State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
J Cell Mol Med. 2024 Aug;28(16):e70006. doi: 10.1111/jcmm.70006.
Limited effective targets have challenged the treatment of oral squamous cell carcinoma (OSCC). Casein kinase 2 interacting protein 1 (CKIP-1) is a scaffold protein involved in various diseases. However, the role of CKIP-1 in OSCC remains unclear. The aim of this study was to explore the regulatory role of CKIP-1 in OSCC, as well as the involved mechanism. First, higher expression of CKIP-1 in OSCC tissues and cell lines were found. Series of gain- and loss-of-function experiments demonstrated suppressed malignant behaviours and enhanced apoptosis of OSCC cells when CKIP-1 was silenced. Also, inhibited tumour growth in CKIP-1-silenced group were proved. Further, mitochondrial transcription factor A (TFAM) downregulation, increased ROS production, decreased mitochondrial membrane potential and cGAS-STING activation in CKIP-1-silenced group were observed. The involvement of mitochondrial homeostasis-related TFAM/cGAS-STING axis in CKIP-1-silenced OSCC cells was finally demonstrated by tetramethylpyrazine (TMP) that inhibits TFAM degradation. Taken together, our study demonstrated that CKIP-1 silencing could significantly antagonize OSCC via TFAM/cGAS-STING axis, which may provide a candidate target for OSCC treatment.
有限的有效靶点一直是口腔鳞状细胞癌（OSCC）治疗的挑战。酪蛋白激酶 2 相互作用蛋白 1（CKIP-1）是一种参与多种疾病的支架蛋白。然而，CKIP-1 在 OSCC 中的作用尚不清楚。本研究旨在探讨 CKIP-1 在 OSCC 中的调控作用及其相关机制。首先，发现 CKIP-1 在 OSCC 组织和细胞系中表达升高。一系列的功能获得和功能丧失实验表明，沉默 CKIP-1 可抑制 OSCC 细胞的恶性行为并增强其凋亡。同时，沉默 CKIP-1 组肿瘤生长受到抑制。此外，在 CKIP-1 沉默组观察到线粒体转录因子 A（TFAM）下调、ROS 产生增加、线粒体膜电位降低和 cGAS-STING 激活。最后，通过抑制 TFAM 降解的四甲基吡嗪（TMP）证实了线粒体稳态相关 TFAM/cGAS-STING 轴在 CKIP-1 沉默的 OSCC 细胞中的作用。综上所述，本研究表明，沉默 CKIP-1 可通过 TFAM/cGAS-STING 轴显著拮抗 OSCC，这可能为 OSCC 的治疗提供一个候选靶点。
