Inhibition of Calcium‐Sensing Receptor Suppresses Malignant Behaviours of Human Hepatocellular Carcinoma

ABSTRACT

Hepatocellular carcinoma (HCC) continues to pose significant worldwide health burdens due to restricted treatment alternatives and unfavourable prognosis. This investigation reveals the pivotal involvement of calcium‐sensing receptor (CaSR) in HCC advancement and its potential as a promising therapeutic target. Through pharmacological blockade with NPS‐2143 and genetic knockdown using siRNA, we found that CaSR inhibition substantially reduced HCC cell proliferation, migration, and invasion, while promoting apoptotic cell death in HepG2 and SMMC‐7721 cells. At the molecular level, CaSR interference triggered p38 MAPK activation, while inhibiting the ERK1/2 cascade, resulting in diminished expression of proliferation indicators (PCNA), metastatic markers (MMP‐2/9), and cell survival proteins (Bcl‐2), concurrent with elevated levels of apoptosis mediators (Bax, cleaved caspase‐3). In vivo, NPS‐2143 significantly suppressed xenograft tumour growth. Western blotting of xenograft tumour tissues further showed increased p‐p38/p38 and Bax levels and decreased p‐ERK/ERK, MMP‐9, and Bcl‐2 levels, consistent with the in vitro findings. Additional validation in a male nude mouse xenograft model using Huh7 cells further supported the anti‐tumour effect of NPS‐2143 in another independent HCC model. These findings suggest that CaSR facilitates malignant HCC cebehaviours through MAPK signalling and may represent a potential therapeutic target for HCC treatment.