H19: An Oncogenic Long Non-coding RNA in Colorectal Cancer

Abstract

Colorectal cancer (CRC) has been recorded amongst the most common cancers in the world, with high morbidity and mortality rates, and relatively low survival rates. With risk factors such as chronic illness, age, and lifestyle associated with the development of CRC, the incidence of CRC is increasing each year. Thus, the discovery of novel biomarkers to improve the diagnosis and prognosis of CRC has become beneficial. Long non-coding RNAs (lncRNAs) have been emerging as potential players in several tumor types, one among them is the lncRNA H19. The paternally imprinted oncofetal gene is expressed in the embryo, downregulated at birth, and reappears in tumors. H19 aids in CRC cell growth, proliferation, invasion, and metastasis via various mechanisms of action, significantly through the lncRNA-microRNA (miRNA)-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network, where H19 behaves as a miRNA sponge. The RNA transcript of H19 obtained from the first exon of the H19 gene, miRNA-675 also promotes CRC carcinogenesis. Overexpression of H19 in malignant tissues compared to adjacent non-malignant tissues marks H19 as an independent prognostic marker in CRC. Besides its prognostic value, H19 serves as a promising target for therapy in CRC treatment.

Keywords: CRC; EMT; H19; biomarker; ceRNA; lncRNA; miR-675; miRNA sponge; prognosis; proliferation.

Figure 1

ceRNA hypothesis. mRNA contains MREs (represented by ovals), which are typically found within the 3’UTR. miRNA binds to identical MREs, and these MREs are present in various ncRNA species, including lncRNA, circRNAs, pseudogenes, and independently transcribed mRNA 3’UTRs. All of these RNA molecules compete for a limited pool of miRNA, thus exhibiting positive regulation of gene expression. lncRNA and circRNA may carry MREs for multiple miRNAs (represented by different colored ovals).

Figure 2

H19 as a ceRNA sponge for target miRNAs. miRNAs in CRC bind to the 3’UTR of target mRNAs associated with tumor progression and control their expression post-transcriptionally, which involves either inhibiting translation or reducing mRNA stability. H19 acts as a miRNA sponge through its MRE binding sites, thereby impeding the mRNAs’ ability to regulate their target genes.

Figure 3

Chromatin modifications by H19. H19 within the cell nucleus engage in interactions with chromatin remodeling factors and transcription factors, thereby orchestrating the control of nearby and distal gene expressions.

Figure 4

Schematic diagram of the molecular mechanisms of H19 in the regulation of CRC growth and metastasis. H19 typically acts as a ceRNA sponge for miRNAs, thereby regulating downstream expressions in CRC progression. H19 also acts as a promoter or repressor lncRNA that modulates the functions of specific proteins intimately involved in CRC.

Figure 5

Mechanism of H19 interaction with HNRNPA2B1 involved in CRC metastasis. H19 interacts with HNRNPA2B1, resulting in the translocation of HNRNPA2B1 from the nucleus to the cytoplasm. This facilitates the binding between HNRNPA2B1 and RAF-1 mRNA, stabilizing the mRNA and consequently leading to the upregulation of RAF-1 that activates the ERK signaling pathway. This activation, in turn, promotes the transcription of SNAI1, inducing the process of EMT.

Figure 6

The functional model underlying the mechanism of H19 in 5-Fu chemoresistance. In response to 5-Fu stress due to chemotherapeutic agents, overexpression of H19 in CRC cell sponges miR-194-5p, which, in turn, inhibits SIRT1-mediated apoptosis and leads to tumor growth by autophagy.