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FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression.

ABSTRACT: Endometrial cancer (EC) is one of the most important gynecological cancers, but its pathogenesis is not clearly understood, and it also lacks an effective treatment. The nuclear transcriptional protein forkhead box protein M1 (FOXM1) has crucial functions in the development and progression of cancer and is treated as a prognostic biomarker and therapeutic target in many types of cancers. However, the situation and underlying mechanisms of FOXM1's involvement in EC is largely underestimated. In our present study, we found FOXM1 was overexpressed in EC, including endometrioid (EEC) and serous (SEC). High expression of FOXM1 was meaningfully associated with a poor prognosis of EC patients as well as with EC pathological stages and clinical grades. Knocking down FOXM1 could significantly reduce the proliferation and migration capacity of AN3CA and ISHIKAWA cells. Furthermore, our RNA-seq results indicated that the knockdown of FOXM1 mainly affects downstream metabolic genes in EC cells. Finally, we also discovered one potential functional pathway, FOXM1-SLC27A2, which may contribute to EC progression. Taken together, the high expression of FOXM1 is closely associated with the prognosis, pathological stages, and clinical grades of EC patients. FOXM1 can promote the proliferation and migration of EC cells. Through SLC27A2, FOXM1 may influence the metabolic activity of EC cells, and FOXM1-SLC27A signaling could be treated as a potential cellular target for a therapeutic strategy of EC.

SUBMITTER: Feng Y

PROVIDER: S-EPMC6962789 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression.

Feng Yichen Y Li Shaojing S Zhang Rong R Liu Fei F Xu Qinyang Q Ding Hongmei H Teng Yincheng Y

International journal of clinical and experimental pathology 20180801 8

Endometrial cancer (EC) is one of the most important gynecological cancers, but its pathogenesis is not clearly understood, and it also lacks an effective treatment. The nuclear transcriptional protein forkhead box protein M1 (FOXM1) has crucial functions in the development and progression of cancer and is treated as a prognostic biomarker and therapeutic target in many types of cancers. However, the situation and underlying mechanisms of FOXM1's involvement in EC is largely underestimated. In o ...[more]

PMID: 31949772

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Project description:BackgroundForkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression.MethodsBioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth.ResultsFOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo.ConclusionThe FOXM1-KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment.

Project description:Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer-alternative mRNA splicing-and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed more SF3B1 protein than non-cancerous tissues. Furthermore, SF3B1 knockdown reduced in vitro proliferation, migration, and invasion of the endometrial cancer cell lines Ishikawa and AN3CA. Similarly, the SF3B1 inhibitor, Pladienolide-B (PLAD-B), reduced the Ishikawa and AN3CA cell proliferation and invasion in vitro. Moreover, PLAD-B reduced tumor growth in an orthotopic endometrial cancer mouse model. Using RNA-Seq approach, we identified ~2000 differentially expressed genes (DEGs) with SF3B1 knockdown in endometrial cancer cells. Additionally, alternative splicing (AS) events analysis revealed that SF3B1 depletion led to alteration in multiple categories of AS events including alternative exon skipping (ES), transcript start site usage (TSS), and transcript termination site (TTS) usage. Subsequently, bioinformatics analysis showed KSR2 as a potential candidate for SF3B1-mediated functions in endometrial cancer. Specifically, loss of SF3B1 led to decrease in KSR2 expression, owing to reduced maturation of KSR2 pre-mRNA to a mature RNA. Importantly, we found rescuing the KSR2 expression with SF3B1 knockdown partially restored the cell growth of endometrial cancer cells. Taken together, our data suggest that SF3B1 plays a crucial oncogenic role in the tumorigenesis of endometrial cancer and hence may support the development of SF3B1 inhibitors to treat this disease.

Dataset Information

FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression.

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FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression.

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