratification of all patients according to median LIPC expression. The number of patients that were evaluable for the indicated analyses and p values are indicated.

Figure 3. LIPC might constitute a predictive biomarker in non-small cell lung carcinoma (NSCLC). (A and B) Kaplan-Meier curves for overall survival (OS) in two independent cohorts of n = 114 (A) and n = 310 (B) NSCLC patients, upon stratification of patients according LIPC expression levels and status of platinum-based adjuvant therapy receiver. The number of patients that were evaluable for the indicated analyses and p values are indicated. Unlabeled p values depict statistical significance for a Cox regression model of interaction. Statistically significant (*p < 0.05) and near-to-statistically significant (#p < 0.1) p values are underlined.