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Objective <p>To investigate the impact of SHP2 on thymic epithelial tumors (TETs) and its underlying mechanisms.</p> Methods <p>Bioinformatic analysis was performed to identify key pathways in TETs. Clinical samples from 40 TET patients and 3 normal controls were analyzed. Immunohistochemistry compared phosphorylated SHP2 (p-SHP2) levels between tumor and normal tissues. In vitro, TET cells were subjected to various treatments: SHP2 inhibition (SHP099, 10&#xa0;μM), PI3K/ERK activation (HH, 100&#xa0;μM), CREB inhibition (SGC-CBP30, 10&#xa0;μM), and SP1 overexpression. The protein expression levels of P-SHP2, total SHP2, P-PI3K, P-ERK1/2, nuclear P-CREB, nuclear P-SP1, nuclear BRD9, nuclear P300, nuclear CBP, HIF1α, EGFR, YAP, and MMP-2 in TET cells were detected by Western blot analysis. Tubulogenesis, invasion, migration, cell proliferation and apoptosis in TET cells were assessed using tube formation, Transwell, scratch, CCK-8 and flow-cytometric quantification assays, respectively.</p> Results <p>Bioinformatic analysis revealed significant enrichment of the PI3K-Akt and HIF-1α signaling pathways in TETs, with positive correlations between SHP2, PI3K, ERK, and CREB. p-SHP2 was significantly upregulated in TET tissues compared to normal thymus. In vitro, SHP2 inhibition suppressed the PI3K/ERK pathway, downregulated nuclear p-CREB and p-SP1, and decreased expression of downstream effectors (HIF1α, EGFR, YAP, MMP-2), concomitantly inhibiting cell proliferation, migration and survival. Conversely, PI3K/ERK activation rescued these effects. CREB inhibition specifically attenuated the SP1-HIF1α/EGFR axis without affecting upstream kinases, while SP1 overexpression reversed the effects of CREB inhibition, restoring HIF1α and EGFR expression.</p> Conclusion <p>The tyrosine phosphatase SHP2 promotes proliferation, migration, tubulogenesis, and anti-apoptotic capacity of TETs by inducing HIF1α and EGFR expression through the PI3K/ERK/CREB/SP1 signaling pathway.</p>

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Tyrosine phosphatase SHP2 accelerated progression of thymic epithelial tumors via promoting PI3K/ERK/CREB/SP1 induced HIF1α and EGFR expression

  • 期刊论文

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  • 发表日期：

    2026年5月26日

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  • Congya Yan,
  • Shuai Zhao,
  • Guoyan Qi

摘要

Objective

To investigate the impact of SHP2 on thymic epithelial tumors (TETs) and its underlying mechanisms.

Methods

Bioinformatic analysis was performed to identify key pathways in TETs. Clinical samples from 40 TET patients and 3 normal controls were analyzed. Immunohistochemistry compared phosphorylated SHP2 (p-SHP2) levels between tumor and normal tissues. In vitro, TET cells were subjected to various treatments: SHP2 inhibition (SHP099, 10 μM), PI3K/ERK activation (HH, 100 μM), CREB inhibition (SGC-CBP30, 10 μM), and SP1 overexpression. The protein expression levels of P-SHP2, total SHP2, P-PI3K, P-ERK1/2, nuclear P-CREB, nuclear P-SP1, nuclear BRD9, nuclear P300, nuclear CBP, HIF1α, EGFR, YAP, and MMP-2 in TET cells were detected by Western blot analysis. Tubulogenesis, invasion, migration, cell proliferation and apoptosis in TET cells were assessed using tube formation, Transwell, scratch, CCK-8 and flow-cytometric quantification assays, respectively.

Results

Bioinformatic analysis revealed significant enrichment of the PI3K-Akt and HIF-1α signaling pathways in TETs, with positive correlations between SHP2, PI3K, ERK, and CREB. p-SHP2 was significantly upregulated in TET tissues compared to normal thymus. In vitro, SHP2 inhibition suppressed the PI3K/ERK pathway, downregulated nuclear p-CREB and p-SP1, and decreased expression of downstream effectors (HIF1α, EGFR, YAP, MMP-2), concomitantly inhibiting cell proliferation, migration and survival. Conversely, PI3K/ERK activation rescued these effects. CREB inhibition specifically attenuated the SP1-HIF1α/EGFR axis without affecting upstream kinases, while SP1 overexpression reversed the effects of CREB inhibition, restoring HIF1α and EGFR expression.

Conclusion

The tyrosine phosphatase SHP2 promotes proliferation, migration, tubulogenesis, and anti-apoptotic capacity of TETs by inducing HIF1α and EGFR expression through the PI3K/ERK/CREB/SP1 signaling pathway.