Wu Lixia, Gu Lina, Zheng Yang, Liu Jingjing, Wei Zishuan, Liu Fei, Li Jiali, Meng Lingjiao, Sang Yang, Sang Meixiang, Zhao Lianmei, Shan Baoen
Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
Key Laboratory of Tumor Prevention and Precision Diagnosis and Treatment of Hebei, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China.
J Transl Med. 2025 Apr 1;23(1):385. doi: 10.1186/s12967-025-06395-5.
Esophageal squamous cell carcinoma (ESCC) is a serious invasive malignancy with an ambiguous etiology. Evidence indicates that circular RNA (circRNA) is significantly involved in the regulatory processes associated with cancer development. Nevertheless, the specific molecular mechanisms through which circRNA facilitates the progression of ESCC are still largely undefined.
Here, we identified that the expression of hsa_circ_0007580 (designated circPRKCA) was markedly elevated in ESCC. Fluorescence in situ hybridization (FISH) was conducted to verify the expression, intracellular localization, and potential prognostic value of circPRKCA based on the tissue microarray. Gain- and loss-of-function assays were employed to investigate the effects of circPRKCA both in vitro and in vivo. RNA pull-down and mass spectrometry (MS) were performed to identify the proteins bound to circPRKCA. mRNA sequencing was conducted to screen the downstream target genes of circPRKCA. Furthermore, immunoprecipitation and methylated RNA immunoprecipitation (MeRIP) analysis were used to explore the regulatory mechanisms.
We found that circPRKCA exhibited significant upregulation in ESCC tissues and correlated with unfavorable prognostic outcomes. Biological function experiments further confirmed that circPRKCA enhances the capabilities of migration, invasion, and angiogenesis in ESCC. Mechanistically, circPRKCA engages in interaction with Y-box binding protein 1 (YBX1) within the cytoplasmic milieu, consequently preventing the ubiquitination-mediated degradation of YBX1. Increased concentrations of YBX1 increase the stability of granulocyte-macrophage colony-stimulating factor (CSF2) mRNA in a 5-methylcytosine (m5C)-dependent manner. This process facilitates metastasis in ESCC.
In this research, we identified a correlation between circPRKCA and unfavorable prognoses in patients with ESCC. It is instrumental in the metastatic progression of ESCC via the YBX1/CSF2 signaling pathway. Consequently, targeting circPRKCA may represent a promising therapeutic strategy for ESCC.
食管鳞状细胞癌（ESCC）是一种严重的侵袭性恶性肿瘤，其病因尚不明确。有证据表明，环状RNA（circRNA）在与癌症发展相关的调控过程中发挥着重要作用。然而，circRNA促进ESCC进展的具体分子机制仍然很大程度上未被阐明。
在此，我们发现hsa_circ_0007580（命名为circPRKCA）在ESCC中表达显著升高。基于组织芯片进行荧光原位杂交（FISH）以验证circPRKCA的表达、细胞内定位及潜在预后价值。采用功能获得和功能缺失实验在体外和体内研究circPRKCA的作用。进行RNA下拉和质谱分析（MS）以鉴定与circPRKCA结合的蛋白质。进行mRNA测序以筛选circPRKCA的下游靶基因。此外，采用免疫沉淀和甲基化RNA免疫沉淀（MeRIP）分析来探索调控机制。
我们发现circPRKCA在ESCC组织中显著上调，并与不良预后结果相关。生物学功能实验进一步证实circPRKCA增强了ESCC的迁移、侵袭和血管生成能力。机制上，circPRKCA在细胞质环境中与Y盒结合蛋白1（YBX1）相互作用，从而阻止YBX1的泛素化介导降解。YBX1浓度增加以5 - 甲基胞嘧啶（m5C）依赖方式增加粒细胞 - 巨噬细胞集落刺激因子（CSF2）mRNA的稳定性。这一过程促进了ESCC的转移。
在本研究中，我们发现circPRKCA与ESCC患者的不良预后相关。它通过YBX1/CSF2信号通路促进ESCC的转移进展。因此，靶向circPRKCA可能是一种有前景的ESCC治疗策略。
