NFATc1 facilitates hepatocellular carcinoma progression by regulating the senescence-associated secretory phenotype

Abstract

Abstract The Nuclear Factor of Activated T-cells cytoplasmic 1 (NFATc1) is identified to be an oncogene in several human cancers. However, its specific role in HCC progression and the relevant mechanisms remain unclear. To investigate this, we analyzed NFATc1 expression in clinical HCC samples (n = 289) using RT-qPCR, Western blotting, and immunohistochemistry (IHC). In vitro assays assessed HCC cell proliferation, migration, invasion, apoptosis, and cell cycle, while in vivo studies using BALB/c nude mice evaluated the effects of NFATc1 on HCC growth and metastasis. Mechanistic studies were conducted to explore NFATc1’s downstream signaling pathways. Results revealed that NFATc1 is significantly upregulated in HCC tissues compared to adjacent non-cancerous tissues, correlating with poor prognosis. Overexpression of NFATc1 enhanced HCC cell proliferation, migration, and invasion both in vitro and in vivo, while silencing NFATc1 reduced these malignant traits. Mechanistic analysis indicated that NFATc1 activation correlates with NF-κB/TMP21 signaling and senescence-associated secretory phenotype (SASP) amplification, independent of growth arrest. These findings suggest that NFATc1 plays a pivotal role in HCC progression, potentially through the modulation of SASP activation. Targeting NFATc1 and its signaling pathways could be a promising therapeutic approach for HCC.

Keywords

• Hepatocellular carcinoma
• Senescence
• Senescence-associated secretory phenotype
• NFATc1
• Tumour microenvironment
• Tumor progression