ABSTRACT
Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In the past decade, novel therapeutic agents such as trabectedin and pazopanib have been approved, but the prognosis of patients remains unsatisfactory. This study aimed to identify potential therapeutic targets for ULMS based on transcriptome analysis. Archival fresh-frozen tumor tissues of 6 ULMS and three leiomyoma samples were used in this study, and total RNA was extracted. First, transcriptome analysis identified 512 significantly differentially expressed genes, and subsequent pathway analysis using IPA software revealed that the functions of cell cycle-related kinases were significantly activated in ULMS. Moreover, our results were validated using 3 independent Gene Expression Omnibus datasets, including 40 ULMS. Therefore, we considered the kinases as novel therapeutic targets and evaluated the anti-cancer effects of several selective inhibitors against them. Most inhibitors exerted a higher anti-cancer effect than pazopanib in three leiomyosarcoma cell lines. Especially, CHEK1 or PLK1 inhibitors strongly induced cell cycle arrest and cell death, and the IC50s were lower nanomolar concentration. Moreover, the inhibitors suppressed the tumor growth in SK-UT-1 bearing mice models. In conclusion, we revealed the unique gene expression profiles of ULMS. CHEK1 and PLK1 are promising therapeutic targets for ULMS, and therefore, further clinical trials are highly anticipated to improve the prognosis of the patients.
ABSTRACT
OBJECTIVES: There is increasing evidence that systemic inflammatory response (SIR) markers are prognostic factors for various types of cancers. This is the first study to evaluate the usefulness of SIR markers for the prognosis of early-stage ovarian clear-cell carcinoma (OCCC). METHODS: We retrospectively investigated 83 patients diagnosed with stage I–II OCCC who underwent surgery between 2005 and 2017. Initially, receiver operating characteristic curve analysis for overall survival (OS) was used to determine optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Patients were stratified into 2 groups by the cut-off values (NLR=3.26, PLR=160). Univariate and multivariate analyses were performed to elucidate the significance of SIR markers as prognostic factors. RESULTS: In the median follow-up period of 64.1 months, 16 patients experienced recurrence, and nine patients died. The Kaplan-Meier curve showed that OS of the NLR-low group was significantly longer than the NLR-high group (p=0.021). There was no significant difference in progression-free survival between the 2 groups (p=0.668), but the post-recurrence survival of the NLR-low group was significantly longer than the NLR-high group (p=0.019). Furthermore, multivariate analysis showed that increase in NLR is a significant independent prognostic factor for poor prognosis (hazard ratio=7.437, p=0.017). There was no significant difference between PLR-low and PLR-high group. CONCLUSION: Results suggest that NLR can be a significant independent prognostic factor for early-stage OCCC.