title: A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas.
abstract: Amplified centrosomes are widely recognized as a hallmark of cancer. Although supernumerary centrosomes would be expected to compromise cell viability by yielding multipolar spindles that results in death-inducing aneuploidy, cancer cells suppress multipolarity by clustering their extra centrosomes. Thus, cancer cells, with the aid of clustering mechanisms, maintain pseudobipolar spindle phenotypes that are associated with low-grade aneuploidy, an edge to their survival. KIFC1, a nonessential minus end-directed motor of the kinesin-14 family, is a centrosome clustering molecule, essential for viability of extra centrosome-bearing cancer cells. Given that ovarian cancers robustly display amplified centrosomes, we examined the overexpression of KIFC1 in human ovarian tumors.
  
  
  
  We found that in clinical epithelial ovarian cancer (EOC) samples, an expression level of KIFC1 was significantly higher when compared to normal tissues. KIFC1 expression also increased with tumor grade. Our In silico analyses showed that higher KIFC1 expression was associated with poor overall survival (OS) in serous ovarian adenocarcinoma (SOC) patients suggesting that an aggressive disease course in ovarian adenocarcinoma patients can be attributed to high KIFC1 levels. Also, gene expression levels of KIFC1 in high-grade serous ovarian carcinoma (HGSOC) highly correlated with expression of genes driving centrosome amplification (CA), as examined in publically-available databases. The pathway analysis results indicated that the genes overexpressed in KIFC1 high group were associated with processes like regulation of the cell cycle and cell proliferation. In addition, when we performed gene set enrichment analysis (GSEA) for identifying the gene ontologies associated to KIFC1 high group, we found that the first 100 genes enriched in KIFC1 high group were from centrosome components, mitotic cell cycle, and microtubule-based processes. Results from in vitro experiments on well-established in vitro models of HGSOC (OVSAHO, KURAMOCHI), OVCAR3 and SKOV3) revealed that they display robust centrosome amplification and expression levels of KIFC1 was directly associated (inversely correlated) to the status of multipolar mitosis. This association of KIFC1 and centrosome amplification with HGSOC might be able to explain the increased aggressiveness in this disease.
  
  
  
  These findings compellingly underscore that KIFC1 can be a biomarker that predicts an aggressive disease course in ovarian adenocarcinomas.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Karuna
authors.initials: K
authors.lastname: Mittal
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Da Hoon
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Klimov
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 Mathematics, Science and Bioinformatics, Mercer University, Atlanta, GA, USA.
authors.forename: Ramneet
authors.initials: R
authors.lastname: Kaur
authors.affiliation: Department of Medical and Molecular Genetics, Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, USA.
authors.forename: Anirban K
authors.initials: AK
authors.lastname: Mitra
authors.affiliation: Department of Pathology, West Georgia Hospital, Lagrange, GA, USA.
authors.forename: Meenakshi V
authors.initials: MV
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Northside Hospital, Atlanta, GA, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Sams
authors.affiliation: Department of Gynecologic Oncology, Northside Hospital Cancer Institute, Atlanta, GA, USA.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Cantuaria
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA, 30303, USA. cgp_rida@yahoo.com.|Novazoi Theranostics, Plano, TX, USA. cgp_rida@yahoo.com.
authors.forename: Padmashree C G
authors.initials: PCG
authors.lastname: Rida
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA, 30303, USA. raneja@gsu.edu.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C486566:KIFC1 protein, human; D016547:Kinesins
keywords: Centrosome amplification; Centrosome clustering; KIFC1; Serous ovarian adenocarcinoma