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CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.

ABSTRACT: Cisplatin-based chemotherapy is the foundation of treatment for major non-small cell lung cancer (NSCLC) patients. However, cisplatin resistance is still a challenging issue, and the molecular mechanisms underlying this resistance remain to be fully explored. CLEC4M, a Ca2+-dependent C-type lectin, has recently been found to correlate with tumourigenesis. This study mainly focused on whether CLEC4M impacts clinical prognosis and how CLEC4M contributes to cisplatin resistance in NSCLC. Our results found that CLEC4M was correlated with poor prognosis in patients with lung cancer. In addition, a positive association between CLEC4M expression and the IC50 values of cisplatin was found, which suggests that CLEC4M may impact cisplatin sensitivity. In vitro results from cultured A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown led to higher sensitivity to cisplatin in these cells. Further experiments showed that the underlying mechanisms included inhibition of cisplatin-induced cell apoptosis by CLEC4M and improved DNA repair capacity by upregulating XPA and ERCC1 expression. In addition, CLEC4M was able to promote cell migration with or without cisplatin treatment. Collectively, these findings suggest the potential clinical significance of CLEC4M inhibition in overcoming cisplatin resistance in NSCLC patients.

SUBMITTER: Tan LM

PROVIDER: S-EPMC6856750 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.

Tan Li-Ming LM Li Xi X Qiu Cheng-Feng CF Zhu Tao T Hu Cheng-Ping CP Yin Ji-Ye JY Zhang Wei W Zhou Hong-Hao HH Liu Zhao-Qian ZQ

Journal of Cancer 20191019 25

Cisplatin-based chemotherapy is the foundation of treatment for major non-small cell lung cancer (NSCLC) patients. However, cisplatin resistance is still a challenging issue, and the molecular mechanisms underlying this resistance remain to be fully explored. CLEC4M, a Ca<sup>2+</sup>-dependent C-type lectin, has recently been found to correlate with tumourigenesis. This study mainly focused on whether CLEC4M impacts clinical prognosis and how CLEC4M contributes to cisplatin resistance in NSCLC. ...[more]

PMID: 31772670

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Project description: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.

Project description:BackgroundOur previous studies have identified CA916798 as a chemotherapy resistance-associated gene in lung cancer. However, the histopathological relevance and biological function of CA916798 in lung adenocarcinoma (LUAD) remains to be delineated. In this study, we further investigated and explored the clinical and biological significance of CA916798 in LUAD.MethodsThe relationship between CA916798 and clinical features of LUAD was analyzed by tissue array and online database. CCK8 and flow cytometry were used to measure cell proliferation and cell cycle of LUAD after knockdown of CA916798 gene. qRT-PCR and western blotting were used to detect the changes of cell cycle-related genes after knockdown or overexpression of CA916798. The tumorigenesis of LUAD cells was evaluated with or without engineering manipulation of CA916798 gene expression. Response to Gefitinib was evaluated using LUAD cells with forced expression or knockdown of CA916798.ResultsThe analysis on LUAD samples showed that high expression of CA916798 was tightly correlated with pathological progression and poor prognosis of LUAD patients. A critical methylation site in promoter region of CA916798 gene was identified to be related with CA916798 gene expression. Forced expression of CA916798 relieved the inhibitory effects of WEE1 on CDK1 and facilitated cell cycle progression from G2 phase to M phase. However, knockdown of CA916798 enhanced WEE1 function and resulted in G2/M phase arrest. Consistently, chemical suppression of CDK1 dramatically inhibited G2/M phase transition in LUAD cells with high expression of CA916798. Finally, we found that CA916798 was highly expressed in Gefitinib-resistant LUAD cells. Exogenous expression of CA916798 was sufficient to endow Gefitinib resistance with tumor cells, but interference of CA916798 expression largely rescued response of tumor cells to Gefitinib.ConclusionsCA916798 played oncogenic roles and was correlated with the development of Gefitinib resistance in LUAD cells. Therefore, CA916798 could be considered as a promising prognostic marker and a therapeutic target for LUAD.

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CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.

Publications

CLEC4M is associated with poor prognosis and promotes cisplatin resistance in NSCLC patients.

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