白细胞介素-13受体α2抑制肝细胞癌侵袭转移的实验性研究

Experimental observation of IL13RA2 inhibiting invasion and metastasis of hepatocellular carcinoma

摘要

目的 探讨白细胞介素-13受体α2(IL13RA2)在肝细胞癌(HCC)中的表达特征、生物学功能及其潜在分子机制。方法 利用公共数据库和临床HCC组织样本,分析IL13RA2在HCC的表达情况。收集并随访临床病理资料,分析IL13RA2的表达与HCC患者预后的相关性。构建IL13RA2敲低或过表达的稳转细胞株,通过Transwell、划痕等实验检测HCC细胞迁移和侵袭能力。建立裸鼠肝癌肺转移模型,观察IL13RA2对HCC体内肺转移的影响。利用转录组测序(RNA-seq)筛选IL13RA2下游靶分子,并在公共数据库及临床样本中验证其表达相关性。利用SRY-box转录因子18(SOX18)抑制剂Sm4进行功能挽救实验,明确SOX18在介导IL13RA2对HCC进展的调控作用。结果 IL13RA2低表达与肿瘤分化程度、淋巴结转移和预后不良有关(P＜0.05)。体内和体外实验表明,上调IL13RA2可逆转HCC的侵袭和转移,而下调IL13RA2则可促进HCC的侵袭与转移(P＜0.05)。利用RNA-seq筛选出与IL13RA2相互作用的潜在分子SOX18。在HCC肿瘤组织中,SOX18的表达与IL13RA2水平呈负相关(P＜0.05)。使用SOX18抑制剂Sm4处理,可逆转由敲低IL13RA2所诱导的HCC转移促进作用(P＜0.05)。结论 IL13RA2在HCC中低表达,并通过负调控SOX18发挥抗转移作用。IL13RA2/SOX18信号轴可能为HCC的靶向治疗提供新的分子干预靶点。

Abstract

Objective To investigate the expression, role, and mechanism of interleukin-13 receptor subunit alpha-2 (IL13RA2) in hepatocellular carcinoma (HCC). Methods Public databases and clinical samples were used to analyze the expression of IL13RA2 in HCC. Clinical data were collected and followed up to assess the correlation between IL13RA2 expression level and patient prognosis. Stable cell lines with IL13RA2 knockdown or overexpression were constructed, and Transwell and wound healing assays were employed to examine the effect of IL13RA2 on HCC cell migration and invasion. A nude mouse model of HCC pulmonary metastasis was established to evaluate the role of IL13RA2 in metastasis in vivo. RNA sequencing (RNA-seq) was performed to identify downstream targets of IL13RA2, and public databases and clinical samples were used to analyze the correlation between IL13RA2 and potential target molecules. Functional rescue experiments using the SRY-box transcription factor 18 (SOX18) inhibitor Sm4 were conducted to determine whether SOX18 is involved in IL13RA2-mediated regulation of HCC progression. Results Decreased expression of IL13RA2 was associated with poor tumor differentiation, lymph node metastasis, and unfavorable prognosis in HCC patients (P＜0.05). Both in vitro and in vivo experiments demonstrated that upregulation of IL13RA2 inhibited HCC invasion and metastasis, whereas downregulation of IL13RA2 promoted these processes (P＜0.05). RNA-seq analysis identified SOX18 as a potential interacting molecule of IL13RA2. The expression of SOX18 was negatively correlated with IL13RA2 levels in HCC tissues (P＜0.05). Treatment with the SOX18 inhibitor Sm4 reversed the prometastatic effect induced by IL13RA2 knockdown in HCC (P＜0.05). Conclusion IL13RA2 expression is downregulated in HCC, and SOX18 may mediate the anti-metastatic effect of IL13RA2. The IL13RA2/SOX18 signaling axis may serve as a novel molecular target for targeted therapy in HCC.

关键词

肝细胞癌(HCC) / 细胞迁移 / 白细胞介素-13受体α2(IL13RA2) / SRY-box转录因子18(SOX18) / 转移

Key words

hepatocellular carcinoma (HCC) / cell migration / interleukin-13 receptor alpha 2(IL13RA2) / SRY-box transcription factor 18 (SOX18) / metastasis

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基金资助

河南省自然科学基金项目(232300420257)

河南省医学科技攻关联合共建项目(LHGJ20210359)

河南阳光医疗健康发展基金会资助项目(HKP2023009)

河南省慈善联合总会·肝胆相照基金资助项目(GDXZ2023022)