Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
Department of Surgery, Hsinchu Branch, National Taiwan University Hospital, Hsinchu, Taiwan.
Hepatol Int. 2022 Jun;16(3):562-576. doi: 10.1007/s12072-022-10315-w. Epub 2022 May 7.
Intrahepatic cholangiocarcinoma (ICC) is characterized by fibrous stroma and clinical behavior more aggressive than that of hepatocellular carcinoma (HCC). Scirrhous HCC is a subtype of HCC with fibrous stroma, frequently has partial cholangiocytic differentiation, and is more likely to have an aggressive behavior. This study explored the interaction of liver cancer cells with the extracellular matrix.
Liver cancer cells grown on collagen 1-coated plates showed upregulation of cholangiocytic marker expression but downregulation of hepatocytic marker expression. Three-dimensional sphere culture and Boyden chamber assay showed enhanced invasion and migration ability in collagen 1-conditioned liver cancer cells. Interaction with collagen 1 reduced liver cancer cell proliferation. RNA sequencing showed that in the liver cancer cells, collagen 1 upregulated cell cycle inhibitor expression and cell-matrix interaction, tumor migration, and angiogenesis pathways, but downregulated liver metabolic function pathways. Cholangiocytic differentiation and invasiveness induced by collagen 1 was mediated by the mitogen-activated protein kinase (MAPK) pathway, which was regulated by cell-matrix interaction-induced Src activation. Analysis of the Cancer Genome Atlas cohort showed that collagen 1 induced and suppressed genes were highly enriched in ICC and HCC, respectively. In HCC samples, collagen 1-regulated genes were strongly coexpressed and correlated with COL1A1 expression.
Liver cancer cell-matrix interaction induces cholangiocytic differentiation and switches liver cancer cells from a proliferative to an invasive phenotype through the Src/MAPK pathway, which may partly explain the differences in the behaviors of HCC and ICC.
肝内胆管癌（ICC）的特征是纤维基质，其临床行为比肝细胞癌（HCC）更为激进。硬癌型 HCC 是一种具有纤维基质的 HCC 亚型，常具有部分胆管细胞分化，并更有可能具有侵袭性行为。本研究探讨了肝癌细胞与细胞外基质的相互作用。
在胶原 1 包被的培养板上生长的肝癌细胞表现出胆管细胞标志物表达上调，但肝细胞标志物表达下调。三维球体培养和 Boyden 室测定显示，在胶原 1 条件培养的肝癌细胞中侵袭和迁移能力增强。与胶原 1 的相互作用降低了肝癌细胞的增殖。RNA 测序显示，在肝癌细胞中，胶原 1 上调了细胞周期抑制剂的表达以及细胞-基质相互作用、肿瘤迁移和血管生成途径，但下调了肝代谢功能途径。胶原 1 诱导的胆管细胞分化和侵袭性是由丝裂原活化蛋白激酶（MAPK）途径介导的，该途径受细胞-基质相互作用诱导的Src 激活调节。对癌症基因组图谱队列的分析表明，胶原 1 诱导和抑制的基因在 ICC 和 HCC 中分别高度富集。在 HCC 样本中，胶原 1 调节的基因强烈共表达，并与 COL1A1 表达相关。
肝癌细胞-基质相互作用通过 Src/MAPK 途径诱导胆管细胞分化，并将肝癌细胞从增殖表型转变为侵袭表型，这可能部分解释了 HCC 和 ICC 行为的差异。
