癌症相关成纤维细胞分泌的 versican 是肝细胞癌的一个不良预后因素。
Versican Secreted by Cancer-Associated Fibroblasts is a Poor Prognostic Factor in Hepatocellular Carcinoma.
机构信息
Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Center for Development of Advanced Diagnostics (C-DAD), Hokkaido University Hospital, Sapporo, Japan.
出版信息
Ann Surg Oncol. 2022 Oct;29(11):7135-7146. doi: 10.1245/s10434-022-11862-0. Epub 2022 May 11.
BACKGROUND
Hepatocellular carcinoma (HCC) is highly recurrent. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, promote malignancy; however, the mechanisms underlying their actions are obscure. We aimed to identify CAF-specific proteins in HCC and determine whether they could be potential therapeutic targets.
METHODS
Using comprehensive proteomic analysis of CAFs and noncancerous fibroblasts (NFs) primary-cultured from resected HCC specimens from the same patients, CAF-specific proteins were identified. Immunohistochemistry for versican (VCAN) was performed on cancerous tissues obtained from 239 patients with HCC. Conditioned medium from CAFs transfected with siRNA for VCAN was analyzed in vitro.
RESULTS
CAFs significantly promoted HCC cell proliferation, migration, and invasion (p < 0.01, 0.01, and 0.01, respectively) compared with NFs. VCAN was upregulated in CAFs, and its stromal level correlated with poor differentiation (p = 0.009) and positive vascular invasion (p = 0.003). Stromal VCAN level was also associated with significantly lower overall (p = 0.002) and relapse-free (p < 0.001) survival rates. It also independently predicted prognosis and recurrence. VCAN-knockdown CAFs significantly suppressed HCC cell migration and invasion compared with negative control.
CONCLUSIONS
VCAN secreted from CAFs promoted malignant transformation of HCC cells and has potential as a new therapeutic target in HCC.
背景
肝细胞癌（HCC）具有高度复发性。癌相关成纤维细胞（CAFs）是肿瘤微环境的主要组成部分，促进恶性肿瘤的发生；然而，其作用机制尚不清楚。我们旨在鉴定 HCC 中的 CAF 特异性蛋白，并确定它们是否可以作为潜在的治疗靶点。
方法
使用综合蛋白质组学分析，鉴定从同一患者切除的 HCC 标本中分离的 CAFs 和非癌性成纤维细胞（NFs）中的 CAF 特异性蛋白。对 239 例 HCC 患者的癌组织进行 versican（VCAN）免疫组化染色。分析转染了 VCAN siRNA 的 CAF 的条件培养基。
结果
与 NFs 相比，CAFs 显著促进了 HCC 细胞的增殖、迁移和侵袭（p<0.01、0.01 和 0.01，分别）。VCAN 在 CAFs 中上调，其基质水平与分化不良（p=0.009）和阳性血管侵犯（p=0.003）相关。基质 VCAN 水平也与总生存率（p=0.002）和无复发生存率（p<0.001）明显降低显著相关。它还独立预测了预后和复发。与阴性对照相比，VCAN 敲低 CAFs 显著抑制了 HCC 细胞的迁移和侵袭。
结论
CAFs 分泌的 VCAN 促进了 HCC 细胞的恶性转化，有望成为 HCC 的新治疗靶点。
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