title: KIFCI, a novel putative prognostic biomarker for ovarian adenocarcinomas: delineating protein interaction networks and signaling circuitries.
abstract: BACKGROUND
  Amplified centrosomes in cancers are recently garnering a lot of attention as an emerging hub of diagnostic, prognostic and therapeutic targets. Ovarian adenocarcinomas commonly harbor supernumerary centrosomes that drive chromosomal instability. A centrosome clustering molecule, KIFC1, is indispensable for the viability of extra centrosome-bearing cancer cells, and may underlie progression of ovarian cancers.
  
  
  METHODS
  Centrosome amplification in low- and high- grade serous ovarian adenocarcinomas was quantitated employing confocal imaging. KIFC1 expression was analyzed in ovarian tumors using publically-available databases. Associated grade, stage and clinical information from these databases were plotted for KIFC1 gene expression values. Furthermore, interactions and functional annotation of KIFC1 and its highly correlated genes were studied using DAVID and STRING 9.1.
  
  
  RESULTS
  Clinical specimens of ovarian cancers display robust centrosome amplification and deploy centrosome clustering to execute an error-prone mitosis to enable karyotypic heterogeneity that fosters tumor progression and aggressiveness. Our in silico analyses showed KIFC1 overexpression in human ovarian tumors (n = 1090) and its upregulation associated with tumor aggressiveness utilizing publically-available gene expression databases. KIFC1 expression correlated with advanced tumor grade and stage. Dichotomization of KIFC1 levels revealed a significantly lower overall survival time for patients in high KIFC1 group. Intriguingly, in a matched-cohort of primary (n = 7) and metastatic (n = 7) ovarian samples, no significant differences in KIFC1 expression were detectable, suggesting that high KIFC1 expression may serve as a marker of metastases onset. Nonetheless, KIFC1 levels in both primary and matched metastatic sites were significantly higher compared to normal tissue . Ingenuity based network prediction algorithms combined with pre-established protein interaction networks uncovered several novel cell-cycle related partner genes on the basis of interconnectivity, illuminating the centrosome clustering independent agenda of KIFC1 in ovarian tumor progression.
  
  
  CONCLUSIONS
  Ovarian cancers display amplified centrosomes, a feature of aggressive tumors. To cope up with the abnormal centrosomal load, ovarian cancer cells upregulate genes like KIFC1 that are known to induce centrosome clustering. Our data underscore KIFC1 as a putative biomarker that predicts worse prognosis, poor overall survival and may serve as a potential marker of onset of metastatic dissemination in ovarian cancer patients.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Pawar
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Shashikiran
authors.initials: S
authors.lastname: Donthamsetty
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Pannu
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Padmashree
authors.initials: P
authors.lastname: Rida
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Ogden
authors.affiliation: Center for Cancer Research and Therapeutic Development (CCRTD), Clark Atlanta University, Atlanta, GA 30314, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bowen
authors.affiliation: Department of Mathematics and Statistics, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Remus
authors.initials: R
authors.lastname: Osan
authors.affiliation: Northside Hospital Cancer Institute, Atlanta, GA 30342, USA.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Cantuaria
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D018385:Centrosome / Q000378:metabolism; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008938:Mitosis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C486566:KIFC1 protein, human; D016547:Kinesins