Zhang Ying, Yao Ruiwei, Li Mingyi, Fang Chongkai, Feng Kunliang, Chen Xiuru, Wang Jinan, Luo Rui, Shi Hanqian, Chen Xinqiu, Zhao Xilin, Huang Hanlin, Liu Shuwei, Yin Bing, Zhong Chong
State Key Laboratory of Traditional Chinese Medicine Syndrome/The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Shenzhen Bao'an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China.
Mol Cancer. 2025 Jan 27;24(1):32. doi: 10.1186/s12943-024-02224-3.
The high mortality rate from hepatocellular carcinoma (HCC) is due primarily to challenges in early diagnosis and the development of drug resistance in advanced stages. Many first-line chemotherapeutic drugs induce ferroptosis, a form of programmed cell death dependent on ferrous iron-mediated oxidative stress, suggesting that drug resistance and ensuing tumor progression may in part stem from reduced ferroptosis. Since circular RNAs (circRNAs) have been shown to influence tumor development, we examined whether specific circRNAs may regulate drug-induced ferroptosis in HCC. Through circRNA sequencing, we identified a novel hsa_circ_0000195 (circTTC13) that is overexpressed in HCC tissues. This overexpression is linked to higher tumor grade, more advanced tumor stage, decreased ferroptosis, and poorer overall survival. Overexpression of CircTTC13 in HCC cell lines and explant tumors was associated with increased proliferation rates, enhanced metastatic capacity, and resistance to sorafenib, while also inhibiting ferroptosis. Conversely, circTTC13 silencing reduced malignant characteristics and promoted ferroptosis. In silico analysis, luciferase assays, and fluorescence in situ hybridization collectively demonstrated that circTTC13 directly targets and reduces miR-513a-5p expression, which in turn leads to the upregulation of the negative ferroptosis regulator SLC7A11. Moreover, the inhibition of SLC7A11 mirrored the effect of circTTC13 knockdown, whereas ferroptosis inhibition mimicked the effect of circTTC13 overexpression. Both circTTC13 and SLC7A11 were highly expressed in drug-resistant HCC cells, and circTTC13 silencing induced ferroptosis and reversed sorafenib resistance in explant tumors. These findings identify circTTC13 as a critical driver of HCC progression and resistance to drug-induced ferroptosis via upregulation of SLC7A11. The cicTTC13/miR-513a-5p/SLC7A11 axis represents a potential therapeutic target for HCC.
肝细胞癌（HCC）的高死亡率主要归因于早期诊断面临的挑战以及晚期耐药性的产生。许多一线化疗药物会诱导铁死亡，这是一种依赖于亚铁离子介导的氧化应激的程序性细胞死亡形式，这表明耐药性以及随之而来的肿瘤进展可能部分源于铁死亡减少。由于环状RNA（circRNA）已被证明会影响肿瘤发展，我们研究了特定的circRNA是否可能调节HCC中药物诱导的铁死亡。通过circRNA测序，我们鉴定出一种新型的hsa_circ_0000195（circTTC13），其在HCC组织中过表达。这种过表达与更高的肿瘤分级、更晚期的肿瘤阶段、铁死亡减少以及总体生存率较差有关。circTTC13在HCC细胞系和外植体肿瘤中的过表达与增殖率增加、转移能力增强和对索拉非尼的耐药性相关，同时还抑制铁死亡。相反，circTTC13沉默降低了恶性特征并促进了铁死亡。计算机分析、荧光素酶测定和荧光原位杂交共同表明，circTTC13直接靶向并降低miR-513a-5p的表达，进而导致铁死亡负调节因子SLC7A11的上调。此外，抑制SLC7A11反映了circTTC13敲低的效果，而抑制铁死亡则模拟了circTTC13过表达的效果。circTTC13和SLC7A11在耐药HCC细胞中均高表达，circTTC13沉默诱导外植体肿瘤中的铁死亡并逆转索拉非尼耐药性。这些发现确定circTTC为HCC进展和对药物诱导的铁死亡耐药的关键驱动因素，其通过上调SLC7A11实现。circTTC13/miR-513a-5p/SLC7A11轴代表了HCC的一个潜在治疗靶点。
