Huang Qionghui, Tang Xiaoyan, Gan Caiyan, Deng Qiaoting, Zhi Shaobin, Huang Qingyan, Zheng Xiaoqi, Li Xueqiong, Pan Zengfeng, Huang Mingfeng
Institute of Cardiovascular Disease, Meizhou People's Hospital, Meizhou Academy of Medical Sciences, Meizhou, China.
GuangDong Engineering Technological Research Center of Molecular Diagnosis in Cardiovascular Diseases, Meizhou, China.
J Cancer. 2025 Jan 20;16(4):1348-1362. doi: 10.7150/jca.103229. eCollection 2025.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, with high rates of metastasis and lethality. EF-hand domain-containing protein D1 (EFHD1) and salt-inducible kinase 3 (SIK3) have been studied in several cancer types. Aberrant expression of EFHD1 and SIK3 has been observed in CRC, but little research has addressed their regulatory abilities and signaling pathways. In this study, we aimed to explore the efficacy of EFHD1 in inhibiting CRC proliferation and metastasis and to elucidate the underlying mechanisms involved in the upregulation of SIK3 expression. Cell viability, colony formation, wound healing, Transwell assay, orthotopic xenograft, and pulmonary metastasis mouse models were used to detect the antiproliferative and anti-metastatic effects of EFHD1 against CRC and . The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to determine EFHD1 and SIK3 expression in CRC. The regulatory roles of EFHD1 and SIK3 in mediating anti-metastatic effects in CRC were measured using western blotting, immunohistochemical, and immunofluorescence analyses. The results showed that EFHD1 expression was significantly repressed in the clinical CRC samples. EFHD1 markedly suppressed cell proliferation, migration, and invasion and inhibited tumor growth and metastasis . Analysis of the GEPIA database revealed that EFHD1 expression positively correlated with SIK3 expression. SIK3 overexpression inhibited the migration of CRC cells, and SIK3 knockdown partially eliminated the inhibitory effects of EFHD1 on CRC metastasis. EFHD1 exerted anti-metastatic effects against CRC via upregulating SIK3 and inhibiting epithelial-mesenchymal transition (EMT) processing through modulating the Hippo signaling pathway. Collectively, these findings identify EFHD1 as a potent SIK3 agonist and highlight the EFHD1-SIK3 axis as a key modulator of the Hippo signaling pathway in CRC. EFHD1 serves as a novel regulator and is worthy of further development as a novel therapeutic target in CRC.
结直肠癌（CRC）是最常被诊断出的癌症之一，具有高转移率和致死率。含EF手结构域蛋白D1（EFHD1）和盐诱导激酶3（SIK3）已在多种癌症类型中得到研究。在结直肠癌中已观察到EFHD1和SIK3的异常表达，但很少有研究涉及其调节能力和信号通路。在本研究中，我们旨在探讨EFHD1抑制结直肠癌增殖和转移的功效，并阐明SIK3表达上调所涉及的潜在机制。使用细胞活力、集落形成、伤口愈合、Transwell实验、原位异种移植和肺转移小鼠模型来检测EFHD1对结直肠癌的抗增殖和抗转移作用。利用基因表达谱交互分析（GEPIA）数据库来确定结直肠癌中EFHD1和SIK3的表达。使用蛋白质印迹、免疫组织化学和免疫荧光分析来测定EFHD1和SIK3在介导结直肠癌抗转移作用中的调节作用。结果表明，临床结直肠癌样本中EFHD1表达明显受到抑制。EFHD1显著抑制细胞增殖、迁移和侵袭，并抑制肿瘤生长和转移。对GEPIA数据库的分析显示，EFHD1表达与SIK3表达呈正相关。SIK3过表达抑制结直肠癌细胞的迁移，而敲低SIK3则部分消除了EFHD1对结直肠癌转移的抑制作用。EFHD1通过上调SIK3并通过调节Hippo信号通路抑制上皮-间质转化（EMT）过程，从而对结直肠癌发挥抗转移作用。总体而言，这些发现确定EFHD1为一种有效的SIK3激动剂，并突出了EFHD1-SIK3轴作为结直肠癌中Hippo信号通路的关键调节因子。EFHD1作为一种新型调节因子，值得进一步开发成为结直肠癌的新型治疗靶点。
