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Background <p>Lipocalin-2 (LCN2), a secreted glycoprotein implicated in inflammation, metabolism, and tumor progression, has emerged as a critical regulator of cancer cell proliferation and metastasis. However, its role in papillary thyroid carcinoma (PTC) remains poorly understood.</p> Methods <p>The expression of LCN2 in PTC and adjacent normal tissues was assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). After LCN2 knockdown or overexpression, cell proliferation, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), colony formation, Transwell, wound-healing, and flow cytometry assays. Glycolytic capacity was assessed via Seahorse extracellular flux analysis, and expression of glycolysis-related genes was determined by RT-qPCR. Differentially expressed genes (DEGs) following LCN2 knockdown were identified via high-throughput sequencing, with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses used to explore potential mechanisms. Co-immunoprecipitation, luciferase reporter assays, and chromatin immunoprecipitation (ChIP) were employed to examine the involvement of the Hippo/YAP1/HIF1α axis in LCN2-mediated glycolytic activation. In vivo, BCPAP cells with stable LCN2 knockdown were injected into nude mice, and tumor growth was monitored.</p> Results <p>LCN2 was significantly upregulated in PTC tissues and cells compared to controls, and its high expression was closely correlated with extrathyroidal extension and lymph node metastasis. In vitro, LCN2 knockdown significantly inhibited PTC cell proliferation, migration, invasion, and glycolysis, while overexpression exerted the opposite effects. These effects were reversed by 2-deoxyglucose (2-DG), a glycolysis inhibitor. In vivo, silencing of LCN2 markedly suppressed tumor growth. GO and KEGG analyses indicated that LCN2 may regulate glycolysis in PTC through the Hippo signaling pathway. Mechanistically, LCN2 directly targeted YAP1, which in turn modulated the transcriptional activity of HIF1α to enhance glycolysis.</p> Conclusions <p>LCN2 is highly expressed in PTC and promotes glycolysis, proliferation, invasion, and migration by activating the Hippo/YAP1/HIF1α axis. This study elucidates the oncogenic mechanism of the LCN2/YAP1/HIF1α axis in PTC and provides a potential target for molecular therapy.</p>

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Lipocalin 2 promotes papillary thyroid cancer progression through activation of glycolysis via Hippo/YAP1/HIF1α axis

  • 期刊论文

  • 发表日期：

    2026年4月11日

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  • Xiaoyu Qian,
  • Jian Tang,
  • Liehao Jiang,
  • Lin Li,
  • Chao Shen,
  • Lisong Teng

摘要

Background

Lipocalin-2 (LCN2), a secreted glycoprotein implicated in inflammation, metabolism, and tumor progression, has emerged as a critical regulator of cancer cell proliferation and metastasis. However, its role in papillary thyroid carcinoma (PTC) remains poorly understood.

Methods

The expression of LCN2 in PTC and adjacent normal tissues was assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). After LCN2 knockdown or overexpression, cell proliferation, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), colony formation, Transwell, wound-healing, and flow cytometry assays. Glycolytic capacity was assessed via Seahorse extracellular flux analysis, and expression of glycolysis-related genes was determined by RT-qPCR. Differentially expressed genes (DEGs) following LCN2 knockdown were identified via high-throughput sequencing, with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses used to explore potential mechanisms. Co-immunoprecipitation, luciferase reporter assays, and chromatin immunoprecipitation (ChIP) were employed to examine the involvement of the Hippo/YAP1/HIF1α axis in LCN2-mediated glycolytic activation. In vivo, BCPAP cells with stable LCN2 knockdown were injected into nude mice, and tumor growth was monitored.

Results

LCN2 was significantly upregulated in PTC tissues and cells compared to controls, and its high expression was closely correlated with extrathyroidal extension and lymph node metastasis. In vitro, LCN2 knockdown significantly inhibited PTC cell proliferation, migration, invasion, and glycolysis, while overexpression exerted the opposite effects. These effects were reversed by 2-deoxyglucose (2-DG), a glycolysis inhibitor. In vivo, silencing of LCN2 markedly suppressed tumor growth. GO and KEGG analyses indicated that LCN2 may regulate glycolysis in PTC through the Hippo signaling pathway. Mechanistically, LCN2 directly targeted YAP1, which in turn modulated the transcriptional activity of HIF1α to enhance glycolysis.

Conclusions

LCN2 is highly expressed in PTC and promotes glycolysis, proliferation, invasion, and migration by activating the Hippo/YAP1/HIF1α axis. This study elucidates the oncogenic mechanism of the LCN2/YAP1/HIF1α axis in PTC and provides a potential target for molecular therapy.