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MiRNA-107 enhances the malignant progression of pancreatic cancer by targeting TGFBR3.

ABSTRACT:

Background

The prognosis of pancreatic cancer (PC) is relatively dismal due to the lack of effective therapy. In this study, we explored the specific functions and molecular mechanisms of miR-107 to uncover effective therapeutic targets for PC.

Method

The miR-107 expression in PC cell lines was assessed via quantitative real-time polymerase chain reaction (qRT-PCR). Besides, online bioinformatics analysis was adopted to predict the underlying targets of miR-107. Meanwhile, TCGA database was employed to explore the prognosis of PC patients. In addition, MTT and transwell assays were conducted to explore the PC cells' biological functions.

Result

MiR-107 was remarkably increased in PC cells which could promote the proliferation, invasion and migration of PC cells. In addition, miR-107 could directly down-regulate TGFBR3 expression through binding to TGFBR3 3'UTR. Survival analysis from TCGA suggested that PC patients with higher miR-107 expression was significantly involved in poorer prognosis.

Conclusion

We concluded that miR-107 promoted proliferation, invasion and migration of PC cells via targeting TGFBR3, which may provide novel underlying therapeutic targets.

SUBMITTER: Tian T

PROVIDER: S-EPMC8133469 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledHepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBP?, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBP?, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBP?. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA-449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis.ImportanceHepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.