MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators - PubMed (original) (raw)

Review

MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators

Afra Z Daoud et al. BMC Cancer. 2019.

Abstract

A severe lack of early diagnosis coupled with resistance to most available therapeutic options renders pancreatic cancer as a major clinical concern. The limited efficacy of current treatments necessitates the development of novel therapeutic strategies that are based on an understanding of the molecular mechanisms involved in pancreatic cancer progression. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the expression of multiple proteins in the post-translation process and thus have promise as biomarkers, prognostic agents, and as advanced pancreatic therapies. Profiling of deregulated miRNAs in pancreatic cancer can correlate to diagnosis, indicate optimal treatment and predict response to therapy. Furthermore, understanding the main effector genes in pancreatic cancer along with downstream pathways can identify possible miRNAs as therapeutic candidates. Additionally, obstacles to the translation of miRNAs into the clinic are also considered. Distinct miRNA expression profiles can correlate to stages of malignant pancreatic disease, and hold potential as biomarkers, prognostic markers and clinical targets. However, a limited understanding and validation of the specific role of such miRNAs stunts clinical application. Target prediction using algorithms provides a wide range of possible targets, but these miRNAs still require validation through pre-clinical studies to determine the knock-on genetic effects.

Keywords: Biomarker; Chemoresistance; Gene therapy; Pancreatic Cancer; Prognosis; microRNA.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Schematic representation of the development of PC and associated genes in each stage. The precursor lesions (PanINs) give rise to PC in a multistage process that is mediated through consecutive genetic mutations starting with early K-RAS oncogenic activation and ending in multiple tumour suppressors silencing. Source: MS Powerpoint

Fig. 2

The process of miRNA biogenesis and role in post-transcriptional suppression. The biogenesis of miRNAs commences in the nucleus where the RNA polymerase II transcribes the genetic sequence encoding the miRNA to produce a primary miRNA hairpin (pri-miRNA) which is capped, polyadenylated and has a stem-loop structure. Further processing by the ribonuclease DROSHA enzyme occurs in the nucleus before the resultant 70 to 100 nt long pre-miRNA hairpin is transported to the cytoplasm via the Exportin5 protein (XPO5). Once the double stranded pre-miRNA is in the cytoplasm, RNAse DICER cleaves the molecule into two single strands, with a leading functional strand, and a passenger strand -often referred to as (*)- which will be degraded. The Ago proteins bind to the leading single stranded miRNA to form the RISC. The RISC is considered to be the functional unit in this process which facilitates the binding of miRNA into the targeted mRNA resulting in either translation repression or target degradation. Source: MS Powerpoint

Fig. 3

Schematic representation of mechanism of miR21 in PC development. miRNA-21 has previously been shown to target the expression of PTEN and PDCD4. Through inhibition of PTEN via miRNA-21, cell survival pathways are activated. With Akt pathway functionality heightened, the inhibition of BAD increases, which is a pro-apoptotic pathway, thus leading to a reduction in apoptosis. PTEN also inhibits angiogenesis within the VEGF pathway, thus miRNA-21 can enhance the establishment of new vasculature. Source: MS Powerpoint

References

1. https://www.who.int/en/news-room/fact-sheets/detail/cancer.
1. “Pancreatic cancer statistics | Cancer Research UK.” [Online]. Available: http://www.cancerresearchuk.org/health-professional/cancer-statistics/st.... [Accessed: 06-Jan-2017].
1. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17(6):816–826. doi: 10.1038/ncb3169. - DOI - PMC - PubMed
1. Paiella S, Sandini M, Gianotti L, Butturini G, Salvia R, Bassi C. The prognostic impact of Para-aortic lymph node metastasis in pancreatic cancer: A systematic review and meta-analysis. Eur J Surg Oncol [Internet] 2016 May;42(5):616–624. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0748798316000974 - PubMed
1. Li Z, Shang H, Zhang X, Zhang H, Bao J, Hao C. Surgical treatment for locally advanced pancreatic cancer localized in the pancreatic body and tail (report of 11 cases). Int J Clin Exp Med [Internet]. 2015;8(3):4676–4681. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26064401. - PMC - PubMed

MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators - PubMed (original) (raw)