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Paired box 2 promotes progression of endometrial cancer via regulating cell cycle pathway.

ABSTRACT: Background: Human paired box 2 (PAX2) plays a key role in cell fate, early patterning and organogenesis. Methods: We investigated the function of PAX2 on the biological behavior of endometrial cancer in vitro and in vivo and to explore the regulation mechanism, stable knocking-down and over-expression PAX2 endometrial cancer cell lines were established. CCK-8 and transwell assays were applied to determine proliferation, invasion and migration ability. Cell cycle distribution was analyzed by flow cytometry. Affymetrix GeneChip® human Exon 1.0 ST arrays was used to screen the downstream target genes of PAX2. Results: PAX2 significantly enhanced proliferation and invasiveness. In addition, PAX2 influenced the expression of cyclin-dependent kinase 1(CDK1), which play pivotal roles in cell cycle pathway. When CDK1 was knocked down, and the cell proliferation promotion role of PAX2 was attenuated dramatically to a level comparable with the control groups. Conclusions: PAX2, though influencing the expression of CDK1, promotes the proliferation, enhances the mobility of endometrial cancer cells, thus exerts an important role in the carcinogenesis of endometrial cancer. PAX2 may be a potential therapeutic target for endometrial cancer.

SUBMITTER: Wang J

PROVIDER: S-EPMC6216001 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Paired box 2 promotes progression of endometrial cancer via regulating cell cycle pathway.

Wang Jieyu J Jia Nan N Lyv Tianjiao T Wang Chao C Tao Xiang X Wong KwongKwok K Li Qin Q Feng Weiwei W

Journal of Cancer 20180925 20

<b>Background:</b> Human paired box 2 (PAX2) plays a key role in cell fate, early patterning and organogenesis. <b>Methods:</b> We investigated the function of PAX2 on the biological behavior of endometrial cancer in vitro and in vivo and to explore the regulation mechanism, stable knocking-down and over-expression PAX2 endometrial cancer cell lines were established. CCK-8 and transwell assays were applied to determine proliferation, invasion and migration ability. Cell cycle distribution was an ...[more]

PMID: 30405846

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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.

Project description:BackgroundBladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear.MethodsThe clinical relevance of ANXA1 in BLCA was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments.ResultsBioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling.ConclusionsThese findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.

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Paired box 2 promotes progression of endometrial cancer via regulating cell cycle pathway.

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Paired box 2 promotes progression of endometrial cancer via regulating cell cycle pathway.

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