IPO5 Mediates EMT and Promotes Esophageal Cancer Development through the RAS-ERK Pathway

Abstract

Objective. In the development of many tumors, IPO5, as a member of the nuclear transporter family, exerts a significant function. Also, IPO5 is used as a therapeutic target for tumors based on some reports. By studying IPO5 expression in esophageal cancer tissues, the mechanism associated with IPO5 improving esophageal cancer development was explored in this study. Methods. To gain differentially expressed genes, this study utilized mRNA microarray and TCGA database for comprehensive analysis of esophageal cancer tissues and normal esophageal cancer tissues, and then the differentially expressed gene IPO5 was screened by us. To assess esophageal cancer patients’ prognosis, this study also applied the Kaplan-Meier analysis, and we also conducted the GSEA enrichment analysis to investigate IPO5-related signaling pathways. This study performed TISIDB and TIMER online analysis tools to study the correlation between IPO5 and immune regulation and infiltration. We took specimens of esophageal cancer from patients and detected the expression of IPO5 in tumor and normal tissues by immunohistochemistry. The IPO5 gene-silenced esophageal cancer cell model was constructed by lentivirus transfection. Through the Transwell invasion assay, CCK-8 assay, and cell scratch assay, this study investigated the effects of IPO5 on cell propagation, invasion, and transfer. What is more, we identified the influences of IPO5 on the cell cycle through flow cytometry and established a subcutaneous tumor-forming model in nude mice. Immunohistochemistry was used to verify the expression of KI-67, and this study detected the modifications of cell pathway-related proteins using Western blot and applied EMT-related proteins to explain the mechanism of esophageal cancer induced by IPO5. Results. According to database survival analysis, IPO5 high-expression patients had shorter disease-free survival than IPO5 low-expression patients. Compared to normal tissues, the IPO5 expression in cancer tissues was significantly higher in clinical trials ( P < 0.05 ). Through TISIDB and TIMER database studies, we found that IPO5 could affect immune regulation, and the age of IPO5 expression grows with the increase of immune infiltration level. The IPO5 expression in esophageal cancer cells was higher than normal, especially in ECA109 and OE33 cells ( P < 0.01 ). After knocking out IPO5 gene expression, cell proliferation capacity and invasion capacity were reduced ( P < 0.05 ) and decreased ( P < 0.01 ) in the IPO5-interfered group rather than the negative control group. The growth cycle of esophageal carcinoma cells was arrested in the G2/M phase after IPO5 gene silencing ( P < 0.01 ). Tumor-forming experiments in nude mice confirmed that after IPO5 deletion, the tumor shrank, the expression of KI67 decreased, the downstream protein expression level of the RAS pathway decreased after sh-IPO5 interference ( P < 0.01 ), and the level of EMT marker delined ( P < 0.05 ). Conclusion. In esophageal cancer, IPO5 is highly expressed and correlates with survival rate. Esophageal cancer cell growth and migration were significantly affected by the inhibition of IPO5 in vitro and in vivo. IPO5 mediates EMT using the RAS-ERK signaling pathway activation and promotes esophageal cancer cell development in vivo and in vitro.

The value of basement membrane-associated genes in the prognosis and immune regulation of glioma

“…Current studies have confirmed that MMP7 promotes the malignant progression of esophageal cancer, colon cancer, and prostate cancer. [33][34][35] Wang et al confirmed through research that the knockout of BCAR4 inhibits the generation of MMP7 by increasing the expression of miR-227, thereby delaying the pathological process of glioma. [36] And MMP7 was found to be one of the targets of miR-227 by fluorescein analysis.…”

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

“…Inhibition of the nuclear transport system, therefore, has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. IPO5 gene also seems to play an important role in the metastatic process via matrix metalloproteinase 7 ( MMP7 ) regulation ( 66 ) and EMT induction ( 67 ). Furthermore, IPO5 expression may affect the tumor immune microenvironment and mediate tumor immune response ( 68 ).…”

TRIM9 Interacts with ZEB1 to Suppress Esophageal Cancer by Promoting ZEB1 Protein Degradation via the UPP Pathway

“…Epithelial-mesenchymal transition (EMT) is a crucial process that cancer cells exploit for metastasis by transition of their epithelial phenotype into a mesenchymal phenotype. Previous research studies have confirmed that EMT not only participates in the carcinogenesis and progression of malignancies but also plays a unique role in cancer metastasis and chemorefractoriness [3][4][5]. In vitro analysis of an immunodeficient mouse model also indicated EMT was involved in the regulation of tumors, which greatly enhanced tumor cell self-renewal and differentiation [6][7][8].…”