Prognostic value of midkine, syndecan-1, hyaluronan synthase-2, sestrin-1, laminin subunit alpha-4 and fibulin-3 for malignant pleural mesothelioma

Abstract

Introduction: The prognosis of malignant pleural mesothelioma (MPM) is poor, with a limited survival time. In this study, we aimed to examine expression levels of genes selected from relevant literature and to utilize in silico methods to determine genes whose expression could reflect the prognosis of patients with MPM by ex-vivo validation experiments.

Material and methods: The study group consisted of 54 MPM patients treated with chemotherapy. Expression of 6 genes - midkine (MDK), syndecan-1 (SDC1), hyaluronan synthase-2 (HAS2), sestrin-1 (SESN1), laminin subunit alpha-4 (LAMA4), and fibulin-3 (FBLN3) - was examined by qPCR in tumor tissues. Sestrin-1 and LAMA4 were identified using an in house R-based script: Unsupervised Survival Analysis Tool. Midkine, SDC1, HAS2, and FBLN3 were selected from current literature. We used two housekeeping genes, i.e. glucose-6-phosphate dehydrogenase and TATA-box binding protein, as controls.

Results: Of the patients, 43 (79.6%) had epithelioid mesothelioma. The median survival for all patients was 10 (±1.2 SE) months (95% CI: 7.7-12.3). In multivariate analyses, MDK (p = 0.007), HAS2 (p = 0.008) and SESN1 (p = 0.014) expression levels were related to survival time in the whole group. In epithelioid type MPM patients, MDK (p = 0.014), FBLN3 (p = 0.029), HAS2 (p = 0.014) and SESN1 (p = 0.045) expression was related to survival time in multivariate analyses.

Conclusions: High HAS2 and SESN1 expressions and low MDK are potential biomarkers of good prognosis in MPM. High HAS2 and SESN1 expression and low MDK and FBLN3 can also be utilized as biomarkers of good prognosis for epithelioid MPM. Those results should be further investigated in sera, plasma, and pleural effusions.

Keywords: fibulin-3; hyaluronan synthase-2; laminin subunit alpha-4; mesothelioma; midkine; prognosis; sestrin-1; syndecan-1.

Figure 1

Log rank multiple cut-off plots genrated for SESN1 (A), LAMA4 (B), MDK (C), FBLN3 (D), SDC1 (E), HAS2 (F) genes in ex-vivo cohort (n = 54). Horizontal line indicates log rank p value of 0.05. Vertical lines indicates 10^th percentile, median and 90th percentile.

Figure 2

Kaplan-Meier survival curves of patients with mesothelioma classified by: A – midkine level in ex-vivo cohort (cutt-off: 2.04); B – syndecan-1 level in ex-vivo cohort (cutt-off: 0.04); C – hayluronan sybthase-2 level in ex-vivo cohort (cutt-off: 0.55); D – sestrin-1 level in ex-vivo cohort (cutt-off: 0.09); E – fibulin 3 level in ex-vivo cohort (cutt-off: 1.04)