LAUSR

[Objective] Uterine leiomyosarcoma (LMS) has a poor prognosis, and no effective treatment other than surgery has been established. Kinesin family member4A (KIF4A) is a member of the kinesin4 subfamily and plays an important role in cell division. KIF4A has been revealed to play significant roles in some cancers with tumor proliferation. The aim of this study is to clarify the relationship between KIF4A and tumor growth of LMS. [Methods] One normal human uterine smooth muscle cell line and three LMS cell lines(SK-UT1, SK-LMS and SKN) were used to identify tumor-specific elevated proteins with iTRAQ(isobaric tags for relative and absolute quantitation). SiRNA and ShRNA were used to downregulate KIF4A in vitro and in in vivo. Cell variability was evaluated by MST-8 assay. Cell cycle analysis by fluorescence-activated cell sorting (FACS) and western blotting (WB) were performed to analyze the signal pathway. Immunostaining of 26 clinical specimen from patients operated at our university hospital since 1999 to 2021. [Results] A total of 2084 proteins were identified by iTRAQ. KIF4A was identified as a protein with more than twice the expression level of normal smooth muscle cells. WB confirmed high expression of KIF4A in all three LMS cell lines. And in immunostaining of clinical specimens, KIF4A was positive in 20/26(76.9%) cases. A trend toward worse prognosis was suggested in the group with high KIF4A expression (no significant difference due to the small number of cases). Downregulation with SiRNA significantly suppressed the growth of LMS cell lines in vitro (-37.2±4.73% in SK-LMS, -87.7±4.02% in SKN and -28.1±3.00% in SK-UT1, p<0.05). By FACS, G2/M phase cells was significantly increased in KIF4A suppressed cell lines and by WB, p-cdc2 was upregulated in KIF4A suppressed cells. In vivo, downregulation of KIF4A was found to significantly suppress tumor size in genograft mice. (1186±118mm³ vs 461±84mm³ in SK-LMS and 1704±441mm³ vs 514±230mm³ in SK-UT1, p<0.05, f). [Conclusion] Downregulating KIF4A inhibited LMS tumor growth and it can be a novel therapeutics target to treat LMS. Citation Format: Satoshi Nakagawa, Chihiro Mizuta-Odani, Mariya Kobayashi, Mamoru Kakuda, Kosuke Hiramatsu, Toshihiro Kimura, Eiji Kobayashi, Yutaka Ueda, Tadashi Kimura. Downregulating KIF4A inhibited growth of uterine leiomyosarcoma by regulating cell cycle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 346.