RETRACTED: H19 suppresses the growth of hepatoblastoma cells by promoting their apoptosis via the signaling pathways of miR‐675/FADD and miR‐138/PTK2

Abstract

Background The objective of this study was to clarify the molecular pathways involved in hepatitis B virus (HBV)‐induced hepatoblastoma. Method The expression of factors in different signaling pathways (H19, miR‐675, miR‐138, protein tyrosine kinase 2 [PTK2], fas‐associated death domain [FADD], hypoxia‐inducible factor 1‐alpha [HIFIA], focal adhesion kinase [FAK], caspase‐8, and caspase‐3) was compared between HBV (+) and HBV (−) groups using quantitative real‐time polymerase chain reaction and Western blot analysis. Subsequently, immunohistochemistry (IHC) and TdT‐mediated dUTP Nick‐End Labeling (TUNEL) assays were used to verify the expression of above proteins in HBV (+) and HBV (−) groups. Computational analysis was conducted to predict the target genes of miR‐675 and miR‐138, whose regulatory relationships were then clarified using luciferase assays and cell transfection studies. Result The expression of H19, miR‐675, PTK2, HIFIA, and FAK was increased in the HBV (+) group, while the expression of miR‐138, FADD, caspase‐8, and caspase‐3 was decreased in the HBV (+) group. FADD and PTK2 were identified as target genes of miR‐675 and miR‐138, respectively. In addition, miR‐675 was upregulated while miR‐138 was downregulated by X protein (HBx). Conclusion In summary, the results of this study revealed the molecular pathways involved in HBV‐induced hepatoblastoma. In the presence of HBV, HBX upregulated the expression of H19 through HIFIA. Consecutively, overexpressed H19 upregulated the expression of PTK2 via targeting miR‐138 and downregulated the expression of FADD via targeting miR‐675. Finally, increased expression of PTK2 and reduced expression of FADD both led to the inhibition of cell apoptosis, thus promoting the tumorigenesis of hepatoblastoma.

Oncogenic role of early growth response-1 in liver cancer through the regulation of the microRNA-675/sestrin 3 and the Wnt/β-catenin signaling pathway

“…miR-675 as well as its host gene H19 has been frequently observed as a cancer driver in many human malignancies such as gastric cancer [ 33 ], thyroid carcinoma [ 34 , 35 ], breast cancer [ 36 ] and nasalpharyngeal cancer [ 37 ]. In hepatoblastoma, miR-675-mediated downregulation of FADD was found to reduce cell apoptosis and promote tumorigenesis [ 15 ]. In addition, high expression of miR-675 was found in AFP-secreting HCC, which usually links to a significant rise in proliferative and growth capacity [ 38 ].…”

“…H19 is involved in embryonic and organ development and also related to the development of a multitude of human malignancies, during which the miR-675 is frequently involved [ 14 ]. Upregulation of H19 and miR-675 reduced cell apoptosis in hepatitis B virus-induced hepatoblastoma [ 15 ]. Therefore, it can be inferred that EGR1 might bind to miR-675 promoter to augment LC development.…”

Dual and Opposing Regulation of MMP1 and MMP13 by Both Arms of miR-675 in Human Articular Chondrocytes

“…However, knockdown of HuR by siRNA and analysis in cells genetically depleted of HuR only showed a moderate increase (2-4 fold) in levels of miR-675, indicating that HuR mediated trapping is only a minor factor regulating miR-675 abundance. Regulatory roles of both arms of miR-675 are focused on cell proliferation [28] and tumorigenesis/ metastasis [29] in context of cancer cell lines and tissues and examples of direct targets identified and experimentally verified so far include GPR55 (non-small lung cell cancer) [30], RB (in colorectal cancer tissue) [31], CDH11 (fibroblasts and keratinocytes) [32], CDH13 (in glioma) [33] and FADD (in gastric cancer cell lines) [34]. miR-675 has also been found within exosomes of keratinocytes [35] and metastatic osteosarcoma [36] contributing to downregulation of CALN1 in the latter model.…”

Long Noncoding RNA H19: A Novel Therapeutic Target Emerging in Oncology Via Regulating Oncogenic Signaling Pathways

“…Moreover, H19 upregulated protein tyrosine kinase 2 (PTK2) by targeting downstream miR-138. H19, as an oncogene, inhibited cell apoptosis in hepatoblastoma via both signaling axes ( Ge et al, 2019b ). Recently, H19 single nucleotide polymorphisms (SNPs) were proven to be associated with cell apoptosis in HCC.…”