Weng Yueh-Shan, Chiang I-Tsang, Tsai Jai-Jen, Liu Yu-Chang, Hsu Fei-Ting
Department of Biological Science and Technology, China Medical University, Taichung 406, Taiwan.
Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, Taiwan; Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan; Department of Medical Imaging and Radiologic Sciences, Central Taiwan University of Science and Technology, Taichung 406, Taiwan; Medical administrative center, Show Chwan Memorial Hospital, Changhua 500, Taiwan, ROC.
Int J Radiat Oncol Biol Phys. 2023 Mar 1;115(3):719-732. doi: 10.1016/j.ijrobp.2022.09.060. Epub 2022 Sep 19.
This study suggested that lenvatinib may incapacitate hepatocellular carcinoma (HCC) to radiation treatment by abrogating radiation-induced Src/signal transducer and the activator of transcription 3 signaling (STAT3)/nuclear factor-κB (NF-κB) to escalate radiation-induced extrinsic and intrinsic apoptosis. These findings uncover the role of targeting Src and its arbitrating epithelial-mesenchymal transition (EMT), which could increase the anti-HCC efficacy of radiation therapy (RT). Lenvatinib and sorafenib are multikinase inhibitors used to treat HCC. Lenvatinib is noninferior to sorafenib in the therapeutic response in HCC. However, whether lenvatinib intensifies the anti-HCC efficacy of RT is ambiguous. Several oncogenic kinases and transcription factors, such as Src, STAT3, and NF-κB, enhance the radiosensitivity of cancers. Therefore, we aimed to investigate the roles of the Src/STAT3/NF-κB axis in HCC after RT treatment and assessed whether targeting Src by lenvatinib may enhance the effectiveness of RT.
Hep3B, Huh7, HepG2, and SK-Hep1 HCC cells and 2 types of animal models were used to identify the efficacy of RT combined with lenvatinib. Cellular toxicity, apoptosis, DNA damage, EMT/metastasis regulation, and treatment efficacy were validated by colony formation, flow cytometry, Western blotting, and in vivo experiments, respectively. Knockdown of Src by siRNA was also used to validate the role of Src in RT treatment.
Silencing Src reduced STAT3/NF-κB signaling and sensitized HCC to radiation. Lenvatinib reversed radiation-elicited Src/STAT3/NF-κB signaling while enhancing the anti-HCC efficacy of radiation. Both lenvatinib and siSrc promoted the radiation effect of cell proliferation on suppression, inhibition of the invasion ability, and induction of apoptosis in HCC. Lenvatinib also alleviated radiation-triggered oncogenic and EMT-related protein expression.
Our findings uncovered the role of the Src/STAT3/NF-κB regulatory axis in response to radiation-induced toxicity and confirmed Src as the key regulatory molecule for radiosensitization of HCC evoked by lenvatinib.
本研究表明，乐伐替尼可能通过消除辐射诱导的Src/信号转导及转录激活因子3信号通路（STAT3）/核因子κB（NF-κB），使肝细胞癌（HCC）对放射治疗失去反应能力，从而增强辐射诱导的外源性和内源性凋亡。这些发现揭示了靶向Src及其介导的上皮-间质转化（EMT）的作用，这可能会提高放射治疗（RT）的抗HCC疗效。乐伐替尼和索拉非尼是用于治疗HCC的多激酶抑制剂。在HCC的治疗反应中，乐伐替尼不劣于索拉非尼。然而，乐伐替尼是否能增强RT的抗HCC疗效尚不清楚。几种致癌激酶和转录因子，如Src、STAT3和NF-κB，可增强癌症的放射敏感性。因此，我们旨在研究Src/STAT3/NF-κB轴在RT治疗后HCC中的作用，并评估乐伐替尼靶向Src是否可增强RT的有效性。
使用Hep3B、Huh7、HepG2和SK-Hep1 HCC细胞以及2种动物模型来确定RT联合乐伐替尼的疗效。分别通过集落形成、流式细胞术、蛋白质免疫印迹和体内实验验证细胞毒性、凋亡、DNA损伤、EMT/转移调节和治疗效果。还使用siRNA敲低Src来验证Src在RT治疗中的作用。
沉默Src可降低STAT3/NF-κB信号通路，并使HCC对辐射敏感。乐伐替尼逆转辐射诱导的Src/STAT3/NF-κB信号通路，同时增强辐射的抗HCC疗效。乐伐替尼和siSrc均促进细胞增殖抑制、侵袭能力抑制以及HCC细胞凋亡的辐射效应。乐伐替尼还减轻了辐射引发的致癌和EMT相关蛋白表达。
我们的研究结果揭示了Src/STAT3/NF-κB调节轴在辐射诱导毒性反应中的作用，并证实Src是乐伐替尼引起的HCC放射增敏作用的关键调节分子。
