Oct4 induces EMT through LEF1/β-catenin dependent WNT signaling pathway in hepatocellular carcinoma

Abstract

Octamer 4 (Oct4), a member of the Pit-Oct-Unc transcription factor family required to maintain self-renewal and pluripotency of embryonic stem cells, has been previously identified to be associated with tumorigenesis and malignant transformation of numerous types of cancer including hepatocellular carcinoma (HCC). The present data shows that Oct4 enhances cancer stem cell properties and increases invasion ability in the Huh7 cell line. To increase understanding of the role of Oct4 in HCC, the present study used a functional genomics approach and analyzed the resulting transcriptional profiles to identify Oct4-dependent genes in Huh7. Affymetrix GeneChip Human genome U133 Plus 2.0 Arrays were used to determine differential gene expression profiles and then validated by quantitative polymerase chain reaction. The present study found that altered expression of 673 genes (fold-change ≥2) affected multiple signaling pathways linked with self-renew and metastasis. Among these differentially expressed genes, the present study noticed that the key component of the WNT signaling pathway lymphoid enhancer binding factor 1 (LEF1) and Twist Family BHLH transcription factor 1 were upregulated by Oct4, whilst cadherin 2 was downregulated. Additional studies found that the nuclear β-catenin aggregation was increased in Oct4 overexpressed HCC cell lines. These results suggest that Oct4 regulates LEF1 to active LEF1/β-catenin dependent WNT signaling pathway and promote epithelial-mesenchymal transition. The present findings provide novel mechanistic insight into an important role of Oct4 in HCC.

Lymphoid Enhancer Factor 1 Contributes to Hepatocellular Carcinoma Progression Through Transcriptional Regulation of Epithelial‐Mesenchymal Transition Regulators and Stemness Genes

“…The mechanisms underlying differential activation of these factors remain poorly understood. Consistent with the report by Sun et al that Oct4 in HCC regulates LEF1 to activate the LEF1/β‐catenin‐dependent WNT signaling pathway and promote EMT, findings of the present study indicate that reciprocal regulation between LEF1 and Oct4 in HCC plays a crucial role in maintaining self‐renewal properties. Such regulation is based on specific promoter binding and transcriptional activation.…”

Role of p38 MAPK in disease relapse and therapeutic resistance by maintenance of cancer stem cells in head and neck squamous cell carcinoma

“…We observed expression of p‐p38 (activated form of p38) and CSC markers (Oct4, SOX2, Klf4, c‐Myc and CD44) was found to be upregulated in cut margin regions of recurrent HNSCC samples as compared to non‐recurrent HNSCC samples. SOX2, Oct4, Klf4, c‐Myc and CD44 serves as CSC markers that play an essential role to maintain stemness and are associated with increased cell migration, invasion and metastasis . Our results highlighted that higher expression of activated form of p38 and CSC markers in the cut margin of recurrent patients might have contributed to minimal residual disease.…”

Prognostic value of association of OCT4 with LEF1 expression in esophageal squamous cell carcinoma and their impact on epithelial‐mesenchymal transition, invasion, and migration

“…A previous study revealed that in hepatocellular carcinoma, OCT4 activates the LEF1/β‐catenin‐dependent Wnt signaling pathway to induce cancer cell EMT 21. Moreover, Tcf/Lef‐Oct4 composite element can bond to the promoter of Mesp1.…”

“…More importantly, previous studies have reported the crosstalk between OCT4 and the components of the Wnt/β‐catenin signaling pathway. For example, as one of the components in the Wnt/β‐catenin signaling pathway, LEF1 mediates the effects of OCT4 in hepatocellular carcinoma cells undergoing EMT 21. These findings highlight the potential importance of crosstalk between these two pathways.…”