Kisspeptin Signaling Suppresses HRas G12V -induced Tumor Growth and Metastasis by Inhibiting SP1-dependent N-cadherin Expression in NIH3T3 Cells

This study found that kisspeptin signaling suppresses tumor growth and metastasis driven by the HRAS G12V mutation in NIH3T3 cells. The mechanism involves reducing expression of the cell adhesion protein N-cadherin by blocking SP1-dependent transcription. These effects were observed in cell culture and in mice.

Journal article — in vitro and xenograft mouse study. Population: NIH3T3 cells expressing HRAS G12V, KISS1, and KISS1R; mice with tumors. Interventions: KISS1; KISS1R; HRAS G12V; N-cadherin expression.

Kisspeptin signaling reduced NIH3T3 cell proliferation, migration, and invasion and activated SRF reporter activity through the KISS1R-Gaq/11-p63RhoGEF-RhoA pathway. In HRAS G12V-expressing NIH3T3 cells, KISS1 reduced N-cadherin expression and suppressed anchorage-independent colony formation. HRAS G12V increased N-cadherin promoter activity, whereas KISS1 reduced both basal and HRAS G12V-induced promoter activation. Deletion of the SP1-responsive region abolished these effects, and chromatin immunoprecipitation showed reduced SP1 binding to the N-cadherin promoter. In vivo, KISS1 suppressed HRAS G12V-induced tumor growth and pulmonary metastasis, and N-cadherin expression reversed these effects.

This paper gives kisspeptin researchers a previously unexplored mechanistic route for its metastasis-suppressive effect: inhibition of SP1-dependent N-cadherin transcription in HRAS G12V-driven cells. It does not establish whether this mechanism operates in human cancers or whether it has any therapeutic application, since the experiments were in a mouse fibroblast cell line.

Key findings

• Kisspeptin signaling reduced NIH3T3 cell proliferation, migration, and invasion.
• KISS1 reduced N-cadherin expression in HRAS G12V-expressing NIH3T3 cells.
• HRAS G12V increased N-cadherin promoter activity, whereas KISS1 reduced both basal and HRAS G12V-induced promoter activation.
• Deletion of the SP1-responsive region abolished the effects on N-cadherin promoter activity.
• Chromatin immunoprecipitation showed reduced SP1 binding to the N-cadherin promoter with KISS1.
• In vivo, KISS1 suppressed HRAS G12V-induced tumor growth and pulmonary metastasis, and N-cadherin expression reversed these effects.

Limitations

• The authors did not report any specific limitations.
• The study was performed only in NIH3T3 mouse fibroblast cells, not human cancer cell lines or patient-derived models.
• In vivo findings rely on xenograft models and do not reflect human tumor microenvironments.
• The duration of in vivo observation and sample sizes were not reported.

The record

• Journal: Anticancer research 46(8): 4331-4343
• Published: 2026-08-01
• PMID: 42527090 — DOI: 10.21873/anticanres.18291
• MeSH terms: NIH 3T3 Cells, Animals, Mice, Lung Neoplasms, Neoplasm Metastasis, Cadherins, Antigens, CD, Signal Transduction, Cell Proliferation, Cell Movement, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Sp1 Transcription Factor, Promoter Regions, Genetic, Kisspeptins, Receptors, Kisspeptin-1
• Author countries: South Korea

Peptide profiles: Kisspeptin.

All indexed evidence: Kisspeptin trials & papers.

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