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

Abstract

Esophageal squamous cell carcinoma (ESCC) is a malignant disease with poor prognosis. Because of early metastasis prior to diagnosis and therapeutic resistance, ESCC has become one of the leading causes of cancer‐related death. Here, we investigated the clinicopathological significance of the association of octamer‐binding transcription factor 4 (OCT4) with lymphoid enhancer‐binding factor 1 (LEF1) expression and the potential molecular mechanism in the epithelial‐mesenchymal transition (EMT), invasion, and migration of ESCC. The expression of OCT4 and LEF1 was detected via immunohistochemistry analysis. High levels of LEF1 expression were observed in 95 ESCC specimens and were obviously associated with aberrant clinicopathological features and poor patient prognosis. Our previous study showed that OCT4 expression level is elevated in ESCC, and statistical analysis showed that the elevated expression of OCT4 and LEF1 in ESCC was significantly associated with histologic grade, lymph node metastasis, TNM stage, and poor patient prognosis. The specific inhibition of OCT4 expression via a lentivirus encoding OCT4‐shRNA (LV‐shOCT4) in Eca109 cells led to decreased levels of OCT4 and LEF1 in vitro. Additionally, we applied a rescue strategy by infecting LV‐shOCT4 Eca109 cells with a LEF1 overexpression plasmid (p‐LEF1) and detected changes in EMT, migration, and invasion. Unsurprisingly, the p‐LEF1 group exhibited greater EMT, invasion, and migration than did the LV‐shOCT4 and negative control groups. This study demonstrates for the first time the relationship between OCT4 and LEF1 expression. The combination of high expression of OCT4 and LEF1 was associated with clinicopathological features of atypical patients, and this combination might be an ideal prognostic factor in ESCC. OCT4 positively regulated LEF1 expression, and LEF1 mediated the effects of OCT4 in cancer cell EMT, invasion, and migration. The data presented here suggest that the inhibition of OCT4‐LEF1 signaling may be a new therapeutic target for the treatment of ESCC.

Transplantation of hMSCs Genome Edited with LEF1 Improves Cardio-Protective Effects in Myocardial Infarction

“…Although we presented several positive aspects of genome editing to lead LEF1 expression in hUCB-MSCs, there are also several studies regarding the aberration of LEF1 gene expression in various cases of tumorigenesis and cancer cell proliferation, migration, and invasion. 43,44 Particularly, LEF1 expression has been reported in cancer cell types, such as some leukemias, lymphoma, squamous cell carcinoma, and colorectal cancer. 45,46 Lack of teratoma formation has been known in MSCs; however, the tumorigenic effect of LEF1 in hUCB-MSCs needs be tested in regard to long-term expression and survival.…”

Identification and Characterization of Copy Number-Associated Driver Genes in Esophageal Squamous Cell Carcinoma

“…In addition, the target genes of TFs such as LEF1 and TEAD4 were found to be differentially expressed in ESCC samples. Based on the ORA and GSEA, we found that the upregulated genes were significantly enriched in the components of the oncogenic pathways and the target genes of LEF1 and TEAD4, respectively, suggesting that the WNT, NOTCH, cell cycle, and Hippo signaling pathways were abnormally activated by their corresponding driver genes [ 26 , 27 ]. These oncogenic signaling pathways have been recurrently reported to lead to uncontrolled proliferation of cancer cells and unfavorable prognostic outcomes in several cancer types [ 28 ].…”

LEF1/Id3/HRAS axis promotes the tumorigenesis and progression of esophageal squamous cell carcinoma

“…International Publisher transition (EMT) of ESCC cells [7,8]. More recently, we found LEF1 could promote the stem-like phenotype and the tumorigenicity in ESCC [9].…”

“…Increasing studies have unveiled that dysregulation of LEF1 is implicated in the progression of multiple cancers, such as breast cancer, colon cancer, prostate cancer, et al 4 - 6 . Our previous studies showed that LEF1 was highly expressed in ESCC tissues and it could promote proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of ESCC cells 7 , 8 . More recently, we found LEF1 could promote the stem-like phenotype and the tumorigenicity in ESCC 9 .…”