Hong Shengqian, Zhang Jialing, Liu Shiqi, Jin Quan, Li Jingqi, Xia Anliang, Xu JianBo
Department of Hepatobiliary Surgery, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, China.
Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, China.
Hepatol Res. 2024 Feb;54(2):189-200. doi: 10.1111/hepr.13971. Epub 2023 Oct 14.
Microvascular invasion (MVI) is an independent risk factor for postoperative recurrence and metastasis in hepatocellular carcinoma (HCC). However, the specific protein expression profiles that differentiate HCC with MVI from those without MVI remain unclear.
The profiles of proteins in early-stage HCC tissues and normal liver tissues were characterized by quantitative proteomics techniques. Immunohistochemical (IHC) staining was undertaken on tissue microarrays from 80 HCC patients to assess the expression of MSH2 and MSH6. Cell counting, colony formation, migration, and invasion assays were carried out in vitro.
We identified 5164 proteins in both HCC tissues and adjacent normal liver tissues. Compared to HCC without MVI, 148 upregulated proteins and 97 downregulated proteins were found in HCC with MVI. Particularly noteworthy was the remarkable upregulation of MSH6/MSH2 among these dysregulated proteins in HCC with MVI. Further validation through bioinformatics prediction and IHC confirmed the elevated expression of MSH6/MSH2, which correlated with aggressive disease characteristics and poor prognosis. Receiver operating characteristic curve analyses revealed a substantial area under the curve of 0.761 (specificity 71.79%, sensitivity 73.17%) for the combined use of MSH6/MSH2. Knockdown of MSH6/MSH2 significantly inhibited HCC cell proliferation and invasion in vitro.
Our study establishes MSH6 or MSH2 as an oncogene that is prominently overexpressed during HCC progression, which provides new targets for HCC with MVI.
微血管侵犯（MVI）是肝细胞癌（HCC）术后复发和转移的独立危险因素。然而，区分伴有MVI的HCC与不伴有MVI的HCC的特定蛋白质表达谱仍不清楚。
采用定量蛋白质组学技术对早期HCC组织和正常肝组织中的蛋白质谱进行表征。对80例HCC患者的组织芯片进行免疫组织化学（IHC）染色，以评估MSH2和MSH6的表达。在体外进行细胞计数、集落形成、迁移和侵袭试验。
我们在HCC组织和相邻正常肝组织中均鉴定出5164种蛋白质。与无MVI的HCC相比，有MVI的HCC中发现148种上调蛋白和97种下调蛋白。特别值得注意的是，在伴有MVI的HCC中，这些失调蛋白中MSH6/MSH2显著上调。通过生物信息学预测和IHC进一步验证证实了MSH6/MSH2的表达升高，这与侵袭性疾病特征和不良预后相关。受试者工作特征曲线分析显示，联合使用MSH6/MSH2时曲线下面积为0.761（特异性71.79%，敏感性73.17%）。敲低MSH6/MSH2可显著抑制体外HCC细胞的增殖和侵袭。
我们的研究确定MSH6或MSH2为一种在HCC进展过程中显著过表达的癌基因，这为伴有MVI的HCC提供了新的靶点。
