The long non-coding RNA H19: an active player with multiple facets to sustain the hallmarks of cancer

Abstract

Cancer cells exhibit hallmarks in terms of proliferation, resistance to cell death, angiogenesis, invasion, metastasis, and genomic instability. Despite the progress in cancer research and the comprehension of tumorigenesis mechanisms, cancer remains a major issue in public health. A better understanding of the molecular factors associated with the appearance or progression of cancer may allow the development of therapeutic alternatives. Increasing data highlight the role of long non-coding RNAs in many diseases, including cancer. The long non-coding RNA H19 was the first discovered riboregulator, and it has been shown to be involved at multiple steps of tumorigenesis. Indeed, this lncRNA exert its action at various molecular scales. Understanding the role of H19 in cancer progression may allow to set up therapeutic strategies to prevent tumor expansion and metastatic dissemination. In this review, we will summarize the overexpression of the long non-coding RNA H19 in several types of cancer and the multiple implications of the long non-coding RNA H19 in the different hallmarks that define human cancer.

Keywords: H19; Hallmarks of cancer; Metastasis; Proliferation; lncRNA; miRNA.

Fig. 1

The long non-coding RNA H19 promotes cancer cell proliferation. aH19 promotes the G1/S transition in breast and colorectal cancer cells, in esophageal squamous cell carcinoma and in pancreatic ductal adenocarcinoma [32, 40, 62, 67]. bH19 sponges several miRNAs to allow β-catenin and DNMTs expression in colorectal, breast, and bladder cancer, respectively [29, 64, 68]

Fig. 2

H19 downregulates growth suppressors. a In gastric cancer, H19 interacts physically with p53 to inhibit its antiproliferative activity [47]. bH19 induces the transcriptional inhibition of PHB1 in liver cancer cells [53]. cH19 is able to sponge miR-152 and so enhance glioma cells proliferation [79]. dH19-derived miR-675 inhibits the expression of well-known growth suppressors such as RB and RUNX1 in colorectal and hepatocellular cancers, and in gastric cancer, respectively [48, 69, 85]

Fig. 3

H19 impedes cancer cell death. a In pancreatic cancer cells, H19 prevents caspase 3 cleavage [62]. bH19 sponges miR-138-5p in cervical cancer to allow the transcription of SIRT1 [70]. cH19 is able to physically interact with PRC2 complex to catalyze the trimethylation of H3K27, that will lead to chromatin condensation and repression of pro-apoptotic factor BIK in breast cancer cells [43]. d miR-675 is able to inhibit the expression of pro-apoptotic factors such as Cbl and FADD in breast and gastric cancers, respectively [49, 82]

Fig. 4

H19 promotes the migration, invasion, and metastasis of cancer cells. a In bladder cancer, H19 is able to interact with PRC2 complex to induce chromatin condensation at the CDH1 promoter, leading to the repression of E-cadherin [66]. bH19 sponges miR-29b-3p and miR-200 in renal cell carcinoma and osteosarcoma, respectively, to activate the transcription of E2F1, ZEB1, and ZEB2 [63, 75]. cH19 acts as a transcriptional activator in esophageal cancer to enhance the expression of vimentin and fibronectin [34]. d miR-675 represses the expression of SNAI2 in ovarian cancer to create an activation loop of the H19 expression and repress E-cadherin expression [39]. e miR-675 inhibits Cbl-b and c-Cbl expression to induce the activation of AKT and ERK pathways in breast cancer cells [45]

Fig. 5

Implication of the long non-coding RNA H19 in the hallmarks of cancer. For each hallmark is figured a representative example of H19 mechanism of action