SEMA7A

Overview

SEMA7A encodes Semaphorin 7A, a GPI-anchored and soluble semaphorin. In gallbladder cancer (GBC), SEMA7A is transcriptionally upregulated in cancer-associated fibroblasts (CAFs) by mechanical stiffness via the YAP1/WWTR1/TEAD1 mechanotransduction axis. Secreted SEMA7A then acts in a paracrine manner on GBC cells via integrin β1 (ITGB1) to promote epithelial-to-mesenchymal transition (EMT) and cancer stemness.

Alterations observed in the corpus

  • Upregulated 3.21-fold by RNA-seq in primary human gallbladder fibroblasts cultured on 16 kPa vs 0.5 kPa hydrogel (PRJNA1182410); most strongly upregulated semaphorin in the family. PMID:24997986
  • Higher expression in GBC than normal gallbladder (GSE76633); co-expressed with YAP1 and CAF markers in scRNA-seq (OEP00001237, 13 patients). PMID:24997986
  • High stromal SEMA7A by IHC associated with larger tumor size (P = 0.006), lymph node metastasis (P = 0.001), and shorter overall survival in 86-patient cohort. PMID:24997986

Cancer types (linked)

  • Gallbladder cancer (GBC): Stromal SEMA7A upregulated by desmoplastic stiffness; high expression confers worse clinical outcomes and mediates CAF-driven tumor progression. PMID:24997986

Co-occurrence and mutual exclusivity

  • SEMA7A expression correlates positively with fibrillar collagens (COL1A1, COL1A2, COL4A1, COL4A2, COL8A1), ACTA2, PDGFRA, TGFBR1, and TGFBR2 in GBC stroma. PMID:24997986

Therapeutic relevance

  • Candidate therapeutic target in GBC: SEMA7A knockdown in GFs reduced xenograft tumor growth, invasion, and stemness markers in vivo. Upstream blockade with verteporfin (YAP inhibitor) abolishes stiffness-induced SEMA7A in GFs; downstream blockade via LY294002 (PI3K inhibitor) or C646 (p300 inhibitor) blocks SEMA7A-induced EMT/stemness. PMID:24997986

Open questions

  • Survival and clinicopathological associations are from a single-institution cohort (n = 86); external validation and multivariable survival analysis are lacking.
  • Whether membrane-bound vs. soluble SEMA7A forms play distinct roles has not been formally dissected.

Sources

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