High GTSE1 expression promotes cell proliferation, metastasis and cisplatin resistance in ccRCC and is associated with immune infiltrates and poor prognosis

Abstract

Background: Clear cell renal cell carcinoma is the most common and fatal form of kidney cancer, accounting for 80% of new cases. Although it has been reported that GTSE1 is highly expressed in a variety of tumors and associated with malignant progression and poor clinical prognosis, its clinical significance, correlations with immune cell infiltration and biological function in ccRCC are still poorly understood.Methods: The gene expression, clinicopathological features, and clinical significance of GTSE1 were analyzed using multiple databases, including TCGA, GEO, TIMER, and UALCAN Kaplan–Meier survival analysis, gene set enrichment analysis gene ontology enrichment Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed. Tumor-infiltrating immune cells and immunomodulators were extracted and analyzed using TCGA-KIRC profiles. Protein‒protein interactions were built using the STRING website. The protein level of GTSE1 in ccRCC patients was detected by immunohistochemistry using a ccRCC tissue chip. Finally, MTT assays, colony-formation assays, cell flow cytometry analyses, EdU-staining assays, wound-healing assays, and transwell migration and invasion assays were conducted to assess the biological function of GTSE1 in vitro.Results: GTSE1 was overexpressed in ccRCC tissues and cells, and GTSE1 overexpression was associated with adverse clinical-pathological factors and poor clinical prognosis. Meanwhile, the functional enrichment analysis indicated that GTSE1 and its coexpressed genes were mainly related to the cell cycle, DNA replication, and immunoreaction, such as T-cell activation and innate immune response, through multiple signaling pathways, including the P53 signaling pathway and T-cell receptor signaling pathway. Furthermore, we observed a significant relationship between GTSE1 expression and the levels of infiltrating immune cells in ccRCC. Biological functional studies demonstrated that GTSE1 could promote the malignant progression of ccRCC by promoting cell proliferation, cell cycle transition, migration, and invasion capacity and decreasing the sensitivity of ccRCC cells to cisplatin.Conclusion: Our results indicate that GTSE1, serving as a potential oncogene, can promote malignant progression and cisplatin resistance in ccRCC. Additionally, high GTSE1 expression contributes to an increased level of immune cell infiltration and is associated with a worse prognosis, providing a potential target for tumor therapy in ccRCC.

GTSE1 promotes nasopharyngeal carcinoma proliferation and angiogenesis by upregulating STMN1

“…Knock-down results showed that downregulation of GTSE1 suppressed proliferation, mobility, invasion and angiogenesis of NPC cells, and also inhibited the tumor growth in the NPC xenografted mice. Similar results was observed that silencing of GTSE1 represses cell proliferation, mobility and invasion have been reported in non-small-cell lung cancer cells [ 21 ], clear cell renal cell carcinoma [ 19 , 20 ], esophageal squamous cell carcinoma [ 27 ], colon cancer [ 32 ], bladder cancer [ 14 ], acral melanoma [ 15 ], and hepatocellular carcinoma [ 17 ]. Collectively, knockdown of GTSE1 attenuated growth, mobility, invasion and angiogenesis of NPC cells.…”

“…Thus, GTSE1 has been revealed to be closely related to the process of different tumors. GTSE1 has been revealed as a biomarker for the immunosuppressive tumor microenvironment based on a pan-cancer analyses [ 13 ], and high expression of GTSE1 is associated with poor patient survival in many cancer types, such as bladder cancer [ 14 ], acral melanoma [ 15 ], hepatocellular carcinoma [ 16 , 17 ], lung cancer [ 18 ], clear cell renal cell carcinoma [ 19 , 20 ], non-small-cell lung cancer [ 21 ], cervical cancer [ 22 ], and breast cancer [ 23 ]. Moreover, GTSE1 is identified to participate in the proliferation, migration, and invasion of bladder cancer [ 14 ].…”

“…acral melanoma [ 15 ], hepatocellular carcinoma [ 17 ], lung cancer [ 18 ], clear cell renal cell carcinoma [ 20 ], and non-small-cell lung cancer [ 21 ]. The role of GTSE1 in drug resistance is shown in gastric cancer cells [ 24 ], osteosarcoma [ 25 ], breast cancer [ 23 ], clear cell renal cell carcinoma [ 19 ], and non-small-cell lung cancer [ 26 ]. In addition, GTSE1 is demonstrated to be involved in apoptosis in clear cell renal cell carcinoma [ 20 ], gastric cancer cells [ 24 ] and esophageal squamous cell carcinoma [ 27 ], and it was also involved in Warburg effect in cervical cancer [ 28 ].Furthermore, GTSE1 has been identified to be upregulated in head and neck squamous cell carcinoma (HNSC) [ 13 ], and GTSE1 can act as one of nine genes contributing to build the model for the prognostic risk prediction of HNSC [ 29 ], which indicated that GTSE1 might be involved in the progression of NPC.…”

GTSE1: A potential prognostic and diagnostic biomarker in various tumors including lung adenocarcinoma

“…Additionally, a high GTSE1 expression level was linked to the decreased overall/disease‐specific survival. Lei et al 29 developed a predictive model for clear cell renal cell carcinoma (ccRCC) patients, utilizing age, gender, and GTSE1 expression level, to estimate survival probabilities at 1, 3, and 5 years. They found that increased GTSE1 expression was associated with lower prognostic survival rates.…”

“…Some previous studies have explored the link of GTSE1 and immune‐related cells, particularly in the context of cancer immunotherapy involving immune checkpoint inhibitors (ICIs). 32 Lei et al 29 discovered a correlation between overexpression of GTSE1 and increased infiltration of immune cells in renal cell carcinoma. Co‐expression analysis revealed a correlation between elevated levels of GTSE1 and the presence of ICIs, including PDCD1 (PD1), LAG3, and CTLA4.…”