Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer

Li, Nanhong; Zeng, Yu; Huang, Jian

doi:10.1007/s00432-020-03188-9

Cited by 21 publications

(21 citation statements)

References 118 publications

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“…As reported in detail in our previous review (Li et al, 2020), we synthesized the results of existing studies on SHOX2 and its related homonymous genes in mice, lung cancer and other tumors and concluded that SHOX2 might play an important role in tumorigenesis, metastasis, and recurrence in lung cancer. Here, we used bioinformatics analysis to verify the above conclusions.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Zeng

Tai

et al. 2021

Front. Mol. Biosci.

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Background: Detection of SHOX2 methylation has been used to assist in the early diagnosis of lung cancer in many hospitals as SHOX2 may be important in the tumorigenesis of lung cancer. However, there are few studies on the mRNA expression, methylation, and molecular mechanism of SHOX2 in lung cancer. We aimed to explore the role of SHOX2 in lung adenocarcinoma (LUAD).Methods: First, we examined the differential expression of SHOX2 mRNA and methylation in cancerous and normal tissues using databases. Second, we analyzed the relationship between SHOX2 expression and common clinical parameters in LUAD patients. Third, we further explored the methylated level and its specific location of SHOX2 and the mainly factors of SHOX2 gene expression. Finally, we screened the correlatively expressed genes to analyze the pathways from the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes using DAVID.Results: We found that the mRNA expression of SHOX2 was higher in multiple cancers, including LUAD and lung squamous cell carcinoma (LUSC), than in normal tissues. Among LUAD patients, SHOX2 expression was higher in patients of middle–young age, with smoking history, in advanced stages, and with nodal distant metastasis. In addition, our results showed that patients with high expression of SHOX2 are prone to recurrence, poor differentiation, and poor prognosis. Thus, we identified that SHOX2 might be an oncogene for LUAD progression. The main factor influencing the high expression of SHOX2 mRNA may be DNA methylation, followed by copy number variation (CNV), but not by gene mutations in LUAD. Unexpectedly, we found that SHOX2 undergoes hypomethylation in the gene body instead of hypermethylation in the promoter. Additionally, SHOX2 has cross talk in the PI3K–Akt signaling pathway and ECM–receptor interaction.Conclusion:SHOX2 is highly expressed in most cancers. SHOX2 gene expression might be mainly regulated by methylation of its gene body in LUAD, and its high expression or hypomethylation indicates poor differentiation and poor prognosis. SHOX2 could be involved in PI3K–Akt and other important cancer-related signaling pathways to promote tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Zeng

Tai

et al. 2021

Front. Mol. Biosci.

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“…According to the statistics, more than 1.8 million new cases of lung cancer and 1.6 million deaths occur annually ( 1 , 3 ). As early-staged lung cancer is not easily detectable, more than 70–80% of lung cancer patients have already missed the optimal chance for surgery by the time of diagnosis ( 1 , 3 , 4 ). Chemotherapy is now a main treatment for patients with advanced lung cancer, but is accompanied with various adverse side effects ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Circular RNA CHST15 Sponges miR-155-5p and miR-194-5p to Promote the Immune Escape of Lung Cancer Cells Mediated by PD-L1

Yang

Wang

et al. 2021

Front. Oncol.

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BackgroundThe effects of up-regulated CircCHST15 on lung cancer remained unclear. In this study, the role of CircCHST15 in lung cancer was investigated.MethodsDual-luciferase reporter verified the bioinformatics prediction that CircCHST15 targeted miR-155-5p and miR-194-5p. The correlation between CircCHST15 and PD-L1 was analyzed by Pearson analysis. CCK-8 and colony formation was performed to determine the viability and proliferation of lung cancer cells. After the lung cancer (subcutaneous-xenotransplant) model was established in mice, the T cell subtype and related cytokines in mouse tumor tissues were detected by flow cytometry and ELISA. Moreover, the expressions of CircCHST15, miR-155-5p, miR-194-5p, immune-related, and proliferation-related factors of the lung cancer cells or mice tumor tissues were detected by immunohistochemistry, RT-qPCR, or Western blot.ResultsCircCHST15 and PD-L1 were high-expressed in lung cancer, and the two was positively correlated. CircCHST15 targeted miR-155-5p and miR-194-5p, the later further targeted PD-L1. Lung cancer cell viability and proliferation were increased by miR-155-5p and inhibited by miR-194-5p. CircCHST15 located in the cytoplasm promoted tumor growth, down-regulated the expressions of miR-155-5p and miR-194-5p, and up-regulated the expressions of PD-L1, Ki-67, PCNA, CCL17, CCL22, IFN-γ, TNF-β, and IL-10. Also, CircCHST15 decreased the CD8+ cells in mouse blood and tumor, but increased the Tregs in mouse tumor. PD-L1 inhibitor showed an opposite effect to CircCHST15 on mouse tumors.ConclusionCircCHST15 sponged miR-155-5p and miR-194-5p to promote the PD-L1-mediated immune escape of lung cancer cells.

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“…The genes CDH1, CDKN2Ap16, RASSF1A, TERT , and WT1 were selected based on their roles as biomarkers in NSCLC and their putative gender sensitivity based on the current literature and our own research findings (reviewed in [ 64 ]). Among the selected markers, RASSF1A [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] and, to a lesser extent, CDKN2Ap16 [ 73 , 74 , 75 , 76 , 77 ] are already accepted as methylation markers. The applicability of CDH1 [ 78 , 79 , 80 , 81 , 82 , 83 ] and WT1 [ 45 , 61 , 84 , 85 ] is still under investigation but may have a broader impact on many cancer entities; their interdependence adds to this potential.…”

Section: Methodsmentioning

confidence: 99%

Promoter Methylation of Selected Genes in Non-Small-Cell Lung Cancer Patients and Cell Lines

Sarne

Huter²,

Braunmueller

et al. 2020

IJMS

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Specific gene promoter DNA methylation is becoming a powerful epigenetic biomarker in cancer diagnostics. Five genes (CDH1, CDKN2Ap16, RASSF1A, TERT, and WT1) were selected based on their frequently published potential as epigenetic markers. Diagnostic promoter methylation assays were generated based on bisulfite-converted DNA pyrosequencing. The methylation patterns of 144 non-small-cell lung cancer (NSCLC) and 7 healthy control formalin-fixed paraffin-embedded (FFPE) samples were analyzed to evaluate the applicability of the putative diagnostic markers. Statistically significant changes in methylation levels are shown for TERT and WT1. Furthermore, 12 NSCLC and two benign lung cell lines were characterized for promoter methylation. The in vitro tests involved a comparison of promoter methylation in 2D and 3D cultures, as well as therapeutic tests investigating the impact of CDH1/CDKN2Ap16/RASSF1A/TERT/WT1 promoter methylation on sensitivity to tyrosine kinase inhibitor (TKI) and DNA methyl-transferase inhibitor (DNMTI) treatments. We conclude that the selected markers have potential and putative impacts as diagnostic or even predictive marker genes, although a closer examination of the resulting protein expression and pathway regulation is needed.

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Signaling pathways and clinical application of RASSF1A and SHOX2 in lung cancer

Cited by 21 publications

References 118 publications

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Analysis of the Prognostic Value and Gene Expression Mechanism of SHOX2 in Lung Adenocarcinoma

Circular RNA CHST15 Sponges miR-155-5p and miR-194-5p to Promote the Immune Escape of Lung Cancer Cells Mediated by PD-L1

Promoter Methylation of Selected Genes in Non-Small-Cell Lung Cancer Patients and Cell Lines

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