Kisspeptin Signaling Suppresses HRasG12V-induced Tumor Growth and Metastasis by Inhibiting SP1-dependent N-cadherin Expression in NIH3T3 Cells.

BACKGROUND/AIM: Kisspeptin signaling is recognized as a metastasis-suppressive pathway, but its role in oncogenic HRAS-driven tumor progression remains incompletely understood. This study investigated whether kisspeptin signaling suppresses HRASG12V-induced tumorigenic and metastatic phenotypes in NIH3T3 cells and examined the involvement of SP1-dependent transcription of N-cadherin.

MATERIALS AND

METHODS

NIH3T3 cells expressing HRASG12V, KISS1, and KISS1R were analyzed for proliferation, migration, invasion, luciferase reporter activity, anchorage-independent growth, and in vivo tumor growth and pulmonary metastasis. N-cadherin expression was examined by RT-PCR and immunoblotting. N-cadherin promoter regulation was analyzed using luciferase reporter and chromatin immunoprecipitation assays.

RESULTS

Kisspeptin signaling reduced NIH3T3 cell proliferation, migration, and invasion and activated SRF reporter activity through the KISS1R-Gaq/11-p63RhoGEF-RhoA pathway. In HRASG12V-expressing NIH3T3 cells, KISS1 reduced N-cadherin expression and suppressed anchorage-independent colony formation. HRASG12V increased N-cadherin promoter activity, whereas KISS1 reduced both basal and HRASG12V-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 HRASG12V-induced tumor growth and pulmonary metastasis, and N-cadherin expression reversed these effects.

CONCLUSION

Kisspeptin signaling suppresses HRASG12V-induced tumor growth and metastasis in NIH3T3 cells by inhibiting SP1-dependent transcription of N-cadherin.