Genes influenced by the non-muscle isoform of Myosin light chain kinase impact human cancer prognosis.
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 (P<0.001), colon cancer (P<0.001), glioma (P<0.001), and lung cancer (P<0.001). In validation cohorts, the M38 signature demonstrated significantly reduced overall survival for high-score patients of breast cancer (P = 0.002), colon cancer (P = 0.035), glioma (P = 0.023), and lung cancer (P = 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.
Arizona Respiratory Center and Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
Tong
T
Zhou
Arizona Respiratory Center and Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
Ting
T
Wang
Arizona Respiratory Center and Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
Joe G N
JG
Garcia
D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009219:Myosin-Light-Chain Kinase / Q000235:genetics* / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D059467:Transcriptome; D047368:Tumor Burden
D009219:Myosin-Light-Chain Kinase; C000593292:non-muscle myosin light-chain kinase, human; C561451:non-muscle myosin light-chain kinase, mouse