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IGF2-derived miR-483 mediated oncofunction by suppressing DLC-1 and associated with colorectal cancer.

ABSTRACT: Emerging evidence indicates that IGF2 plays an important role in various human malignancies, including colorectal cancer (CRC). Hsa-miR-483 is located within intron 7 of the IGF2 locus. However, the mechanism by which increased IGF2 induces carcinogenesis remains largely elusive. DLC-1 has been identified as a candidate tumor suppressor. In this study, we aimed at investigating whether miR-483 transcription is IGF2-dependent, identifying the functional target of miR-483, and evaluating whether tissue and serum miR-483-3p or miR-483-5p levels are associated with CRC. Our results showed that sequences upstream miR-483 had undetectable promoter activity and levels of IGF2, miR-483-3p, and miR-483-5p were synchronously increased in CRC tissues. Positive correlations between IGF2 and miR-483-3p (r=0.4984, ***p<0.0001), and between IGF2 and miR-483-5p (r=0.6659, ***p<0.0001) expression were found. In addition, patients with CRC had a significantly higher serum miR-483-5p level (*p<0.05) compared to normal controls. DLC-1 expression was decreased in colorectal cancer tissues and diminished through transient transfection with miR-483-3p. Our results suggest that IGF2 may exert its oncofunction, at least partly, through its parasitic miR-483 which suppressed DLC-1 in CRC cells. Thus, miR-483 might serve as a new target for therapy and a potential biomarker for the detection of colorectal cancer.

SUBMITTER: Cui H

PROVIDER: S-EPMC5217031 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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IGF2-derived miR-483 mediated oncofunction by suppressing DLC-1 and associated with colorectal cancer.

Cui Hengmi H Liu Yuan Y Jiang Jingrui J Liu Yangyang Y Yang Zhe Z Wu Shaogen S Cao Wangsen W Cui Isabelle H IH Yu Chenggong C

Oncotarget 20160701 30

Emerging evidence indicates that IGF2 plays an important role in various human malignancies, including colorectal cancer (CRC). Hsa-miR-483 is located within intron 7 of the IGF2 locus. However, the mechanism by which increased IGF2 induces carcinogenesis remains largely elusive. DLC-1 has been identified as a candidate tumor suppressor. In this study, we aimed at investigating whether miR-483 transcription is IGF2-dependent, identifying the functional target of miR-483, and evaluating whether t ...[more]

PMID: 27366946

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Project description:Background: Cancer stem cells (CSCs) have been recognized as an important drug target, however, the underlying mechanisms have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 promotes colorectal cancer (CRC) stem cells (CRC-SCs) and the underlying mechanisms have remained elusive.Methods: Human CRC cell lines and primary human CRC cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels of target genes were examined by qRT-PCR and western blot. The sphere-forming and in vitro migration capacities were determined by sphere formation and transwell assay. The self-renewal was determined by limiting dilution assay. The tumorigenicity and metastasis of cancer cells were examined by xenograft model. The promoter activity was examined by luciferase reporter assay. Nuclear run-on and Chromatin immunoprecipitation-PCR (ChIP-PCR) assay were employed to examine the transcription and protein-DNA interaction. Co-immunoprecipitation assay was used to test protein-protein interaction. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean?±?SD and the significance was determined by Student's t test.Results: SKP1 was upregulated in CRC-SCs and predicted poor prognosis of colon cancer patients. Overexpression of SKP1 promoted the stemness of CRC cells reflected by increased sphere-forming, migration and self-renewal capacities as well as the expression of CSCs markers. In contrast, SKP1 depletion produced the opposite effects. SKP1 strengthened YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of CRC cells. SKP1 suppressed RASSF1 at both mRNA and protein level. Overexpression of RASSF1 abolished the effect of SKP1 on YAP activity and CRC stemness.Conclusion: Our results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of CRC cells.

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IGF2-derived miR-483 mediated oncofunction by suppressing DLC-1 and associated with colorectal cancer.

Publications

IGF2-derived miR-483 mediated oncofunction by suppressing DLC-1 and associated with colorectal cancer.

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