miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1.

Abstract

BACKGROUND/AIMS:

MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290.

METHODS:

We used miRCURYTM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual-luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting.

RESULTS:

In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722-0.936 and 0.749-0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo.

CONCLUSION:

MiR-1290 may act as an oncogene by directly targeting the 3'-untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC.

• Authors: Na Ta, Xiaoyi Huang, Kailian Zheng, Yunshuo Zhang, Yisha Gao, Lulu Deng, Bingbing Zhang, Hui Jiang, Jianming Zheng
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 51 Issue 2 Pg. 711-728 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30463064 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• 3' Untranslated Regions
• Antagomirs
• MIRN1290 microRNA, human
• MicroRNAs
• RNA, Small Interfering
• CHUK protein, human
• I-kappa B Kinase

Topics

• 3' Untranslated Regions
• Adult
• Aged
• Animals
• Antagomirs (metabolism, therapeutic use)
• Area Under Curve
• Carcinoma, Pancreatic Ductal (diagnosis, drug therapy, pathology)
• Cell Line, Tumor
• Female
• Humans
• I-kappa B Kinase (antagonists & inhibitors, genetics, metabolism)
• Male
• Mice
• Mice, Nude
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Middle Aged
• Pancreatic Neoplasms (diagnosis, drug therapy, pathology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• ROC Curve