The non-coding RNAs of the H19-IGF2 imprinted loci: a focus on biological roles and therapeutic potential in Lung Cancer

Abstract

Since it was first described, the imprinted cluster 11p15.5 has been reported to be deregulated in a variety of pediatric and adult cancers including that of the lung. Both protein coding and non-coding genes functioning as oncogenes or as tumor suppressor genes reside within this cluster. Oncomirs that can function as oncogenes or as tumor suppressors have also been reported. While a complete account of the role played by the 11p15.5 imprinted cluster in lung cancer is beyond the scope of this review, we will focus on the role of the non-coding RNAs processed from the H19-IGF2 loci. A special emphasis will be given to the H19/miR-675 gene locus. Their potential diagnostic and therapeutic use in lung cancer will be described.

Figure 1

Validated signaling pathways that modulate H19 lncRNA expression. Shown are different signaling pathways reported recently that modulate the H19 lncRNA expression. Inside the circle are upstream transcription factors and signal transducers that modulate H19 lncRNA expression. Outside the circle are the downstream targets of either H19/miR-675. These signaling pathways play different fundamental roles in tumor biology including lung tumorigenesis.

Figure 2

Validated/possible patterns through which H19 lncRNA can perform its function. The H19 gene can function in cis to control the imprinting of IGF2 by competing for common enhancers located downstream of H19 gene. In trans H19 lncRNA was reported to function through various patterns illustrated above. The possibility that H19 can function as an antisense transcript for HOTS is still not proven.

Figure 3

Different therapeutic approaches based on H19-IGF2 gene loci for the treatment options of lung tumorigenesis. Different therapeutic approaches can be harnessed to target specifically lung cancer cells with aberrant H19/miR-675 and IGF2/miR483 expressions. (Left): Transcriptional targeting approach utilizes transcription factors that activate the expression of the endogenous H19 lncRNA to drive the expression of a cytotoxic gene (DT-A) from the therapeutic plasmid vector (BC-819) in a manner specific for tumor expressing H19 gene products. BC-821 therapeutic vector in addition to H19-DT-A cassette contains another therapeutic cassette that drive the expression of DT-A under the transcriptional control of P4-IGf2 promoter. Thus BC-821 would increase both the cell killing capacity and the therapeutic index. (Right): Different cancer specific transcriptional products of the H19-IGF2 loci ( e.g. H19, miR-675, P4-IGF2, miR-483), can be specifically knocked down alone or in combinations utilizing siRNA and antisense technologies. The phenotype predicted is retardation of lung cancer growth and progression depending on the targeted product.