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

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.

SERPINE1 Overexpression Promotes Malignant Progression and Poor Prognosis of Gastric Cancer.

The serine protease inhibitor clade E member 1 (SERPINE1) is a major inhibitor of tissue plasminogen activator and urokinase, and has been implicated in the development and progression of a variety of tumors. In this study, mRNA microarray and TCGA database were used to comprehensively analyze the upregulation of SERPINE1 in gastric cancer (GC) tissues compared with the normal stomach tissues. Kaplan-Meier results confirmed that patients with high SERPINE1 expression exhibited worse overall survival and disease-free survival. In addition, cell proliferation, cell scratches, transwell migration and invasion assay showed that SERPINE1 knockdown inhibited the proliferation, migration and invasion of GC ells. Western blot showed that the expression of VEGF and IL-6 was significantly upregulated after overexpression of SERPINE1. Meanwhile, SERPINE1 was positively correlated with the level of immune infiltration using the online analysis tools TISIDB and TIMER. And SERPINE1 expression increased with the increase of malignancy of GC which were detected by Immunohistochemistry. Finally, tumorigenesis experiments in nude mice further demonstrated that SERPINE1 could promote the occurrence and development of GC, while deletion of SERPINE1 inhibited the progression of GC. In summary, SERPINE1 was highly expressed in GC tissues, and SERPINE1 was helpful for differential diagnosis of pathological grade of gastric mucosal lesions. SERPINE1 might regulate the expression of VEGF and IL-6 through the VEGF signaling pathway and JAK-STAT3 inflammatory signaling pathway, thus ultimately affecting the invasion and migration of GC cells.

Comprehensive bioinformatics analyses identified Homeobox B9 as a potential prognostic biomarker and therapeutic target for gastric cancer.

BACKGROUND: The Homeobox B (HOXB) family promotes tumor progression, but the mechanism of its action in gastric cancer (GC) is unclear. We sought to identify the HOXB family members that are critical to the prognosis of GC patients. METHODS: The Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, UALCAN, Kaplan-Meier plotter, and the GeneMANIA databases were used to analyze the messenger RNA (mRNA) expression levels, prognostic value, and gene-gene interaction network of the HOXB9 family members in GC. The expression of HOXB9 in GC and its relationship with various clinicopathological parameters and the prognosis of patients were verified by immunohistochemistry. RESULTS: The expression of HOXB3, HOXB5, HOXB6, HOXB7, HOXB9, and HOXB13 mRNA was significantly upregulated in GC. There was a significant correlation between the upregulation of HOXB3, HOXB5, and HOXB9 mRNA and a low overall survival (OS) rate. The high expression of HOXB7, HOXB9, and HOXB13 mRNA was closely correlated to tumor grade and stage. HOXB9 was the HOXB family member most closely related to the occurrence and development of GC. A further analysis showed that HOXB9 might be involved in deoxyribonucleic acid repair and division regulation. A validation study showed that the advanced cancer group had a higher level of HOXB9 expression than the early cancer group. The high expression of HOXB9 in gastric tissue plays an important role in the survival and prognosis of GC patients. CONCLUSIONS: HOXB family members have different degrees of abnormal expression in GC. High HOXB9 expression in GC tissues was significantly correlated with a worse prognosis. Thus, HOXB9 is a potential novel biomarker and therapeutic target for GC.