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Background <p>Claudin-3, Claudin-4, and Claudin-7 are expressed on the surface of epithelial cells. Their absence in neoplastic cells of epithelial origin is an aggressiveness marker in different cancers. The <i>NF-YA</i> gene codes for the <i>Nuclear-Transcription-Factor-Y-Subunit-A</i>, which is overexpressed in various tumors. In tumors, the relative ratio of the two major <i>NF-YA</i> alternative splicing isoforms, <i>NF-YA&#xa0;long</i> and <i>NF-YA&#xa0;short</i>, is associated with a mesenchymal phenotype and a poor prognosis. Based on a high <i>NF-YA&#xa0;long</i>/<i>NF-YA&#xa0;short</i> ratio, we generated a 158-gene signature that is common to Claudin<sup>low</sup> Breast Carcinomas (BRCA) and Stomach Adenocarcinomas (STAD).</p> Methods <p>To better classify STAD Claudin<sup>low</sup> tumors, we employed a hierarchical clustering approach based on our 158-gene signature to classify STAD into a Claudin<sup>low</sup> subgroup. We tested the classification potential of our signature in TCGA as well as in two additional datasets of tumors. We used the deep-learning <i>DeepCC</i> tool and the 158-gene signature to classify the STAD cell lines available in the CCLE platform. Obtained data were validated with qRT-PCR and Western blots.</p> Results <p>The 158-gene signature resulted in the selection of a STAD subgroup with effective Claudin<sup>low</sup> expression and with a high <i>NF-YA&#xa0;long</i>/<i>NF-YA&#xa0;short</i> ratio. This Claudin<sup>low</sup> subgroup was separated from the EMT subgroup of STAD and it is characterized by poor clinical outcome. We identified nine Claudin<sup>low</sup> STAD cell lines with a high <i>NF-YA&#xa0;long</i>/<i>NF-Y short</i> ratio and validated the expression of selected markers.</p> Conclusions <p>Our work supports the notion that three overlapping features—low expression of Claudin-3/4/7, high <i>NF-YA&#xa0;long</i>/<i>NF-YA&#xa0;short</i> ratio and a 158-gene signature—mark a specific subset of STAD characterized by mesenchymal features and poor prognosis.</p>

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A gene-expression signature defines a subtype of Stomach Adenocarcinomas with low levels of Claudins and a high ratio of NF-YA long/NF-YA short splicing variants

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  • 发表日期：

    2025年10月13日

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  • Alberto Gallo,
  • Mirko Ronzio,
  • Maria Barbara Campbell,
  • Sofia Polettini,
  • Enrico Garattini,
  • Roberto Mantovani,
  • Diletta Dolfini

摘要

Background

Claudin-3, Claudin-4, and Claudin-7 are expressed on the surface of epithelial cells. Their absence in neoplastic cells of epithelial origin is an aggressiveness marker in different cancers. The NF-YA gene codes for the Nuclear-Transcription-Factor-Y-Subunit-A, which is overexpressed in various tumors. In tumors, the relative ratio of the two major NF-YA alternative splicing isoforms, NF-YA long and NF-YA short, is associated with a mesenchymal phenotype and a poor prognosis. Based on a high NF-YA long/NF-YA short ratio, we generated a 158-gene signature that is common to Claudinlow Breast Carcinomas (BRCA) and Stomach Adenocarcinomas (STAD).

Methods

To better classify STAD Claudinlow tumors, we employed a hierarchical clustering approach based on our 158-gene signature to classify STAD into a Claudinlow subgroup. We tested the classification potential of our signature in TCGA as well as in two additional datasets of tumors. We used the deep-learning DeepCC tool and the 158-gene signature to classify the STAD cell lines available in the CCLE platform. Obtained data were validated with qRT-PCR and Western blots.

Results

The 158-gene signature resulted in the selection of a STAD subgroup with effective Claudinlow expression and with a high NF-YA long/NF-YA short ratio. This Claudinlow subgroup was separated from the EMT subgroup of STAD and it is characterized by poor clinical outcome. We identified nine Claudinlow STAD cell lines with a high NF-YA long/NF-Y short ratio and validated the expression of selected markers.

Conclusions

Our work supports the notion that three overlapping features—low expression of Claudin-3/4/7, high NF-YA long/NF-YA short ratio and a 158-gene signature—mark a specific subset of STAD characterized by mesenchymal features and poor prognosis.