血清外泌体miR-223联合AFP与PIVKA-II在肝细胞癌诊断中的研究进展与展望

Research Progress and Prospects of Serum Exosomal miR-223 Combined with AFP and PIVKA-II in the Diagnosis of Hepatocellular Carcinoma

摘要: 肝细胞癌(HCC)早期诊断是改善预后的关键。传统筛查依赖腹部超声与甲胎蛋白(AFP)，但敏感性与特异性有限。异常凝血酶原(PIVKA-II)与液体活检标志物如外泌体miR-223为HCC无创诊断提供了新方向。本文系统综述AFP、PIVKA-II及血清外泌体miR-223在HCC诊断中的研究进展，重点阐述三者联合应用的生物学基础与临床价值。其中AFP反映肿瘤细胞去分化状态与负荷，PIVKA-II关联肿瘤代谢异常与侵袭性，外泌体miR-223则表征肿瘤微环境免疫状态。基于生物学互补性，整合三类标志物构建多维度诊断模型在理论上有望提升早期及AFP阴性HCC的检出率、鉴别诊断准确性及预后评估效能，但目前尚缺乏直接针对该三联模型的前瞻性研究证据。外泌体miR-223检测面临分离得率低、标准化不足及成本高昂等技术瓶颈，微流控芯片与数字PCR等新技术有望突破这些限制；同时miR-223功能双重性所带来的诊断不确定性，可通过联合免疫细胞亚群分析等指标予以规避。未来需推进检测标准化、开展前瞻性验证并融合多组学数据，以实现该联合策略的临床转化。

Abstract: Early diagnosis of hepatocellular carcinoma (HCC) is essential for improving prognosis. Conventional surveillance relies on abdominal ultrasound and alpha-fetoprotein (AFP), yet both exhibit limited sensitivity and specificity. Protein induced by vitamin K absence or antagonist-II (PIVKA-II) and liquid biopsy markers such as exosomal miR-223 have opened new avenues for non-invasive diagnosis of HCC. This review systematically summarizes the research progress on AFP, PIVKA-II, and serum exosomal miR-223 in HCC diagnosis, with emphasis on the biological rationale and clinical value of their combined application. AFP reflects the dedifferentiation status and tumor burden of cancer cells, PIVKA-II is associated with metabolic dysregulation and tumor invasiveness, and exosomal miR-223 characterizes the immune status of the tumor microenvironment. Based on biological complementarity, an integrated multi-dimensional diagnostic model incorporating these three markers is theoretically expected to improve the detection rate of early-stage and AFP-negative HCC, enhance differential diagnostic accuracy, and strengthen prognostic assessment. However, direct prospective evidence for this specific triple-marker panel is currently lacking. Detection of exosomal miR-223 faces technical bottlenecks including low isolation yield, insufficient standardization, and high cost; emerging technologies such as microfluidic chips and digital PCR hold promise to overcome these limitations. Meanwhile, the diagnostic uncertainty arising from the dual functionality of miR-223 may be mitigated by incorporating complementary indicators such as immune cell subset profiling. Future efforts should focus on standardizing detection methods, conducting prospective validation studies, and integrating multi-omics data to achieve clinical translation of this combined strategy.