Taha Safa, Aljishi Muna, Sultan Ameera, Bakhiet Moiz
Princess Al Jawhara Center for Molecular Medicine, Genetics and Inherited Diseases, Department of Molecular Medicine, College of Medicine and Health Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain.
Int J Mol Sci. 2025 May 7;26(9):4426. doi: 10.3390/ijms26094426.
Hepatocellular carcinoma (HCC), a highly aggressive liver malignancy, is often associated with disrupted calcium homeostasis. Store-operated calcium entry (SOCE), involving components such as STIM1, Orai1, and SARAF, plays a critical role in calcium signaling and cancer progression. While STIM1 and Orai1 have been extensively studied, SARAF's role as a negative regulator of SOCE in HCC remains poorly understood. This preliminary study investigated SARAF's effects on calcium homeostasis, proliferation, and migration in HepG2 liver cancer cells, providing initial evidence of its tumor-suppressive role. SARAF expression was modulated using siRNA knockdown and overexpression plasmids, with validation by qRT-PCR. Functional assays demonstrated that SARAF silencing increased proliferation by 50% and migration by 40% ( < 0.05), while SARAF overexpression reduced proliferation by 50% and migration by 45% ( < 0.01), highlighting its tumor-suppressive role. Intracellular calcium levels, elevated in HepG2 cells, were partially restored by SARAF overexpression, though SARAF silencing did not further disrupt calcium regulation. These findings suggest that SARAF negatively regulates proliferation and migration in HCC, potentially through its role in maintaining calcium homeostasis. SARAF represents a promising therapeutic target in HCC. Future studies should explore the downstream molecular mechanisms governing SARAF's effects, investigate its role in other cancers, and assess its clinical potential for liver cancer therapy.
肝细胞癌（HCC）是一种侵袭性很强的肝脏恶性肿瘤，常与钙稳态紊乱有关。储存性钙内流（SOCE）涉及STIM1、Orai1和SARAF等成分，在钙信号传导和癌症进展中起关键作用。虽然STIM1和Orai1已得到广泛研究，但SARAF作为HCC中SOCE的负调节因子的作用仍知之甚少。这项初步研究调查了SARAF对HepG2肝癌细胞钙稳态、增殖和迁移的影响，为其肿瘤抑制作用提供了初步证据。使用siRNA敲低和过表达质粒调节SARAF表达，并通过qRT-PCR进行验证。功能分析表明，SARAF沉默使增殖增加50%，迁移增加40%（<0.05），而SARAF过表达使增殖减少50%，迁移减少45%（<0.01），突出了其肿瘤抑制作用。HepG2细胞中升高的细胞内钙水平通过SARAF过表达得到部分恢复，尽管SARAF沉默并未进一步破坏钙调节。这些发现表明，SARAF可能通过其在维持钙稳态中的作用对HCC的增殖和迁移起负调节作用。SARAF是HCC中一个有前景的治疗靶点。未来的研究应探索控制SARAF作用的下游分子机制，研究其在其他癌症中的作用，并评估其在肝癌治疗中的临床潜力。
