Lactic Acid-Linked lncRNAs in Wilms Tumor: Decoding the Tumor Microenvironment & Prognosis

Abstract

Background: Lactic acid (LA) can promote the malignant progression of tumors through crosstalk with the tumor microenvironment (TME). However, the function of long non-coding RNAs (lncRNAs) related to LA metabolism in Wilms tumor (WT) remains unclear.

Methods: Gene expression data and clinical data of WT patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Through the ESTIMATE algorithm and Pearson correlation analysis, lncRNAs related to tumor immunity and LA metabolism were screened. Subsequently, Cox regression analysis and Lasso Cox regression analysis were used to construct a model. Furthermore, candidate genes were identified, and a competitive endogenous RNA (ceRNA) network was conducted to explore the specific mechanism of characteristic genes. Finally, based on the strong clinical relevance of UNC5B-AS1, its expression and function were experimentally verified.

Results: The immune score and stromal score were found to be closely related to the prognosis of WT. Eventually, a prognostic model (TME-LA-LM) consisting of 6 lncRNAs was successfully identified. The model demonstrated favorable predictive ability and accuracy, with significant variation in immune infiltration and drug susceptibility observed between risk groups. Additionally, the study revealed the involvement of 2 candidate genes and 5 microRNAs (miRNAs) in the tumor's development. Notably, UNC5B-AS1 was highly expressed and found to promote the proliferation and migration of tumor cells.

Conclusion: This study, for the first time, elucidated the prognostic signatures of WT using lncRNAs related to TME and LA metabolism. The findings of this research offer valuable insights for future studies on immunotherapy, personalized chemotherapy, and mechanism research.

Introduction

Wilms tumor (WT), a common pediatric renal malignancy, presents unique challenges in diagnosis and treatment due to its complex biology and interaction with the tumor microenvironment (TME). Recent studies have emphasized the significant role of metabolic byproducts, particularly lactic acid (LA), in influencing tumor behavior and immune responses within the TME. The accumulation of LA, often a result of enhanced glycolytic activity in tumors, has been shown to promote tumor progression, immune evasion, and therapeutic resistance.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various biological processes, including tumorigenesis and immune responses. However, the specific roles of lncRNAs associated with LA metabolism in Wilms tumor remain largely unexplored. This article aims to provide a comprehensive analysis of the relationship between LA-related lncRNAs and WT prognosis, emphasizing the importance of TME in shaping tumor behavior.

Materials and Methods

Data Collection

Gene expression data and clinical information for WT patients were obtained from two prominent databases: The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). These datasets provide valuable insights into gene expression patterns and clinical outcomes, enabling researchers to identify potential biomarkers and therapeutic targets.

Screening for LncRNAs

Using the ESTIMATE algorithm, which estimates the immune and stromal components of the TME, researchers screened for lncRNAs associated with LA metabolism and tumor immunity. Pearson correlation analysis was employed to identify lncRNAs that exhibited significant correlations with immune scores and stromal scores.

Construction of the Prognostic Model

To construct a prognostic model, Cox regression analysis and Lasso Cox regression analysis were utilized. This approach allowed for the identification of key lncRNAs associated with patient prognosis. A final model, designated as TME-LA-LM, comprising six lncRNAs, was developed based on their predictive accuracy and clinical relevance.

Identification of Candidate Genes

In addition to lncRNAs, candidate genes involved in the tumor's development were identified through further analysis. A competitive endogenous RNA (ceRNA) network was established to explore the interactions between lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs), providing insights into the regulatory mechanisms at play within the TME.

Experimental Verification

To validate the findings, the expression and functional roles of UNC5B-AS1, one of the identified lncRNAs, were experimentally verified. This included assessing its impact on tumor cell proliferation and migration, further elucidating its role in WT progression.

Results

Relationship Between Immune Score, Stromal Score, and Prognosis

The analysis revealed a significant correlation between immune scores and stromal scores with patient prognosis. Higher immune scores were associated with improved survival outcomes, highlighting the importance of immune infiltration in the TME of WT. Conversely, lower stromal scores indicated a more aggressive tumor phenotype.

Identification of the Prognostic Model

The TME-LA-LM prognostic model, consisting of six lncRNAs, demonstrated favorable predictive ability and accuracy. Risk stratification based on this model revealed significant differences in immune infiltration and drug susceptibility among patient groups. Patients classified into high-risk groups exhibited poorer prognosis and increased resistance to standard therapies.

Discovery of Candidate Genes and miRNAs

The study identified two candidate genes and five miRNAs that were significantly associated with WT progression. These findings underscore the complex regulatory network involving lncRNAs, miRNAs, and mRNAs within the TME, contributing to tumor development and immune evasion.

Functional Validation of UNC5B-AS1

Experimental validation confirmed that UNC5B-AS1 was highly expressed in WT tissues compared to normal renal tissues. Functional assays demonstrated that silencing UNC5B-AS1 led to reduced proliferation and migration of tumor cells, indicating its role as an oncogenic lncRNA in WT.

Discussion

This study is the first to elucidate the prognostic signatures of Wilms tumor using lncRNAs associated with lactic acid metabolism and the tumor microenvironment. The findings emphasize the interplay between metabolic alterations and immune responses in shaping tumor behavior. The identification of the TME-LA-LM prognostic model provides a valuable tool for predicting patient outcomes and tailoring therapeutic strategies.

Lactic acid-related lncRNAs may serve as potential biomarkers for monitoring disease progression and response to therapy. Understanding the mechanisms through which these lncRNAs influence tumor behavior can pave the way for the development of targeted therapies and immunotherapeutic approaches in pediatric oncology.

Conclusion

In conclusion, this study highlights the significance of lactic acid-related lncRNAs in the prognosis of Wilms tumor. The identification of the TME-LA-LM model and the functional validation of UNC5B-AS1 provide important insights into the molecular mechanisms underlying tumor progression. These findings offer a foundation for future research focused on personalized treatment strategies and the exploration of immunotherapy in pediatric neoplasms.

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