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Tumor suppression by miR-31 in esophageal carcinoma is p21-dependent.

ABSTRACT: microRNA regulation network is important for the cancer genetic heterogeneity. Relative to the increasing numbers of microRNA's targets identified, upstream regulatory mechanisms that control functional microRNAs are less well-documented. Here, we investigated the function of miR-31, a pleiotropically-acting microRNA, in esophageal squamous cell cancer (ESCC). We demonstrated that miR-31 only exerted tumor-suppressive effects in TE-7 ESCC cells, but not in TE-1 ESCC cells, although both of these cell lines harbor inactive p53. Interestingly, TE-1 cells highly expressed p21, while p21 levels were virtually undetectable in TE-7 cells, suggesting a p21-dependent mechanism of miR-31-mediated tumor suppression. Accordingly, knockdown of p21 in TE-1 cells reversed the tumor suppressive actions of miR-31. In patient ESCC specimens, real-time RT-PCR analysis revealed that expression of E2F2 and STK40, two known miR-31 target oncogenes, was negatively correlated with the expression of miR-31 in a p21-dependent manner, supporting the conclusion that miR-31 only downregulates its target oncogenes when p21 levels are low. Collectively, these data suggest a novel mechanism through which the tumor-suppressive effect of miR-31 is p21-dependent. In addition, we speculate that delivery of miR-31 could provide therapeutic benefit in the personalized management of a subgroup of ESCC patients with p21-deficient tumors.

SUBMITTER: Ning Z

PROVIDER: S-EPMC4279440 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Tumor suppression by miR-31 in esophageal carcinoma is p21-dependent.

Ning Zhifeng Z Zhu Hua H Li Feifei F Liu Qing Q Liu Gefei G Tan Tao T Zhang Bo B Chen Shaobin S Li Guanwu G Huang Dongyang D Meltzer Stephen J SJ Zhang Hao H

Genes & cancer 20141101 11-12

microRNA regulation network is important for the cancer genetic heterogeneity. Relative to the increasing numbers of microRNA's targets identified, upstream regulatory mechanisms that control functional microRNAs are less well-documented. Here, we investigated the function of miR-31, a pleiotropically-acting microRNA, in esophageal squamous cell cancer (ESCC). We demonstrated that miR-31 only exerted tumor-suppressive effects in TE-7 ESCC cells, but not in TE-1 ESCC cells, although both of these ...[more]

PMID: 25568668

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Project description:PurposeEsophageal squamous cell carcinoma (ESCC) is an aggressive disease with a poor prognosis, caused by the inactivation of critical cell growth regulators that lead to uncontrolled proliferation and increased malignancy. Although Serine/Threonine Kinase 3 (STK3), also known as Mammalian STE20-like protein kinase 2 (MST2), is a highly conserved kinase of the Hippo pathway, plays a critical role in immunomodulation, organ development, cellular differentiation, and cancer suppression, its phenotype and function in ESCC require further investigation. In this study, we report for the first time on the role of STK3 kinase and its activation condition in ESCC, as well as the mechanism and mediators of kinase activation.MethodsIn this study, we investigated the expression and clinical significance of STK3 in ESCC. We first used bioinformatics databases and immunohistochemistry to analyze STK3 expression in the ESCC patient cohort and conducted survival analysis. In vivo, we conducted a tumorigenicity assay using nude mouse models to demonstrate the phenotypes of STK3 kinase. In vitro, we conducted Western blot analysis, qPCR analysis, CO-IP, and immunofluorescence (IF) staining analysis to detect molecule expression, interaction, and distribution. We measured proliferation, migration, and apoptosis abilities in ESCC cells in the experimental groups using CCK-8 and transwell assays, flow cytometry, and EdU staining. We used RNA-seq to identify genes that were differentially expressed in ESCC cells with silenced STK3 or FOXO1. We demonstrated the regulatory relationship of the TP53INP1/P21 gene medicated by the STK3-FOXO1 axis using Western blotting and ChIP in vitro.ResultsWe demonstrate high STK3 expression in ESCC tissue and cell lines compared to esophageal epithelium. Cellular ROS induces STK3 autophosphorylation in ESCC cells, resulting in upregulated p-STK3/4. STK3 activation inhibits ESCC cell proliferation and migration by triggering apoptosis and suppressing the cell cycle. STK3 kinase activation phosphorylates FOXO1Ser212, promoting nuclear translocation, enhancing transcriptional activity, and upregulating TP53INP1 and P21. We also investigated TP53INP1 and P21's phenotypic effects in ESCC, finding that their knockdown significantly increases tumor proliferation, highlighting their crucial role in ESCC tumorigenesis.ConclusionSTK3 kinase has a high expression level in ESCC and can be activated by cellular ROS, inhibiting cell proliferation and migration. Additionally, STK3 activation-mediated FOXO1 regulates ESCC cell apoptosis and cell cycle arrest by targeting TP53INP1/P21. Our research underscores the anti-tumor function of STK3 in ESCC and elucidates the mechanism underlying its anti-tumor effect on ESCC.

Dataset Information

Tumor suppression by miR-31 in esophageal carcinoma is p21-dependent.

Publications

Tumor suppression by miR-31 in esophageal carcinoma is p21-dependent.

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