MicroRNAs Targeting MYC Expression: Trace of Hope for Pancreatic Cancer Therapy. A Systematic Review

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and a major health problem worldwide. There were no major advances in conventional treatments in inhibiting tumor progression and increasing patient survival time. In order to suppress mechanisms responsible for tumor cell development such as those with oncogenic roles, more advanced therapeutic strategies should be sought. One of the most important oncogenes of pancreatic cancer is the MYC gene. The overexpression of MYC can activate many tumorigenic processes such as cell proliferation and pancreatic cancer cell invasion. MiRNAs are important molecules that are confirmed by targeting mRNA transcripts to regulate the expression of the MYC gene. Therefore, restoring MYC-repressing miRNAs expression tends to be an effective method of treating MYC-driven cancers.

Objective: The purpose of this study was to identify all validated microRNAs targeting C-MYC expression to inhibit PDAC progression by conducting a systematic review.

Methods: In this systematic review study, the papers published between 2000 and 2020 in major online scientific databases including PubMed, Scopus, and Web of Science were screened, following inclusion and exclusion criteria. We extracted all the experimental studies that showed miRNAs could target the expression of the MYC gene in PDAC.

Results: Eight papers were selected from a total of 89 papers. We found that six miRNAs (Let-7a, miR-145, miR-34a, miR-375, miR-494, and miR-148a) among the selected studies were validated for targeting MYC gene and three of them confirmed Let-7a as a direct MYC expression regulator in PC cells. Finally, we summarized the latest shreds of evidence of experimentally validated miRNAs targeting the MYC gene with respect to PDAC's therapeutic potential.

Conclusion: Restoring the expression of MYC-repressing miRNAs tends to be an effective way to treat MYC-driven cancers such as PDAC. Several miRNAs have been proposed to target this oncogene via bioinformatics tools, but only a few have been experimentally validated for pancreatic cancer cells and models. Further studies should be conducted to find the interaction network of miRNA-MYC to develop more successful therapeutic strategies for PC, using the synergistic effects of these miRNAs.

Keywords: MYC; cancer therapy; micro RNA; pancreatic cancer.

Figure 1

MYC-regulated activities and gene targets associated with tumorigenesis. Notes: MYC either as a transcription factor or transcription inhibitor targets various target genes downstream. Based on the type of the target genes activity, MYC can impact on different cell pathways and processes.

Figure 2

The flowchart of selecting articles.

Figure 3

(A) The complete MiRNA/Target genes interaction network showing MYC is targeted by all 6 miRNAs as the center of the network. (B) A module showing that some other critical genes also may be targeted by the considered miRNAs.

Figure 4

A schematic picture of how miRNAs can inhibit pancreatic cancer progression by targeting MYC. Notes: Let-7a, miR-375, miR-34a, miR-145, miR-148a, and miR-494 as experimentally validated miRNAs targeting MYC mRNAs post-transcriptionally can suppress pancreatic cancer tumor progression by inhibiting MYC’s downstream molecular pathways.