Early detection and intervention are key strategies to reduce mortality, increase long-term survival, and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomic strategy was used to study the secretomes in conditioned media from HCC cancerous tissues, surrounding noncancerous tissues, and distal noncancerous tissues to identify diagnostic and prognostic biomarkers for HCC. In total, 22 and 49 dysregulated secretory proteins were identified in the cancerous and surrounding noncancerous tissues, respectively, compared with the distal noncancerous tissues. Among these proteins, carbonic anhydrase II (CA2) was identified to be significantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients compared with that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after radical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence and overall survival. Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition pathway. Taken together, this study identified a novel biomarker for HCC diagnosis and prognosis, and provided a valuable resource of HCC secretome for investigating serological biomarkers.

早期发现和干预是降低肝细胞癌（HCC）患者死亡率、提高长期生存率和改善治疗效果的关键策略。在此，基于等压标签相对和绝对定量 (iTRAQ) 的定量蛋白质组学策略用于研究 HCC 癌组织、周围非癌组织和远端非癌组织的条件培养基中的分泌组，以确定 HCC 的诊断和预后生物标志物。与远端非癌组织相比，在癌组织和周围非癌组织中总共发现了 22 和 49 种失调的分泌蛋白。在这些蛋白质中，碳酸酐酶 II(CA2) 被确定在癌组织的分泌组中显着上调；相应地，与正常人群相比，HCC患者的血清CA2浓度显着升高。有趣的是，与未复发的 HCC 患者相比，根治性切除术后复发 HCC 患者的血清 CA2 显着增加，并且血清 CA2 水平可作为复发时间和总生存期的独立预后因素。关于机制，分泌的CA2通过激活上皮间质转化增强HCC细胞的迁移和侵袭途径。总之，本研究确定了一种用于 HCC 诊断和预后的新型生物标志物，并为研究血清学生物标志物提供了宝贵的 HCC 分泌组资源。