Observations on spontaneous tumor formation in mice overexpressing mitotic kinesin Kif14

Kamakshi Sishtla,Anthony L Sinn,George E Sandusky,Keith Condon,Timothy W Corson,Rania S Sulaiman,Mehdi Shadmand,Natalie Pitt,Michael N O’Hare,Karen E Pollok

doi:10.1038/s41598-018-34603-4

Abstract

The KIF14 locus is gained and overexpressed in various malignancies, with prognostic relevance. Its protein product, a mitotic kinesin, accelerates growth of normal mammary epithelial cells in vitro and retinoblastoma tumours in a mouse model, while KIF14 knockdown blocks growth of brain, liver, ovarian, breast, prostate, and other tumour cells and xenografts. However, the tumour-initiating effects of Kif14 overexpression have not been studied. We aged a cohort of Kif14-overexpressing transgenic mice and wild-type littermates and documented survival, cause of death, and tumour burden. The Kif14 transgene was expressed in all tissues examined, and was associated with increased proliferation marker expression. Neither mouse weights nor overall survival differed between genotypes. However, Kif14 transgenic mice showed a higher incidence of fatal lymphomas (73 vs. 50%, p = 0.03, Fisher’s exact test), primarily follicular and diffuse B-cell lymphomas. Non-tumour findings included a bilateral ballooning degeneration of lens in 12% of Kif14 transgenic mice but no wild-type mice (p = 0.02). Overall, this work reveals a novel association of Kif14 overexpression with lymphoma but suggests that Kif14 does not have as prominent a role in initiating cancer in other cell types as it does in accelerating tumour development in response to other oncogenic insults.

Highlights

The ATP- and microtubule dependent molecular motors known as kinesins have garnered considerable interest as cancer targets
The KIF14 locus is gained in breast carcinoma[5], hepatocellular carcinoma[5,7], ovarian carcinoma[8], papillary renal cell carcinoma[9], and medulloblastoma[10]
Complementing this genomic gain, KIF14 is overexpressed in multiple tumour types, including retinoblastoma[4,11,12] and cancers of the breast[13], cervix[14], liver[15], lung[16], ovary[8], larynx[17], brain[18,19], and prostate[20]

Summary

Introduction

The ATP- and microtubule dependent molecular motors known as kinesins have garnered considerable interest as cancer targets. The KIF14 locus is gained in breast carcinoma[5], hepatocellular carcinoma[5,7], ovarian carcinoma[8], papillary renal cell carcinoma[9], and medulloblastoma[10] Complementing this genomic gain, KIF14 is overexpressed in multiple tumour types, including retinoblastoma (both human and murine)[4,11,12] and cancers of the breast[13], cervix[14], liver[15], lung[16], ovary[8], larynx[17], brain[18,19], and prostate[20]. In characterizing the laggard mutant, the Sakisaka group generated a Kif[14] overexpressing transgenic (Tg) mouse, which could rescue the phenotype of laggard and Kif[14] knock-out animals[26] The advent of this model raised the appealing possibility of exploring Kif14’s cancer-promoting effects in animals. We report the effects of Kif[14] overexpression on tumour formation in a population of otherwise normal mice allowed to live out their lifespans

Methods

Results

Conclusion