A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas

Karuna Mittal, Da Hoon Choi, Sergey Klimov, Shrikant Pawar, Ramneet Kaur, Anirban Mitra, Meenakshi V. Gupta, Ralph Sams, Guilherme Cantuaria, Padmashree C G Rida, Ritu Aneja

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: 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. Results: 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. Conclusion: These findings compellingly underscore that KIFC1 can be a biomarker that predicts an aggressive disease course in ovarian adenocarcinomas.

Original languageEnglish (US)
Article number224
JournalJournal of Ovarian Research
Volume9
Issue number1
DOIs
StatePublished - Mar 18 2016

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Centrosome
Cluster Analysis
Adenocarcinoma
Proteins
Neoplasms
Aneuploidy
Carcinoma
Cell Cycle
Genes
Gene Expression
Kinesin
Gene Ontology
Survival
Mitosis
Microtubules
Computer Simulation
Ovarian Neoplasms
Cell Survival
Biomarkers
Cell Proliferation

Keywords

  • Centrosome amplification
  • Centrosome clustering
  • KIFC1
  • Serous ovarian adenocarcinoma

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas. / Mittal, Karuna; Choi, Da Hoon; Klimov, Sergey; Pawar, Shrikant; Kaur, Ramneet; Mitra, Anirban; Gupta, Meenakshi V.; Sams, Ralph; Cantuaria, Guilherme; Rida, Padmashree C G; Aneja, Ritu.

In: Journal of Ovarian Research, Vol. 9, No. 1, 224, 18.03.2016.

Research output: Contribution to journalArticle

Mittal, K, Choi, DH, Klimov, S, Pawar, S, Kaur, R, Mitra, A, Gupta, MV, Sams, R, Cantuaria, G, Rida, PCG & Aneja, R 2016, 'A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas', Journal of Ovarian Research, vol. 9, no. 1, 224. https://doi.org/10.1186/s13048-016-0224-0
Mittal, Karuna ; Choi, Da Hoon ; Klimov, Sergey ; Pawar, Shrikant ; Kaur, Ramneet ; Mitra, Anirban ; Gupta, Meenakshi V. ; Sams, Ralph ; Cantuaria, Guilherme ; Rida, Padmashree C G ; Aneja, Ritu. / A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas. In: Journal of Ovarian Research. 2016 ; Vol. 9, No. 1.
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AU - Mittal, Karuna

AU - Choi, Da Hoon

AU - Klimov, Sergey

AU - Pawar, Shrikant

AU - Kaur, Ramneet

AU - Mitra, Anirban

AU - Gupta, Meenakshi V.

AU - Sams, Ralph

AU - Cantuaria, Guilherme

AU - Rida, Padmashree C G

AU - Aneja, Ritu

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N2 - Background: 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. Results: 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. Conclusion: These findings compellingly underscore that KIFC1 can be a biomarker that predicts an aggressive disease course in ovarian adenocarcinomas.

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KW - Centrosome amplification

KW - Centrosome clustering

KW - KIFC1

KW - Serous ovarian adenocarcinoma

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