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MicroRNA-155 increases colon cancer chemoresistance to cisplatin by targeting forkhead box O3.

ABSTRACT: To investigate the effect of microRNA (miR)-155 on colon cancer chemoresistance to cisplatine and its mechanism. Reverse transcription quantitative polymerase chain reaction was used to measure the levels of miR-155 and forkhead box O3 (FOXO3) in colon cancer specimens and cell lines. Overexpression of miR-155 and miR-155 inhibitor were transfected into colon cancer cell lines to investigate its role of chemoresistance to cisplatin in colon cancer. MTS assays were used to analyse cell viability in vitro. In vivo tumor formation assays were performed in C57BL/6 wild type and miR-155 knockout mice (miR-155-/-). A luciferase reporter assay was used to measure the translation of FOXO3. Additionally, the expression of FOXO3 was detected by western blot analysis. It was identified that miR-155 was markedly upregulated in colon cancer tissue and cell lines. Overexpression of miR-155 enhanced colon cancer cell chemoresistance to cisplatin in vitro and tumorigenesis in vivo. In addition, overexpression of miR-155 was associated with decreased levels of FOXO3, primarily through inhibiting the expression of FOXO3 to increase colon cancer resistanec to cisplatin. The present study demonstrated that miR-155 increased colon cancer drug resistance and decreased FOXO3 expression in vivo and in vitro. This may provide a novel method for the treatment of drug-resistant colon cancer.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5840649 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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MicroRNA-155 increases colon cancer chemoresistance to cisplatin by targeting forkhead box O3.

Gao Yuewen Y Liu Zhaoyan Z Ding Zhaohong Z Hou Shicai S Li Jun J Jiang Kehua K

Oncology letters 20180207 4

To investigate the effect of microRNA (miR)-155 on colon cancer chemoresistance to cisplatine and its mechanism. Reverse transcription quantitative polymerase chain reaction was used to measure the levels of miR-155 and forkhead box O3 (FOXO3) in colon cancer specimens and cell lines. Overexpression of miR-155 and miR-155 inhibitor were transfected into colon cancer cell lines to investigate its role of chemoresistance to cisplatin in colon cancer. MTS assays were used to analyse cell viability ...[more]

PMID: 29552117

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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.

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MicroRNA-155 increases colon cancer chemoresistance to cisplatin by targeting forkhead box O3.

Publications

MicroRNA-155 increases colon cancer chemoresistance to cisplatin by targeting forkhead box O3.

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