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 miRCURY^TM 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.

LncRNA LINC00857 strengthens the malignancy behaviors of pancreatic adenocarcinoma cells by serving as a competing endogenous RNA for miR-340-5p to upregulate TGFA expression

“…Several literatures revealed that miRNAs are involved in the development of human diseases, including malignancies [16][17][18]. Currently, abundant miR-NAs, such as miR-1290 [19], miR-216b [20], and miR-454 [21], were illustrated to be abnormally expressed in PDAC patients. Significantly, miR-340-5p was served as a downstream target of LINC00857 by visiting bioinformatics software.…”

Serum miR-1290 and miR-1246 as Potential Diagnostic Biomarkers of Human Pancreatic Cancer

“…However, considering the inconsistency among these miRNA profiling studies, we carried out an integrated analysis of three GEO datasets and discovered that serum miR-1290 and miR-1246 were significantly upregulated in PC patients. Moreover, previous studies have shown that miR-1290 and miR-1246 both underwent significant changes in PC tissues compared with non-cancer specimens [19][20][21]. Hence, we inferred that these two miRNAs may be novel biomarkers for PC and explored the potential of candidate miRNAs (miR-1290 and miR-1246) for PC diagnosis in this study.…”

“…Results of logistic analyses showed that both of them were determined as independent risk factors for the onset of PC, indicating that both miR-1290 and miR-1246 might play an important role in oncogenesis of PC. Ta N et al [20] declared that miR-1290 functioned as a tumor oncogene and enhanced PC cell proliferation, invasion, and migration by directly targeting the 3' UTR of IKK1 [21]. Meantime, a previous study also proved that miR-1290 could promote pancreatic ductal adenocarcinoma malignant progression by silencing the FOXA1/2, which was involved in epithelial-to-mesenchymal transitions [23].…”

Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma

“…Recent therapeutic research showed that restoring either miR-143 or miR-145 significantly inhibited pancreatic metastasis [73,80]. Another study by Ta et al showed that NF-kβ, constitutively active in pancreatic cancer patients, is promoted by miR-1290, relates to the expression of IKK1 [91], and is implicated in the downregulation of miR-146a, suggesting its role as a tumor suppressor in most cancers. Meanwhile, miR-27a becomes highly upregulated and could be a target for therapeutics during metastasis.…”

“…Interestingly, both miR-1290 and miR-1246. because of their detectability in serum, are being studied as potential biomarkers [91,96]. In metastasis, miR-34a is found downregulated since it is a direct target of TP53 to reduce pro-inflammatory cytokines.…”