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Background <p>Calmodulin functions crucially in tumor growth. A systematic analysis of the molecular characteristics of calmodulin-related genes (CRGs) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) may provide guidance for the development of prognostic treatment strategies for CESC.</p> Methods <p>This study utilized the Cancer Genome Atlas (TCGA)–CESC and GSE52903 datasets to identify CRGs-associated molecular subtypes via consensus clustering and screen for differentially expressed genes (DEGs). LASSO–Cox regression and stepwise regression analysis were employed to construct prognostic models, with their predictive efficacy evaluated via Kaplan–Meier (KM) survival analysis and receiver operating characteristic (ROC) curves. Immune microenvironment characteristics and immune therapy responses were analyzed using CIBERSORT, ESTIMATE, and TIDE algorithms. Gene set enrichment analysis (GSEA) and drug sensitivity prediction were applied to examine the association between the prognostic model and CESC pathway activity and drug sensitivity. The mRNA expression of key genes were detected via quantitative real-time PCR (qRT-PCR). Cell migration and invasion were evaluated through wound healing and transwell assays.</p> Results <p>Two CESC subtypes (C1 and C2) associated with CRGs were identified, with the C2 subtype showing a better prognosis. A prognostic model based on four key genes (<i>DSG2</i>, <i>CST7</i>, <i>CXCL8</i>, and <i>POSTN</i>) was constructed, and the overall survival (OS) rate of CESC in the high-risk group was significantly lower. The low-risk group had higher ImmuneScore and StromalScore, while the high-risk group showed higher TIDE scores. The high-risk group was significantly enriched in pathways, such as ANGIOGENESIS, while the low-risk group was significantly enriched in pathways, such as IL6_JAK_STAT3_SIGNALING&#xa0;pathway. Drug sensitivity analysis revealed that <i>DSG2</i> and <i>CXCL8</i> were significantly negatively related to the IC<sub>50</sub> of multiple targeted drugs (e.g., Thapsigargin, BI-5236, JW-7-52-1, and WH-4-023). <i>In vitro</i> assays displayed that <i>DSG2</i> silence markedly inhibited cervical cancer cell migration and invasion.</p> Conclusions <p>This study established a CESC prognostic model associated with CRGs, revealing that CRGs influence disease progression by regulating the immune microenvironment and cancer-related pathways. The model has both prognostic prediction and immunotherapy response assessment value, and may provide potential targets for targeted treatment strategies for CESC.</p>

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Calmodulin-related genes reveal distinct immune microenvironment and therapeutic vulnerabilities in cervical carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Liyuan Wang,
  • Chunyuan Zhang,
  • Ruifang Zhai,
  • He Zhang,
  • Ruifan Gao,
  • Min Su,
  • Zengrong Tu,
  • Chunhai Tang

摘要

Background

Calmodulin functions crucially in tumor growth. A systematic analysis of the molecular characteristics of calmodulin-related genes (CRGs) in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) may provide guidance for the development of prognostic treatment strategies for CESC.

Methods

This study utilized the Cancer Genome Atlas (TCGA)–CESC and GSE52903 datasets to identify CRGs-associated molecular subtypes via consensus clustering and screen for differentially expressed genes (DEGs). LASSO–Cox regression and stepwise regression analysis were employed to construct prognostic models, with their predictive efficacy evaluated via Kaplan–Meier (KM) survival analysis and receiver operating characteristic (ROC) curves. Immune microenvironment characteristics and immune therapy responses were analyzed using CIBERSORT, ESTIMATE, and TIDE algorithms. Gene set enrichment analysis (GSEA) and drug sensitivity prediction were applied to examine the association between the prognostic model and CESC pathway activity and drug sensitivity. The mRNA expression of key genes were detected via quantitative real-time PCR (qRT-PCR). Cell migration and invasion were evaluated through wound healing and transwell assays.

Results

Two CESC subtypes (C1 and C2) associated with CRGs were identified, with the C2 subtype showing a better prognosis. A prognostic model based on four key genes (DSG2, CST7, CXCL8, and POSTN) was constructed, and the overall survival (OS) rate of CESC in the high-risk group was significantly lower. The low-risk group had higher ImmuneScore and StromalScore, while the high-risk group showed higher TIDE scores. The high-risk group was significantly enriched in pathways, such as ANGIOGENESIS, while the low-risk group was significantly enriched in pathways, such as IL6_JAK_STAT3_SIGNALING pathway. Drug sensitivity analysis revealed that DSG2 and CXCL8 were significantly negatively related to the IC50 of multiple targeted drugs (e.g., Thapsigargin, BI-5236, JW-7-52-1, and WH-4-023). In vitro assays displayed that DSG2 silence markedly inhibited cervical cancer cell migration and invasion.

Conclusions

This study established a CESC prognostic model associated with CRGs, revealing that CRGs influence disease progression by regulating the immune microenvironment and cancer-related pathways. The model has both prognostic prediction and immunotherapy response assessment value, and may provide potential targets for targeted treatment strategies for CESC.