Dataset Information

Forkhead box O3 promotes colon cancer proliferation and drug resistance by activating MDR1 expression.

ABSTRACT:

Background

Globally, colon cancer (CC) is the third reason of tumor-related deaths. Previous reports indicate that Forkhead box O3 (FOXO3) is involved in the development of various tumors and may have different effects depending upon the types of tumors. Hence, this study was to examine the effects of FOXO3 on CC cells and uncover the possible mechanisms.

Methods

MTT and cell count assay were applied to analyze the viability of transfected CC cells. rVista, dual luciferase reporter assay, and chromatin immunoprecipitation assay were used to identify the downstream target of FOXO3 in HCT116 cells. The mRNA and protein abundance of FOXO3 and MDR1 were determined by quantitative PCR and Western blot, respectively.

Results

Forkhead box O3 stimulated the proliferation of both HCT116 and DLD1 cells. Moreover, FOXO3 overexpression inhibited doxorubicin sensitivity of HCT116 cells, while the knockout of FOXO3 by FOXO3 shRNA restored the doxorubicin sensitivity in doxorubicin-resistant HCT116 DR cells. Next, we found that FOXO3 directly bound to the promoter of MDR1 and enhanced MDR1 expression in HCT116 cells. MDR1 overexpression enhanced the viability and doxorubicin resistance of CC cells. Besides, MDR1 overexpression plasmid significantly abrogated the decrease in cell proliferation and resistance of HCT116 cells to doxorubicin caused by FOXO3 knockout.

Conclusion

Forkhead box O3 exhibited promotive effects on the proliferation and doxorubicin resistance in CC cells via targeting MDR1.

SUBMITTER: Gao Z

PROVIDER: S-EPMC6418361 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Forkhead box O3 promotes colon cancer proliferation and drug resistance by activating MDR1 expression.

Gao Zhuanglei Z Li Zhaoxia Z Liu Yuelin Y Liu Zhonghao Z

Molecular genetics & genomic medicine 20190108 3

<h4>Background</h4>Globally, colon cancer (CC) is the third reason of tumor-related deaths. Previous reports indicate that Forkhead box O3 (FOXO3) is involved in the development of various tumors and may have different effects depending upon the types of tumors. Hence, this study was to examine the effects of FOXO3 on CC cells and uncover the possible mechanisms.<h4>Methods</h4>MTT and cell count assay were applied to analyze the viability of transfected CC cells. rVista, dual luciferase reporte ...[more]

PMID: 30623608

Similar Datasets

Project description:BACKGROUND & AIMS:Diminished forkhead box O3 (FOXO3) function drives inflammation and cancer growth; however, mechanisms fostering these pathobiologies are unclear. Here, we aimed to identify in colon loss of FOXO3-dependent cellular and molecular changes that facilitate inflammation-mediated tumor growth. METHODS:FOXO3 knockout (KO) and wild-type (WT) mice were used in the AOM/DSS model of inflammation-mediated colon cancer. Bioinformatics were used for profiling of mRNA sequencing data from human and mouse colon and tumors; specific targets were validated in human colon cancer cells (shFOXO3). RESULTS:In mice, FOXO3 deficiency led to significantly elevated colonic tumor burden (incidence and size) compared with WT (P < .05). In FOXO3 KO colon, activated molecular pathways overlapped with those associated with mouse and human colonic inflammation and cancer, especially human colonic tumors with inflammatory microsatellite instability (false discovery rate < 0.05). FOXO3 KO colon, similar to tumors, had increased neutrophils, macrophages, B cells, T cells, and decreased natural killer cells (false discovery rate < 0.05). Moreover, in KO colon differentially expressed transcripts were linked to activation of inflammatory nuclear factor kappa B, tumorigenic cMyc, and bacterial Toll-like receptor signaling. Among differentially expressed transcripts, we validated altered expression of integrin subunit alpha 2 (ITGA2), ADAM metallopeptidase with thrombospondin type 1 motif 12, and ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 5 in mouse WT and FOXO3 KO colon and tumors (P < .05). Similarly, their altered expression was found in human inflammatory bowel disease and colon cancer tissues and linked to poor patient survival. Ultimately, in human colon cancer cells, FOXO3 knockdown (shFOXO3) led to significantly increased ITGA2, and silencing ITGA2 (siRNA) alone diminished cell growth. CONCLUSIONS:We identified the loss of FOXO3-mediated immune landscape, pathways, and transcripts that could serve as biomarkers and new targets for inflammatory colon cancer treatment.

Dataset Information

Forkhead box O3 promotes colon cancer proliferation and drug resistance by activating MDR1 expression.

Background

Methods

Results

Conclusion

Publications

Forkhead box O3 promotes colon cancer proliferation and drug resistance by activating MDR1 expression.

Similar Datasets

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