Genes Influenced by the Non-Muscle Isoform of Myosin Light Chain Kinase Impact Human Cancer Prognosis

<div><p>The multifunctional non-muscle isoform of myosin light chain kinase (nmMLCK) is critical to the rapid dynamic coordination of the cytoskeleton involved in cancer cell proliferation and migration. We identified 45 nmMLCK-influenced genes by bioinformatic filtering of genome–wide expression in wild type and nmMLCK knockout (KO) mice exposed to preclinical models of murine acute inflammatory lung injury, pathologies that are well established to include nmMLCK as an essential participant. To determine whether these nmMLCK-influenced genes were relevant to human cancers, the 45 mouse genes were matched to 38 distinct human orthologs (M38 signature) (GeneCards definition) and underwent Kaplan-Meier survival analysis in training and validation cohorts. These studies revealed that in training cohorts, the M38 signature successfully identified cancer patients with poor overall survival in breast cancer (<i>P</i><0.001), colon cancer (<i>P</i><0.001), glioma (<i>P</i><0.001), and lung cancer (<i>P</i><0.001). In validation cohorts, the M38 signature demonstrated significantly reduced overall survival for high-score patients of breast cancer (<i>P</i> = 0.002), colon cancer (<i>P</i> = 0.035), glioma (<i>P</i> = 0.023), and lung cancer (<i>P</i> = 0.023). The association between M38 risk score and overall survival was confirmed by univariate Cox proportional hazard analysis of overall survival in the both training and validation cohorts. This study, providing a novel prognostic cancer gene signature derived from a murine model of nmMLCK-associated lung inflammation, strongly supports nmMLCK-involved pathways in tumor growth and progression in human cancers and nmMLCK as an attractive candidate molecular target in both inflammatory and neoplastic processes.</p></div

nmMLCK-mediated mouse genes.

a<p>FC: fold change, which is calculated by dividing the expression in VILI-exposed WT mice by the expression in WT control mice.</p>b<p>FC: fold change, which is calculated by dividing the expression in VILI-exposed nmMLCK KO mice by the expression in WT VILI-exposed mice.</p

M38 signature.

<p>M38 signature.</p

nmMLCK-mediated mouse genes.

<p>(A) Enriched pathways among the differentially expressed genes between WT VILI-exposed and VILI-exposed nmMLCK KO mice. The red line indicates the cutoff of significance (<i>P</i><0.05). (B) Enriched pathways among the 45 nmMLCK-mediated genes. The red line indicates the cutoff of significance (<i>P</i><0.05). (C) Heatmap of expression for WT control, WT VILI-exposed, and VILI-exposed nmMLCK KO mice. Red represents increased gene expression; Blue represents down-regulation.</p

Multivariate Cox proportional hazards regression of overall survival.

<p>Multivariate Cox proportional hazards regression of overall survival.</p

Univariate Cox proportional hazards regression of overall survival against M38 signature status.

<p>Univariate Cox proportional hazards regression of overall survival against M38 signature status.</p

Expression of M38 signature predicts poor clinical outcome in multiple human cancers.

<p>Kaplan-Meier survival curves for patient groups identified by M38 risk score. Red curves are for the high-score patients while blue curves are for the low-score patients. High-score patients are defined as those having a M38 risk score greater than or equal to the group median score. <i>P</i>-values indicate significant differences in overall survival as measured by log-rank tests.</p

NTM-related deaths and age-adjusted mortality rates per 100,000 person-years by States, United States, 1999–2010.

<p>Legend: Alaska had NTM related mortality less than 9, therefore data were suppressed to meet the criteria for confidentiality constraints.</p

NTM and TB-related mortality rates per 100,000 person-years by year, United States, 1999–2010.

<p>NTM and TB-related mortality rates per 100,000 person-years by year, United States, 1999–2010.</p

Age-adjusted NTM and tuberculosis-related mortality rates per 100,000 person-years and Age-adjusted mortality rate ratios by gender, race/ethnicity, urbanization and age group, United States, 1999–2010.

<p>* 95% CIs: 95% Confidence intervals,</p><p>**UR: Unreliable.</p